More than a relay

The retinogeniculate synapse has been an invaluable workhorse for neuroscience research. In recent years, it has served as a powerful model for understanding the molecular and circuit-level mechanisms that influence normal development and disease (Bishop et al., Reference Bishop, Burke and Davis1959; Sengpiel & Kind, Reference Sengpiel and Kind2002; Kastner et al., Reference Kastner, Schneider and Wunderlich2006; Guido, Reference Guido2008; Kano & Hashimoto, Reference Kano and Hashimoto2009; Hong & Chen, Reference Hong and Chen2011; Stephan et al., Reference Stephan, Barres and Stevens2012; Kaplan, Reference Kaplan2014). The ability to independently label Retinal Ganglion Cells (RGCs) from opposite eyes has enabled the identification of cellular and molecular mechanisms of axon mapping, arbor pruning, and synapse elimination that drive the refinement of retinotopic maps and eye-specific lamination (Wong, Reference Wong1999; Luo & O’Leary, Reference Luo and O’Leary2005; Huberman et al., Reference Huberman, Feller and Chapman2008a ; Feller, Reference Feller2009; Kano & Hashimoto, Reference Kano and Hashimoto2009; Hong & Chen, Reference Hong and Chen2011). In vitro, the easily accessible bundle of RGC axons in the optic nerve provides a convenient means of selectively activating presynaptic inputs in studies of synaptic physiology and plasticity, and is also an excellent system for uncovering mechanisms of axon regeneration (Guido, Reference Guido2008; Hong & Chen, Reference Hong and Chen2011; Benowitz et al., Reference Benowitz, He and Goldberg2017). In vivo, the retinogeniculate synapse has been a prominent model system for the study of subcortical visual processing. Numerous studies have capitalized on the ease of manipulating visual stimulation, combined with the ability to simultaneously monitor the activity patterns of inputs and outputs of the thalamus to reliably demonstrate that the transfer of information from the retina to the visual cortex is the major function of the retinogeniculate synapse (Sherman, Reference Sherman2005; Usrey & Alitto, Reference Usrey and Alitto2015; Weyand, Reference Weyand2016).

Despite the tenacity of the term “relay” to describe the function of the dLGN, the retinogeniculate synapse does not simply transfer a copy of RGC activity patterns to the cortex. Over the past few decades, a number of retinogeniculate attributes have been shown to play a role in modifying visual information before conveying it to the cortex (Blitz et al., Reference Blitz, Foster and Regehr2004; Sherman, Reference Sherman2007; Usrey & Alitto, Reference Usrey and Alitto2015; Weyand, Reference Weyand2016). Simultaneous recording of the firing patterns of RGC inputs and TC target neurons in vivo has shown that the reliability of action potential generation in TC neurons depends on the local activity context, such as neuromodulatory signaling or the membrane potential. These factors can dictate or modulate the firing pattern (“tonic” or “burst”) of a TC neuron (McCormick & Bal, Reference McCormick and Bal1994; Usrey et al., Reference Usrey, Reppas and Reid1998; Sherman & Guillery, Reference Sherman and Guillery2002; Wang et al., Reference Wang, Wei, Vaingankar, Wang, Koepsell, Sommer and Hirsch2007). In some cases, a TC neuron is much more likely to generate a response to the second of a pair of visually-driven potentials arriving in quick succession (separated by less than 30 ms, Mastronarde, Reference Mastronarde1987; von Krosigk et al., Reference von Krosigk, Bal and McCormick1993; Usrey et al., Reference Usrey, Reppas and Reid1998; Levine & Cleland, Reference Levine and Cleland2001; Rowe & Fischer, Reference Rowe and Fischer2001; Carandini et al., Reference Carandini, Horton and Sincich2007; Weyand, Reference Weyand2007; Sincich et al., Reference Sincich, Adams, Economides and Horton2007, Reference Sincich, Horton and Sharpee2009; Alitto et al., Reference Alitto, Moore, Rathbun and Martin Usrey2011). This integrative function increases the amount of information encoded in thalamic spiking (Wang et al., Reference Wang, Hirsch and Sommer2010). In other cases, a single RGC impulse can result in a postsynaptic burst of multiple action potentials (Usrey et al., Reference Usrey, Reppas and Reid1998; Blitz & Regehr, Reference Blitz and Regehr2003).

Recent work is revealing new receptive field complexity and plasticity in the dLGN that further demonstrates significant thalamic processing of visual information en route to the cortex, at least in some species. Stimulus orientation selectivity is one salient example of a complex feature encoded in subpopulations of dLGN neurons in a variety of species: mouse (Marshel et al., Reference Marshel, Kaye, Nauhaus and Callaway2012; Piscopo et al., Reference Piscopo, El-Danaf, Huberman and Niell2013; Scholl et al., Reference Scholl, Tan, Corey and Priebe2013; Zhao et al., Reference Zhao, Chen, Liu and Cang2013) and rabbit (Levick et al., Reference Levick, Oyster and Takahashi2010; Hei et al., Reference Hei, Stoelzel, Zhuang, Bereshpolova, Huff, Alonso and Swadlow2014), with weaker orientation or direction bias occurring in the cat (Hubel & Wiesel, Reference Hubel and Wiesel1961; Daniels et al., Reference Daniels, Norman and Pettigrew1977; Levick & Thibos, Reference Levick and Thibos1980; Vidyasagar & Urbas, Reference Vidyasagar and Urbas1982; Soodak et al., Reference Soodak, Shapley and Kaplan1987; Shou & Leventhal, Reference Shou and Leventhal1989; Thompson et al., Reference Thompson, Zhou and Leventhal1994), squirrel (Zaltsman et al., Reference Zaltsman, Heimel and Van Hooser2015), and primate (Lee et al., Reference Lee, Creutzfeldt and Elepfandt1979; Smith et al., Reference Smith, Chino, Ridder, Kitagawa and Langston1990; Cheong et al., Reference Cheong, Tailby, Solomon and Martin2013). Complex feature selectivity persists in TC neurons after inactivation of the primary visual cortex, suggesting that the dLGN may compute orientation or direction selectivity rather than inherit it from cortical feedback (cat Vidyasagar & Urbas, Reference Vidyasagar and Urbas1982; mouse Zhao et al., Reference Zhao, Chen, Liu and Cang2013; Scholl et al., Reference Scholl, Tan, Corey and Priebe2013). Furthermore, cat TC neurons have a higher stimulus contrast sensitivity than their individual inputs, suggesting TC neurons can functionally integrate information from multiple RGC inputs (Rathbun et al., Reference Rathbun, Alitto, Warland and Usrey2016). The presence of binocularly innervated dLGN neurons in mice, cats, and primates further supports the possibility of convergence of multiple RGCs onto single geniculate neurons in mice, cat, and primate dLGN (Sanderson et al., Reference Sanderson, Bishop and Darian-Smith1971; Howarth et al., Reference Howarth, Walmsley and Brown2014; Zeater et al., Reference Zeater, Cheong, Solomon, Dreher and Martin2015; Rompani et al., Reference Rompani, Mullner, Wanner, Roth, Yonehara, Zhang and Roska2017). Here, we explore synaptic mechanisms and structural attributes that could support the diversity of features and functions now emerging in studies of the dLGN. In this review, we describe the structural properties of RGC axons and TC neurons, together with their biophysical features and plasticity mechanisms. These properties may combine to impart novel and adaptive functionality to the dLGN, and to dynamically regulate information flow between retina and cortex.

