Astrocytes constitute a major group of glial cells which were long regarded as passive elements, fulfilling nutritive and structural functions for neurons. Calcium rise in astrocytes propagating to neurons was the first demonstration of direct interaction between the two cell types. Since then, calcium has been widely used, not only as an indicator of astrocytic activity but also as a stimulator switch to control astrocyte physiology. As a result, astrocytes have been elevated from auxiliaries to neurons, to cells involved in processing synaptic information. Curiously, while there is evidence that astrocytes play an important role in synaptic plasticity, the data relating to calcium's pivotal role are inconsistent. In this review, we will detail the various mechanisms of calcium flux in astrocytes, then briefly present the calcium-dependent mechanisms of gliotransmitter release. Finally, we will discuss the role of calcium in plasticity and present alternative explanations that could reconcile the conflicting results published recently.

There is no question about the fact that astrocytes and other glial cells release neurotransmitters that activate receptors on neurons, glia and vascular cells, and that calcium is an important second messenger regulating the release. This occurs in cell culture, tissue slice and in vivo. Negative results from informative experiments designed to test the mechanism of calcium-dependent neurotransmitter release from astrocytes and the ensuing effects on synaptic transmission, have been cited as evidence calling into question whether astrocytes release neurotransmitters under normal circumstances with effects on synaptic transmission. The special feature section in this issue of Neuron Glia Biology addresses these issues and other aspects of neurotransmitter release from astrocytes in communicating with neurons and glial cells. Together these studies suggest that application of vocabulary and concepts developed for synaptic communication between neurons can lead to confusion and apparent paradoxes with respect to communication by extracellular signaling molecules released from glia in response to functional activity.

Adhesive and repellent molecular cues guide migrating cells and growing neurites during development. They also contribute to synaptic function, learning and memory in adulthood. Here, we review the roles of cell adhesion molecules of the immunoglobulin superfamily (Ig-CAMs) and semaphorins (some of which also contain Ig-like domains) in regulation of synaptic transmission and plasticity. Interestingly, among the seven studied Ig-CAMs, the neuronal cell adhesion molecule proved to be important for all tested forms of hippocampal plasticity, while its associated unusual glycan polysialic acid is necessary and sufficient part for synaptic plasticity only at CA3-CA1 synapses. In contrast, Thy-1 and L1 specifically regulate long-term potentiation (LTP) at synapses formed by entorhinal axons in the dentate gyrus and cornu ammonis, respectively. Contactin-1 is important for long-term depression but not for LTP at CA3-CA1 synapses. Analysis of CHL1-deficient mice illustrates that at intermediate stages of development a deficit in a cell adhesion molecule is compensated but appears as impaired LTP during early and late postnatal development. The emerging mechanisms by which adhesive Ig-CAMs contribute to synaptic plasticity involve regulation of activities of NMDA receptors and L-type Ca2+ channels, signaling via mitogen-activated protein kinase p38, changes in GABAergic inhibition and motility of synaptic elements. Regarding repellent molecules, available data for semaphorins demonstrate their activity-dependent regulation in normal and pathological conditions, synaptic localization of their receptors and their potential to elevate or inhibit synaptic transmission either directly or indirectly.

Neurogenesis, the generation of new neurons from neural precursor cells (NPCs), is a multi-step process that includes the proliferation of NPCs, fate determination, migration, and neuronal maturation. Neurogenesis is regulated by several extrinsic factors, such as enriched environment, physical exercise, hormones and stress, many of which also induce the expression of neurotrophins. In this review, we summarize studies on the role of neurotrophins in neurogenesis during development and in adults. We discuss the functional significance of neurogenesis in learning and memory, and how neurotrophins regulate this process. In this context, we describe recent experiments linking adult neurogenesis to long-term synaptic plasticity in the hippocampal dentate gyrus. Further study of the relationship between neurotrophins, adult neurogenesis and dentate synaptic plasticity might provide new insights into the mechanisms by which gene–environment interactions control cognition and brain plasticity.

Members of the major histocompatibility complex (MHC) class I family of proteins are well known for their central role in the adaptive immune system, where they present self and non-self peptides for immune surveillance. Although the brain has been long considered immune privileged, in part because of an apparent lack of neuronal MHC class I, it has since been shown that MHC class I proteins are expressed by normal, uninfected neurons. Moreover, expression of MHC class I is unusually dynamic in the developing and adult brain, and MHC class I levels in neurons can be regulated by endogenous and exogenous electrical activity. Unexpectedly, several recent studies find that MHC class I is required for distinct activity-dependent events during brain development, adult plasticity, and in response to injury. Together, these studies indicate a novel role for MHC class I proteins in translating electrical activity into changes in synaptic strength and neuronal connectivity in vivo.

Early in development, steroid hormones structurally organize various regions of the CNS. However, steroid hormones continue to affect the structure and function of the CNS throughout the life of the individual. In this review, we discuss sex differences and similarities in steroid-induced synaptic plasticity in the adult brain. Particular emphasis is placed on steroid-induced plasticity in the hippocampus, a brain region important in learning and memory. This topic is relevant to the growing evidence for the actions of sex hormones outside of the reproductive neuroendocrine axis. It also tells an important and emerging story about non-genomic and genomic actions of steroids at the cellular and molecular levels. Specifically, the effects of estrogen and progesterone as well as the androgens and glucocorticoids are discussed. The influence of steroids on hippocampal structure and function can differ vastly between the sexes. However, there are certain similarities that might aid in our understanding of how steroids affect CNS plasticity in general. Although future studies will undoubtedly lead us to a greater understanding of these phenomena, the data reviewed indicate that when studying synaptic plasticity, the sex and hormonal milieu of the individual might significantly influence the outcome and interpretation of the research.