Retinogeniculate synaptic structure

To appreciate the functional complexity in retinogeniculate processing, we first describe the underlying synaptic structure. The architecture of the retinogeniculate synapse is conserved across species. Glutamate is the excitatory neurotransmitter packed into numerous round vesicles contained in large synaptic terminals along the axon (Montero & Wenthold, Reference Montero and Wenthold1989). A single retinal axon terminal can span ∼1–4 microns in diameter and contain multiple spatially distinct neurotransmitter release sites (cat and mouse studies: Famiglietti & Peters, Reference Famiglietti and Peters1972; Rafols & Valverde, Reference Rafols and Valverde1973; Sur & Sherman, Reference Sur and Sherman1982; Hamos et al., Reference Hamos, Van Horn, Raczkowski and Sherman1987; Robson, Reference Robson1993; Bickford et al., Reference Bickford, Slusarczyk, Dilger, Krahe, Kucuk and Guido2010; Budisantoso et al., Reference Budisantoso, Matsui, Kamasawa, Fukazawa and Shigemoto2012; Morgan et al., Reference Morgan, Berger, Wetzel and Lichtman2016). RGC boutons contact a TC neuron near its cell body, synapsing directly onto the dendritic shaft or dendritic appendages that protrude from the proximal shaft or primary dendritic branch points (Rafols & Valverde, Reference Rafols and Valverde1973; Robson & Mason, Reference Robson and Mason1979; Wilson et al., Reference Wilson, Friedlander and Sherman1984; Hamos et al., Reference Hamos, Van Horn, Raczkowski and Sherman1987; Bickford et al., Reference Bickford, Slusarczyk, Dilger, Krahe, Kucuk and Guido2010; Morgan et al., Reference Morgan, Berger, Wetzel and Lichtman2016). Retinal inputs account for only 5–10% of a TC neuron’s synaptic input, whereas cortical feedback projections from Layer 6 occupy the distal dendrites, providing as much as 50% of synaptic input (Wilson et al., Reference Wilson, Friedlander and Sherman1984; Montero, Reference Montero1991; Van Horn et al., Reference Van Horn, Erişir and Sherman2000). Nonetheless, the proximal position of retinogeniculate synapses along the dendrite, their synaptic structure with multiple release sites, and their large number of synaptic contacts drives powerful and reliable transmission that has earned the retinal input the moniker of “driver” to all other inputs’ “modulator” (Guillery & Sherman, Reference Guillery and Sherman2002).

The fine details of retinogeniculate connectivity reveal potential heterogeneity of circuit organization and, thereby, of function. A RGC axon contacts a TC neuron with as many as 59 terminals in cat or mouse (Fig. 1A–1C; Hamos et al., Reference Hamos, Van Horn, Raczkowski and Sherman1987; Robson, Reference Robson1993; Morgan et al., Reference Morgan, Berger, Wetzel and Lichtman2016). The morphology of these numerous synaptic contacts between a single RGC axon and its target TC neuron can range from the simple to the complex (Jones & Powell, Reference Jones and Powell1969; Famiglietti & Peters, Reference Famiglietti and Peters1972; Hammer et al., Reference Hammer, Monavarfeshani, Lemon, Su and Fox2015; for finer categorization, see Lund & Cunningham, Reference Lund and Cunningham1972; Robson & Mason, Reference Robson and Mason1979; Morgan et al., Reference Morgan, Berger, Wetzel and Lichtman2016). Simple retinogeniculate contacts consist of one small or large crenulated bouton contacting a dendrite or dendritic appendage. Complex contacts comprise a glomerular structure containing multiple boutons from retinal, inhibitory, and neuromodulatory inputs (Robson & Mason, Reference Robson and Mason1979; Koch, Reference Koch1985; Sherman & Guillery, Reference Sherman and Guillery1996; Sherman, Reference Sherman2004). Although it is not known whether differences in bouton morphology correlate with specializations for retinogeniculate information transfer, work on cerebellar parallel fibers shows that bouton size can predict sensitivity to neuromodulation, and induction of LTP or LTD can induce plasticity in the size of hippocampal presynaptic boutons (Toni et al., Reference Toni, Buchs, Nikonenko, Bron and Muller1999; Becker et al., Reference Becker, Wierenga, Fonseca, Bonhoeffer and Nägerl2008; Zhang & Linden, Reference Zhang and Linden2009). Furthermore, the morphology of synaptic contacts is optimized to the requirements of sensory transmission in the retina, inner ear, and central auditory synapses (Taschenberger et al., Reference Taschenberger, Leão, Rowland, Spirou and von Gersdorff2002; Matthews & Fuchs, Reference Matthews and Fuchs2010; Freche et al., Reference Freche, Pannasch, Rouach and Holcman2011; Graydon et al., Reference Graydon, Cho, Diamond, Kachar, von Gersdorff and Grimes2014). It is therefore likely that the diversity of retinogeniculate contact morphologies reflects differences in their contribution to transmission. Indeed, different TC neuron types in cats exhibit biases in presynaptic morphology. Cat RGCs and TC neurons are distinguished into three categories (X, Y, W) based on the properties of their responses to visual stimuli, including the size of the receptive field and the degree of linearity of spatial summation, as well as morphological markers. The X and Y classifications refer to relatively homogeneous populations (and are often compared to primate M and P pathways), whereas the W (compared to K in primates) encompasses a more diverse set of cells with rarely-encountered physiological responses (Wilson et al., Reference Wilson, Rowe and Stone1976; Fukuda et al., Reference Fukuda, Hsiao, Watanabe and Ito1984; Felch & Van Hooser, Reference Felch and Van Hooser2012). Simple contacts dominate retinal input onto cat Y cells, whereas X cell dendritic appendages preferentially participate in complex synaptic structures (Robson & Mason, Reference Robson and Mason1979; Hamos et al., Reference Hamos, Van Horn, Raczkowski, Uhlrich and Sherman1985; Koch, Reference Koch1985; Sherman & Guillery, Reference Sherman and Guillery1996; Sherman, Reference Sherman2004). Similar distinctions among TC neurons have been observed in the mice by morphological analysis, but have not been associated with distinct patterns of synaptic structures nor delineated by physiology (Krahe et al., Reference Krahe, El-Danaf, Dilger, Henderson and Guido2011; El-Danaf et al., Reference El-Danaf, Krahe, Dilger, Bickford, Fox and Guido2015; Sriram et al., Reference Sriram, Meier and Reinagel2016).

Fig. 1. Synaptic structure shapes retinogeniculate transmission. (A) Tracing of an HRP-filled X-RGC arbor in the cat dLGN shows the location and morphology of a single branch (red box) of the X-RGC arbor used for EM reconstruction. This branch of the axon contacts 4 TC neurons out of 40 available neurons in the territory of the arbor. The remainder of the axon was not reconstructed, and likely contacts several other TC neurons. Bottom inset shows the location of the axonal arbor in the context of the cat LGN. Figure modified from Hamos et al. (Reference Hamos, Van Horn, Raczkowski and Sherman1987). Unmarked scale bar = 100 μm. (B, C) Reconstructed arbors of single RGC axons showing distribution of presynaptic boutons into dense clusters in the LGN of (B) an adult cat and (C) a p20 mouse. Note the clustering of boutons along the arbor. Image in B is modified from Robson et al. (Reference Robson1993), showing a segment of a RGC axon; Image in C is from Hong et al. (Reference Hong, Park, Litvina, Morales, Sanes and Chen2014), showing a BD-RGC axon. Scales bars are 100 μm. (D) A 3D reconstruction of a TC neuron dendrite and sites of contact between two neighboring RGC boutons from Budisantoso et al. (Reference Budisantoso, Matsui, Kamasawa, Fukazawa and Shigemoto2012). In the top image, the dendrite and its appendages are depicted in blue, whereas pink and red sites label the postsynaptic densities of the two axons. In the bottom image, the structure of the terminals of two axons has been added. Spillover can occur between these two nearby terminals. (E) Evidence of spillover-mediated responses to the stimulation of a single RGC axon before eye opening. Two different synaptic responses were observed in response to single retinal fiber stimulation. Shown are recordings from TC neurons in whole cell voltage clamp at −70 mV in a dLGN slice in the presence of the NMDAR blocker, 20 µM CPP. On the left is an example of a retinogeniculate AMPAR EPSC with characteristic rapid rise time and decay kinetics (black trace). On the right is an atypical AMPAR EPSC response notable for significantly slower rise time and decay kinetics (black trace). The two types of EPSCs differ in their sensitivity to the low-affinity AMPAR antagonist, γ-DGG. Low affinity antagonists can be used to assess the relative concentration of glutamate in the synaptic cleft (Clements et al., Reference Clements, Lester, Tong, Jahr and Westbrook1992; Diamond & Jahr, Reference Diamond and Jahr1997). As γ-DGG competes with glutamate for binding to AMPAR, its efficacy of inhibition decreases with increasing glutamate concentration. γ-DGG has only a small effect on the amplitude of the fast EPSC, but dramatically reduces the amplitude of the slow EPSC (overlaid gray traces), consistent with lower peak glutamate concentration in the synaptic cleft of the slow EPSC. Because the EPSCs are evoked by minimal stimulation, the rapid EPSC represents a direct input from a single RGC axon that forms a direct synapse onto the voltage-clamped relay neuron, whereas the slow EPSC corresponds to the activation of a RGC axon that does not directly synapse onto the voltage-clamped neuron. Modified from Hauser et al. (Reference Hauser, Liu, Litvina and Chen2014). All figures reprinted with permission.

In addition to potential functional differences reflected in the morphology of presynaptic geniculate boutons, the close proximity of clustered multisynaptic boutons in the mature synapse makes possible novel interactions between glutamate transients originating in separate RGC inputs. Large simple boutons in the rat contain an average of 27 independent release sites, whereas each of the boutons in a glomerulus has approximately 6 (Hamos et al., Reference Hamos, Van Horn, Raczkowski and Sherman1987; Budisantoso et al., Reference Budisantoso, Matsui, Kamasawa, Fukazawa and Shigemoto2012; Hammer et al., Reference Hammer, Monavarfeshani, Lemon, Su and Fox2015). Notably, multiple RGCs may contribute to the same cluster or glomerulus of boutons (Hammer et al., Reference Hammer, Monavarfeshani, Lemon, Su and Fox2015; Morgan et al., Reference Morgan, Berger, Wetzel and Lichtman2016). At other CNS synapses, glia ensheath individual boutons and interdigitate into the synaptic cleft, preventing glutamate from diffusing, or “spilling over,” to neighboring boutons, in part through the action of glutamate transporters, which clear glutamate from the extracellular space (Diamond & Jahr, Reference Diamond and Jahr1997; Danbolt, Reference Danbolt2001; Tzingounis & Wadiche, Reference Tzingounis and Wadiche2007; Hauser et al., Reference Hauser, Edson, Hooks and Chen2013; Rimmele & Rosenberg, Reference Rimmele and Rosenberg2016). In contrast, glia do not interdigitate into the cleft of single RGC boutons nor within geniculate glomeruli, making the retinogeniculate connection conducive to glutamate spillover within and between individual boutons (Famiglietti & Peters, Reference Famiglietti and Peters1972; Robson & Mason, Reference Robson and Mason1979; Winfield et al., Reference Winfield, Hiorns and Powell1980; Mason, Reference Mason1982; Bickford et al., Reference Bickford, Slusarczyk, Dilger, Krahe, Kucuk and Guido2010). Although interbouton spillover has not been experimentally assessed in the mature dLGN, a simulation that demonstrated the likelihood of spillover between distant synapses within the same bouton also implies the possibility of spillover of glutamate between closely spaced boutons. Fig. 1D shows an example of two such close retinogeniculate boutons along one TC neuron dendrite, highlighting that glutamate released from one bouton can diffuse to postsynaptic release sites of the neighboring bouton (Budisantoso et al., Reference Budisantoso, Matsui, Kamasawa, Fukazawa and Shigemoto2012). At a developmental phase when boutons are less clustered (Sur et al., Reference Sur, Weller and Sherman1984; Hong et al., Reference Hong, Park, Litvina, Morales, Sanes and Chen2014) and glomeruli have not yet formed, retinogeniculate transmission exhibits extensive glutamate spillover between neighboring boutons. In fact, glutamate from the bouton of one RGC axon can spill over to the synaptic cleft of a neighboring RGC axon before eye opening (Hauser et al., Reference Hauser, Liu, Litvina and Chen2014). Glutamate spillover can be distinguished from direct retinogeniculate synaptic activation by the slower kinetics of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-mediated Excitatory Postsynaptic Current (EPSC) and increased sensitivity to γ-DGG (gray traces), a low affinity AMPAR antagonist (Fig. 1E). These characteristics indicate that the receptors mediating the spillover current are exposed to a lower glutamate concentration than those mediating the direct EPSC. Glutamate spillover can therefore diminish synaptic specificity, but also result in complex and graded integration of information transmitted from different RGC inputs. This mechanism of transmission may be particularly relevant for high-frequency presynaptic activity (RGCs can reach up to 500 Hz, Nirenberg & Meister, Reference Nirenberg and Meister1997), which would promote the pooling and spillover of glutamate. Therefore, the intricate morphology of retinogeniculate contacts presents the possibility for a diversity of modes of retinogeniculate information transfer, which could vary as a function of preceding sensory or modulatory activity.

Short-term plasticity

The mature retinogeniculate synapse boasts multiple bouton contacts, each with many release sites, leading to a high probability of release (Yeow & Peterson, Reference Yeow and Peterson1991; Chen & Regehr, Reference Chen and Regehr2000; Budisantoso et al., Reference Budisantoso, Matsui, Kamasawa, Fukazawa and Shigemoto2012). Combined with the proximity of retinal contacts to the cell body that minimizes potential dendritic filtering of the synaptic signal, these structural features give rise to an EPSC characterized by rapid kinetics (time constant of decay ∼2 ms) and large amplitudes in vitro (Chen & Regehr, Reference Chen and Regehr2000; example recording in Fig. 2A, p26–32). Studies in slices have identified several pre and postsynaptic mechanisms of short-term plasticity that modulate these EPSCs to further shape transmission based on the activity of the RGC input itself as well as other retinal and nonretinal inputs to that neuron. In shaping retinogeniculate transmission, these short-term plasticity mechanisms provide the means to dynamically modify the information transmitted from RGC to TC neuron output.

Fig. 2. Contributions of retinogeniculate short-term plasticity. (A) Representative traces of AMPAR and NMDAR mediated currents recorded before eye opening (left) and in a mature mouse (right) in response to the stimulation of the optic tract. Whole-cell voltage clamp recordings were performed with bicuculline to block GABA_A-receptor mediated currents. At −70 mV holding potential, AMPARs mediate the fast activating and decaying current. AMPAR and NMDAR currents both contribute to the EPSCs recorded at +40 mV with AMPARs contributing to the rapid rise and the NMDAR currents contributing to the slow decay of the EPSC. The average amplitude of AMPAR currents increases over development. (B) 5-CT-mediated activation of serotonin receptors alters retinogeniculate short-term plasticity. Experiments were performed in retinogeniculate slices from mature mice. Top and bottom traces overlay pairs of retinogeniculate EPSCs evoked with varying ISI before (top) and after (bottom) the application of 5-CT to active 5HT-1 receptors expressed in presynaptic retinogeniculate boutons. Application of 5-CT reduces the amplitude of the first EPSC and relieves short-term depression, increasing the amplitude of the second EPSC preferentially at short interstimulus interval. (C) Physiologically relevant stimulation frequencies preferentially diminish the contribution of AMPARs to relay neuron firing. Current clamp recordings of action potential firing in response to trains of optic tract stimulation in the presence of AMPAR (NBQX) or NMDAR (CPP) antagonists. Holding potential −50 mV. Blockade of AMPARs alters the latency to first spike but only minimally reduces the overall number of spikes. In contrast, blockade of NMDARs abolished EPSC summation toward action potential firing; only the first stimulus evokes an action potential, reflecting the contribution of AMPARs that rapidly desensitize after the first pulse. Therefore, NMDAR currents can sustain action potential generation without AMPAR contribution. Adapted from (A) Chen and Regehr (Reference Chen and Regehr2000), B) Liu and Chen (Reference Liu and Chen2008) and (C) Augustinaite and Heggelund (Reference Augustinaite and Heggelund2007). All figures reprinted with permission.

A prominent feature of retinogeniculate transmission studied in vitro is short-term depression: the second of two impulses separated by a short interval generates a weaker response than the first. Both presynaptic mechanisms involving vesicle depletion and postsynaptic mechanisms including AMPAR desensitization and N-methyl-D-aspartate receptor (NMDAR) saturation contribute to this plasticity (Chen et al., Reference Chen, Blitz and Regehr2002; Blitz et al., Reference Blitz, Foster and Regehr2004; Budisantoso et al., Reference Budisantoso, Matsui, Kamasawa, Fukazawa and Shigemoto2012). In contrast to the short-term depression observed in vitro in mice, extracellular recordings of TC neuron activity in vivo in cats and primates consistently show paired-stimulus enhancement, such that the second of two retinal impulses separated by a brief (<30 ms) interval is more effective at driving a postsynaptic action potential (Mastronarde, Reference Mastronarde1987; Usrey et al., Reference Usrey, Reppas and Reid1998; Levine & Cleland, Reference Levine and Cleland2001; Rowe & Fischer, Reference Rowe and Fischer2001; Carandini et al., Reference Carandini, Horton and Sincich2007; Rathbun et al., Reference Rathbun, Alitto and Weyand2007; Sincich et al., Reference Sincich, Adams, Economides and Horton2007, Reference Sincich, Horton and Sharpee2009). In part, this contradiction is due to the dependence of short-term depression on the recent history of activity at the synapse. Activation of the retinogeniculate synapse in slice usually follows a period of quiescence, whereas baseline spontaneous activity maintains synaptic transmission in a chronically depressed state in vivo (Levick & Williams, Reference Levick and Williams1964; Stoelzel et al., Reference Stoelzel, Huff, Bereshpolova, Alonso, Swadlow, Zhuang, Hei, Alonso and Swadlow2015). A train of spikes preceding optic tract stimulation in vitro attenuates the degree of synaptic depression (Seeburg et al., 2004; Augustinaite & Heggelund, Reference Augustinaite and Heggelund2007; Liu & Chen, Reference Liu and Chen2008). Further, neurotransmitter inputs from the brainstem and inhibitory neurons can modulate retinogeniculate transmission in a context-dependent manner in vivo. To understand the relationship between in vitro and in vivo manifestations of short-term plasticity, we review the prominent sources of modulation of retinogeniculate transmission.

Postsynaptic modulation

In addition to presynaptic depression, postsynaptic glutamate receptor properties also contribute to short-term depression and shape the efficacy of retinogeniculate transmission. Postsynaptic AMPA and NMDA receptors both exhibit short-term depression, and perform complementary functions in retinogeniculate transmission.

AMPAR channel gating properties and the high density of their expression contribute to the large, rapid activation, and decay kinetics of the retinogeniculate EPSC (Tarusawa et al., Reference Tarusawa, Matsui, Budisantoso, Molnár, Watanabe, Matsui, Fukazawa and Shigemoto2009). Because AMPARs readily conduct at negative potentials, they are effective at initiating postsynaptic spiking, even from a relatively hyperpolarized membrane potential (Blitz & Regehr, Reference Blitz and Regehr2003; Augustinaite & Heggelund, Reference Augustinaite and Heggelund2007; Liu & Chen, Reference Liu and Chen2008). However, AMPARs desensitize upon exposure to glutamate and recover with a time constant of ∼100 ms (Chen et al., Reference Chen, Blitz and Regehr2002; Kielland & Heggelund, Reference Kielland and Heggelund2002). These properties lead to short-term depression of the AMPAR EPSC. Therefore, AMPARs contribute to the onset of an action potential train transmitted from a RGC, initiating robust short-latency spikes during low frequency activity, but cannot sustain the robust transmission of high-frequency retinogeniculate activity (Blitz & Regehr, Reference Blitz and Regehr2003). Fig. 2C demonstrates that pharmacological blockade of AMPAR with NBQX reduces the initial spikes in response to a stimulus train (Turner et al., Reference Turner, Leresche, Guyon, Soltesz and Crunelli1994; Augustinaite & Heggelund, Reference Augustinaite and Heggelund2007).

NMDA receptor-mediated currents have distinct kinetics and voltage dependence from AMPAR (Fig. 3A and 3B). At the retinogeniculate synapse, NMDARs exhibit short-term depression due to their high affinity to glutamate and receptor saturation (Traynelis et al., Reference Traynelis, Wollmuth, McBain, Menniti, Vance, Ogden, Hansen, Yuan, Myers and Dingledine2010). Recovery from NMDAR saturation occurs more quickly than from AMPAR desensitization (Chen et al., Reference Chen, Blitz and Regehr2002; Kielland & Heggelund, Reference Kielland and Heggelund2002). TC neuron NMDARs experience incomplete Mg²⁺ block at hyperpolarized potentials, and therefore conduct significant current at negative potentials (Liu & Chen, Reference Liu and Chen2008). Fig. 3B and 3C illustrates the contribution of NMDAR to transmission over development. NMDARs conduct current for many tens of milliseconds during a prolonged decay, which permits the summation of closely timed EPSCs, especially within the range of interstimulus intervals (ISIs) that exhibit paired-pulse enhancement in vivo, and supports multiple TC neuron spikes even in “tonic” mode (Chen et al., Reference Chen, Blitz and Regehr2002; Blitz & Regehr, Reference Blitz and Regehr2003; Augustinaite & Heggelund, Reference Augustinaite and Heggelund2007; Liu & Chen, Reference Liu and Chen2008; Budisantoso et al., Reference Budisantoso, Matsui, Kamasawa, Fukazawa and Shigemoto2012). Blockade of NMDAR dramatically reduces retinogeniculate transmission in vivo (Sillito et al., Reference Sillito, Murphy, Salt and Moody1990; Kwon et al., Reference Kwon, Esguerra and Sur1991), and NMDAR current summation in vitro can even drive action potential firing in the presence of AMPAR blockers, though with less temporal precision (Fig. 2C; Chen et al., Reference Chen, Blitz and Regehr2002; Blitz & Regehr, Reference Blitz and Regehr2003; Augustinaite & Heggelund, Reference Augustinaite and Heggelund2007; Budisantoso et al., Reference Budisantoso, Matsui, Kamasawa, Fukazawa and Shigemoto2012). In fact, the NMDAR component of the first EPSC may sufficiently depolarize a TC neuron to spike threshold, such that a small or depressed AMPAR current can shorten the latency to first spike (Kielland & Heggelund, Reference Kielland and Heggelund2002; Augustinaite & Heggelund, Reference Augustinaite and Heggelund2007; Budisantoso et al., Reference Budisantoso, Matsui, Kamasawa, Fukazawa and Shigemoto2012). Therefore, summation of NMDAR currents enhances the probability of TC neuron spiking in response to the second and later RGC action potentials during a train. Together with modulation and postsynaptic integration (Carandini et al., Reference Carandini, Horton and Sincich2007), the properties of NMDA and AMPA receptor currents can reconcile the robust short-term depression seen in vitro with paired-pulse enhancement observed in vivo.

Fig. 3. Contribution of NMDAR-currents to retinogeniculate transmission over development. (A) NMDAR EPSCs recorded in the presence of the AMPAR blocker, NBQX, at +40 and −55 mV holding potentials in a p10 (left) and a p29 (right) retinogeniculate slice. Normalized traces are shown. Note the acceleration in NMDAR current decay time over development. (B) Example EPSCs recorded in young (top) and mature (bottom) TC neuron in slice before (left) and during (right) the application of NBQX. Holding potential, −55 mV. (C) NMDAR currents contribute more to the total retinogeniculate charge transfer at p9–11 than p26–32; however, even at the mature synapse, NMDARs contribute nearly half of the total charge transfer. Figure adapted from Liu and Chen (Reference Liu and Chen2008). All figures reprinted with permission.

An additional factor that could contribute to differences in in vitro and in vivo short-term plasticity is the expression of calcium-permeable AMPARs. The retinogeniculate synapse differs from other synapses in that the expression of calcium-permeable AMPARs increases over development (see Fig. 4A and 4B; Budisantoso et al., Reference Budisantoso, Matsui, Kamasawa, Fukazawa and Shigemoto2012; Hauser et al., Reference Hauser, Liu, Litvina and Chen2014; Louros et al., Reference Louros, Hooks, Litvina, Carvalho and Chen2014; compare to Kumar et al., Reference Kumar, Bacci, Kharazia and Huguenard2002; Soto et al., Reference Soto, Coombs, Kelly, Farrant and Cull-Candy2007). Calcium permeable AMPARs (those lacking the GluA2 subunit) exhibit stronger desensitization-mediated paired pulse depression (Budisantoso et al., Reference Budisantoso, Matsui, Kamasawa, Fukazawa and Shigemoto2012). However, depolarization-mediated reduction of polyamine block may partly rescue this effect (Rozov et al., Reference Rozov, Zilberter, Wollmuth and Burnashev1998; Soto et al., Reference Soto, Coombs, Kelly, Farrant and Cull-Candy2007), increasing the contribution from AMPARs to transmission later in a train of high frequency activity.

Fig. 4. Substrates for retinogeniculate plasticity. (A) Overlaid AMPAR current traces recorded from different holding potentials to assess the current voltage (I–V) relationship. Currents in the presence of CPP to block NMDAR currents and with spermine in the internal solution to examine the degree of I–V rectification. Calcium-permeable AMPARs exhibit a rectifying I–V relationship. Traces were recorded at 20 mV increments from −60 to +60 mV holding potentials. Left-example obtained before eye opening; right, example from a mature slice. From Hauser et al. (Reference Hauser, Liu, Litvina and Chen2014). (B) Change in the average AMPAR EPSC I–V relationship over development. Rectification of I–V currents increases significantly from p9–11 to maturity, indicating a gradual increase in the contribution of CP-AMPARs to AMPAR-mediated currents. Modified from Hauser et al. (Reference Hauser, Liu, Litvina and Chen2014). Red: p9–11; blue: p15–16; black: p27–32. (C) Changes in AMPAR subunit composition in response to visual experience. The effect of visual deprivation from p20 (late-dark rear, LDR) or dark rearing from birth (chronic dark reared, CDR) on the AMPAR EPSC I–V relationship. Rectification of AMPAR currents is reduced in LDR but not in chronically dark reared (CDR) mice when compared to normally reared mice (light rear, LR) mice. P = 0.03. Recordings performed at p27–32. Modified from Louros et al. (Reference Louros, Hooks, Litvina, Carvalho and Chen2014). (D) Comparison of the distribution of amplitudes of single fiber RGC inputs in juvenile (p27–34) and adult (p60+) mice show the persistence of weak (small-amplitude) inputs with age. Modified from Hong et al. (Reference Hong, Park, Litvina, Morales, Sanes and Chen2014). All figures reprinted with permission.

The in vitro retinogeniculate preparation has permitted the identification of mechanisms regulating retinogeniculate synaptic transmission at an unmatched resolution. The synaptic mechanisms discussed above are part of a larger array of factors that affect retinogeniculate information transfer, including circuit elements that influence postsynaptic integration in the TC neuron: local and extrageniculate GABAergic circuits, reciprocal connectivity with the cortex, and brainstem modulatory inputs (reviewed in Sherman & Guillery, Reference Sherman and Guillery2002). Together, these synaptic and circuit mechanisms impart the dynamic features that regulate transmission of information at the retinogeniculate synapse. Interestingly, the paired-stimulus enhancement of retinogeniculate transmission in vivo acts not only to increase the signal-to-noise of retino-geniculo-cortical information transfer, but also encode emergent features in the spike code (Sincich et al., Reference Sincich, Horton and Sharpee2009; Rathbun et al., Reference Rathbun, Warland and Usrey2010; Wang et al., Reference Wang, Hirsch and Sommer2010). Thus these synaptic mechanisms may also impart novel functionality at the level of dLGN. Further, as these mechanisms can rapidly alter the contribution of a particular retinal input to postsynaptic spiking, they may regulate the contribution of strong versus weak RGC inputs to visual processing (discussed below).

Neurotransmission before eye-opening

The distinct features of the immature retinogeniculate synapse suggest that the immature dLGN carries out a different set of computations on incoming retinal information than the mature dLGN. Many of the modulatory circuits that shape transmission in the adult dLGN begin to innervate TC neurons shortly before eye-opening: corticogeniculate innervation is not complete in mice until p14 (Jacobs et al., Reference Jacobs, Campagnoni, Kampf, Reyes, Kalra, Handley, Xie, Hong-Hu, Spreur, Fisher and Campagnoni2007; Seabrook et al., Reference Seabrook, Eleftheriou, Krahe, Fox and Guido2013; Grant et al., Reference Grant, Hoerder-Suabedissen and Molnar2016), and cholinergic innervation develops over several postnatal weeks in cats (Carden et al., Reference Carden, Datskovskaia, Guido, Godwin and Bickford2000). GABAergic interneurons continue to be recruited into the dLGN at the end of the first postnatal week in mice, and GABAergic innervation in rodents and carnivores occurs gradually (Shatz and Kirkwood, Reference Shatz and Kirkwood1984; Ramoa & McCormick, Reference Ramoa and McCormick1994a ; Pirchio et al., Reference Pirchio, Turner, Williams, Asprodini and Crunelli1997; Ziburkus et al., Reference Ziburkus, Lo and Guido2003; Golding et al., Reference Golding, Pouchelon, Bellone, Murthy, Di Nardo, Govindan, Ogawa, Shimogori, Lüscher, Dayer and Jabaudon2014). In addition, presynaptic ultrastructural morphology and TC dendritic arbor complexity are immature at eye-opening (Bickford et al., Reference Bickford, Slusarczyk, Dilger, Krahe, Kucuk and Guido2010). Therefore, retinogeniculate transmission before eye-opening occurs in a very different environment than after circuits have matured.

Whereas mature TC neurons receive and integrate information from one or several strong retinal inputs that can reach several nA in amplitude, numerous weak inputs, measuring on average ∼40 pA in amplitude (peak AMPAR EPSC) innervate a TC neuron before eye opening (in vitro in mice; Hooks and Chen, Reference Hooks and Chen2006). Remarkably, retinogeniculate transmission to cortex does occur before input refinement: both the spontaneous patterns of activity (retinal waves) that prominently feature in the developing retina, and visually-evoked stimuli detectable through the closed eyelid influence the activity of the visual cortex (Katz & Shatz, Reference Katz and Shatz1996; Mooney et al., Reference Mooney, Penn, Gallego and Shatz1996; Feller, Reference Feller1999; Akerman et al., Reference Akerman, Smyth and Thompson2002; Hanganu et al., Reference Hanganu, Ben-Ari and Khazipov2006; Ackman et al., Reference Ackman, Burbridge and Crair2012). In slice, the synaptic charge transfer needed to drive TC neuron spiking before eye-opening is relatively small: an AMPAR EPSC with a peak amplitude of 120 pA is adequate (Liu & Chen, Reference Liu and Chen2008). The coincident activation of a subset of the dozen or more converging RGC inputs, perhaps relying on synchronous activity that dominates retinal activity during this period of development, can achieve this amplitude (Wong et al., Reference Wong, Meister and Shatz1993; Wong, Reference Wong1999; Butts & Rokhsar, Reference Butts and Rokhsar2001; Feller, Reference Feller2009).

Multiple mechanisms contribute to the efficacy of neurotransmission at the immature weak retinogeniculate synapse. A study using the slow calcium chelator, EGTA-AM, suggested that the distance between the presynaptic release machinery and calcium channels at retinal terminals is greater at immature presynaptic specializations, resulting in delayed or asynchronous release (Borst & Sakmann, Reference Borst and Sakmann1996; Hauser et al., Reference Hauser, Liu, Litvina and Chen2014). Additionally, the immature nervous system produces a slower action potential waveform (Taschenberger & von Gersdorff, Reference Taschenberger and von Gersdorff2000; Murphy & du Lac, Reference Murphy and du Lac2001) and a lower density of glutamate transporters in surrounding astrocytes (Thomas et al., Reference Thomas, Tian and Diamond2011). These properties of the immature synapse lead to the prolonged exposure of postsynaptic receptors to glutamate, promoting the integration of retinal EPSCs over a longer time scale than after maturation.

Several postsynaptic mechanisms also improve the integration of weak RGC inputs at young ages. The temporal window for postsynaptic summation is much greater before eye opening (Liu & Chen, Reference Liu and Chen2008). This is due in part to the higher input resistance in immature neurons (Ramoa & McCormick, Reference Ramoa and McCormick1994b ; Macleod et al., Reference Macleod, Turner and Edgar1997; Pirchio et al., Reference Pirchio, Turner, Williams, Asprodini and Crunelli1997), as well as enhanced conduction through NMDA receptors at negative potentials because of a greater contribution of both NR2B as well as NR2C/D subunits at young synapses (Ramoa & McCormick, Reference Ramoa and McCormick1994a ; Liu & Chen, Reference Liu and Chen2008). These receptors exhibit slower decay kinetics and a lower sensitivity to magnesium block (compare between ages in Fig. 3), and their contribution declines over development in an activity-regulated manner (Ramoa & Prusky, Reference Ramoa and Prusky1997; Chen & Regehr, Reference Chen and Regehr2000; Liu & Chen, Reference Liu and Chen2008).

AMPAR current amplitudes at the immature retinogeniculate synapse are much smaller than later in life (Figs. 2A and 3B). In fact, a substantial fraction (22%) of immature RGC inputs are “silent” (lacking detectable AMPAR currents; Isaac et al., Reference Isaac, Nicoll and Malenka1995; Liao et al., Reference Liao, Hessler and Malinow1995; Chen & Regehr, Reference Chen and Regehr2000). Transmission before eye opening therefore seems to rely almost entirely on NMDAR transmission, with AMPARs influencing the latency to spike (Liu & Chen, Reference Liu and Chen2008). Finally, immature neurons also exhibit calcium plateau potentials (Jaubert-Miazza et al., Reference Jaubert-Miazza, Green, Lo, Bui, Mills and Guido2005; Lo et al., Reference Lo, Ziburkus and Guido2013), and more depolarized resting membrane potentials that are closer to firing threshold (Ramoa & McCormick, Reference Ramoa and McCormick1994b ; Macleod et al., Reference Macleod, Turner and Edgar1997; Pirchio et al., Reference Pirchio, Turner, Williams, Asprodini and Crunelli1997), increasing the efficacy of individual inputs.

In summary, the developing retinogeniculate synapse exhibits numerous adaptations that permit it to integrate and transfer visual signals to cortex even while it undergoes dramatic synaptic rearrangement. As these signals arise from the summation of multiple weak convergent RGC inputs, the computations that the immature dLGN performs, and therefore its role in visual processing, is substantially different from that of the mature dLGN. In addition to a role in conveying visual information, retinogeniculate transmission is important for cortical map formation (Huberman et al., Reference Huberman, Manu, Koch, Susman, Lutz, Ullian, Baccus and Barres2008b ; Cang & Feldheim, Reference Cang and Feldheim2013; Owens et al., Reference Owens, Feldheim, Stryker and Triplett2015), though its precise computational role is not yet understood.

Retinogeniculate connectivity

Retinogeniculate plasticity

In addition to short-term plasticity, the retinogeniculate circuit exhibits long-term plasticity of synaptic weights. The finding that both weak and strong inputs innervate mature TC neurons and contribute to their spiking activity highlights the possibility that experience-dependent plasticity of RGC input strength and number relies on the balancing of synaptic weights in the adult circuit (Thompson et al., Reference Thompson, Picard, Min, Fagiolini and Chen2016). The retinogeniculate connectivity map remodels to experience during development, and may also do so in mature animals. Depriving juvenile mice of visual experience for a week starting at p20 (late dark rearing) disrupts retinogeniculate connectivity, decreasing the amplitude of the average retinal input and increasing the overall number of RGC inputs onto TC neurons (Hooks & Chen, Reference Hooks and Chen2006, Reference Hooks and Chen2008; Narushima et al., Reference Narushima, Uchigashima, Yagasaki, Harada, Nagumo, Uesaka, Hashimoto, Aiba, Watanabe, Miyata and Kano2016). This manipulation also reduces the clustering of RGC axon boutons without significantly altering the size of the arbor or the number of boutons (Hong et al., Reference Hong, Park, Litvina, Morales, Sanes and Chen2014). Together, these observations suggest that while connectivity between axons and targets is selective, the large size of the arbor builds flexibility into the system: dramatic change in visual experience, such as late dark rearing can resculpt connectivity by rearranging boutons and adjusting input strength (Louros et al., Reference Louros, Hooks, Litvina, Carvalho and Chen2014) without investing into remodeling the entire axonal arbor. Because excess branches of RGC arbors do not prune down until at least p60 in mice, retinogeniculate connectivity may exhibit substantial plasticity until at least this age (Hong et al., Reference Hong, Park, Litvina, Morales, Sanes and Chen2014).

A well-established mechanism for altering synaptic strength in response to activity or experience is through changes in AMPAR content of the post-synaptic density (Huganir & Nicoll, Reference Huganir and Nicoll2013). Several studies link the regulation of AMPAR trafficking and function to modulation of the strength of juvenile retinogeniculate synapses. The retinogeniculate synapse is one among several synapses that recruit GluA1-containing AMPARs in response to sensory stimulation (Clem & Barth, Reference Clem and Barth2006; Kielland et al., Reference Kielland, Bochorishvili, Corson, Zhang, Rosin, Heggelund and Zhu2009; Louros et al., Reference Louros, Hooks, Litvina, Carvalho and Chen2014), suggesting that GluA1-dependent AMPAR-driven forms of transmission play an important role in the development and plasticity at this synapse (Fig. 4A–4C; activity-dependent changes in AMPAR subunit composition reviewed in Cull-Candy et al., Reference Cull-Candy, Kelly and Farrant2006; Liu & Zukin, Reference Liu and Zukin2007; Lee et al., Reference Lee, Brott, Kirkby, Adelson, Cheng, Feller, Datwani and Shatz2014). AMPAR subunit content is sensitive to visual experience: mice subjected to late dark rearing exhibited a decrease in AMPAR current rectification, a measure of the fraction of calcium-permeable to calcium-impermeable AMPARs in the postsynaptic density. In contrast, mice that never had any visual experience (chronically dark reared from birth) exhibited normal rectification (Fig. 4C; Louros et al., Reference Louros, Hooks, Litvina, Carvalho and Chen2014). Experience-dependent changes in AMPAR content and function at the retinogeniculate synapse rely in part on stargazin, a transmembrane AMPA regulatory protein that modifies the trafficking and channel kinetics of AMPARs (Straub & Tomita, Reference Straub and Tomita2012). Indeed, late dark rearing increases the expression and phosphorylation of stargazin, which can in turn regulate the composition of postsynaptic AMPARs in both a Hebbian (Tomita et al., Reference Tomita, Stein, Stocker, Nicoll and Bredt2005) or homeostatic manner (Louros et al., Reference Louros, Hooks, Litvina, Carvalho and Chen2014). Finally, changes in AMPAR expression also mediate the role of MHC class I molecule H2-D^b in retinogeniculate developmental refinement (Lee et al., Reference Lee, Brott, Kirkby, Adelson, Cheng, Feller, Datwani and Shatz2014). H2-D^b is one of a series of immune-related molecules that shape retinogeniculate development (Shatz, Reference Shatz2009; Schafer & Stevens, Reference Schafer and Stevens2010). Mice lacking H2-D^b expression exhibit an increase in calcium-permeable AMPARs at retinogeniculate synapses, corresponding to a deficit in LTD. Together, these studies bespeak a critical role of AMPAR regulation in retinogeniculate synaptic plasticity, which may persist into adulthood.

Both Hebbian and homeostatic mechanisms of synaptic plasticity have been shown to alter retinogeniculate synaptic strength during development (Mooney et al., Reference Mooney, Madison and Shatz1993; Butts et al., Reference Butts, Kanold and Shatz2007; Ziburkus et al., Reference Ziburkus, Dilger, Lo and Guido2009; Krahe & Guido, Reference Krahe and Guido2011; Lin et al., Reference Lin, Kang and Chen2014; Louros et al., Reference Louros, Hooks, Litvina, Carvalho and Chen2014). High frequency stimulation of the optic tract, or low frequency stimulation coincident with postsynaptic depolarization in slices from immature ferret dLGN result in long-term enhancement of the EPSC, with contribution from NMDAR activation (Mooney et al., Reference Mooney, Madison and Shatz1993). However, in rat, the same high-frequency stimulus results in long-term depression in dLGN explants before eye-opening, but long-term potentiation later in development (Ziburkus et al., Reference Ziburkus, Dilger, Lo and Guido2009). Finally, plasticity rules based on burst timing have been identified before eye-opening (Butts et al., Reference Butts, Kanold and Shatz2007 in rat), but these plasticity rules have not been examined in more mature slices. On the other hand, the contribution of homeostatic plasticity in retinogeniculate plasticity has been suggested through studies involving monocular deprivation, chronic dark rearing, manipulation of stargazin, and deletion of Mecp2 (a transcription factor necessary for homeostatic scaling up in the visual cortex; Blackman et al., Reference Blackman, Djukic, Nelson and Turrigiano2012; Noutel et al., Reference Noutel, Hong, Leu, Kang and Chen2011; Krahe & Guido, Reference Krahe and Guido2011; Lin et al., Reference Lin, Kang and Chen2014; Louros et al., Reference Louros, Hooks, Litvina, Carvalho and Chen2014). Similar paradigms likely also drive synaptic plasticity at the fully mature retinogeniculate synapse.

Recently described instances of rapid plasticity across species could also engage Hebbian or homeostatic mechanisms at the retinogeniculate synapse and cause a shift in the strength of individual retinogeniculate inputs (Moore et al., Reference Moore, Kiley, Sun and Usrey2011; Aguila et al., Reference Aguila, Cudeiro and Rivadulla2017). In fact, dLGN neurons readily adapt to changes in visual input. For example, pharmacologic blockade of On-center RGC activity in adult cats rapidly uncovers Off-center responses in dLGN neurons previously exhibiting On-center responses, instead of silencing them (Moore et al., Reference Moore, Kiley, Sun and Usrey2011). Further, acute suppression of cortical feedback in awake monkeys shifted the receptive field position of a subset of TC neurons (Aguila et al., Reference Aguila, Cudeiro and Rivadulla2017). Finally, rabbit geniculate neurons exhibit bidirectional sensory adaptation that improves signal detection (Stoelzel et al., Reference Stoelzel, Huff, Bereshpolova, Alonso, Swadlow, Zhuang, Hei, Alonso and Swadlow2015). While modulatory mechanisms could shape the response of the TC neuron to rapid changes in upstream inputs, the specificity that TC neuron responses exhibit in these studies indicates instead a role for rapid shifts in the synaptic efficacy of retinogeniculate connections. These changes occur too rapidly to rely on structural rearrangements of retinogeniculate connections, their timecourse is consistent with possible unsilencing or strengthening of functionally silent or weak subthreshold inputs via the insertion of postsynaptic receptors at dormant synaptic sites. Of course, local inhibitory circuits may also contribute to rapid shifts in RGC input efficacy (Fisher et al., Reference Fisher, Alitto and Usrey2017). Changes that occur over days rather than hours may also recruit the redistribution of presynaptic boutons along the broad RGC axon arbor. The capacity of the diverse types of retinogeniculate synaptic contacts for functional plasticity remains unexplored.

The expression of a variety of mechanisms for modification of synaptic weights is layered on top of a potentially densely interconnected network that is evident in considerable retinogeniculate divergence and convergence. Combined with the observation that both weak and strong inputs innervate mature TC neurons, these plasticity mechanism may endow the dLGN with a role in visual learning on multiple time scales (Ramos et al., Reference Ramos, Schwartz and Roy1976; Albrecht et al., Reference Albrecht, Davidowa and Gabriel1990).