A key neurotrophin responsible for the survival and function of basal forebrain (BF) cholinergic neurons is brain-derived neurotrophic factor (BDNF). A number of studies now indicate that a source of this factor may be BF astrocytes. This study was designed to define the role of BF-astrocyte-derived BDNF on cholinergic neurons. Moreover, it investigated regulatory events that modulate BDNF content and release. In initial work BDNF derived from BF-astrocyte-conditioned medium (ACM) was found to increase both numbers of BF acetylcholinesterase (AChE+) cholinergic neurons and the cholinergic synthetic enzyme choline acetyltransferase (ChAT). Western blots, immunocytochemistry and pharmacological inhibition studies revealed that glutamate, through group I metabotropic glutamate receptors (mGluR), increases the intracellular levels of BDNF in BF astrocytes in culture, as well as its release. Furthermore, the release of BDNF is mediated by the actions of PLC, IP3 and internal stores of Ca2+. These results suggest that BF astrocytes serve as local sources of BDNF for cholinergic neurons, and that they may be regulated as such by the neuronal signal, glutamate, through the mediation of group I metabotropic receptors and the PLC pathway.

Synapse development and remodeling are regulated by a plethora of molecules such as receptor tyrosine kinases (RTKs), a family of cell surface receptors that play critical roles in neural development. Two families of RTKs implicated in synaptic functions, ErbBs and Ephs, share similar characteristics in terms of exhibiting forward and reverse signaling. In this review, we will discuss the latest advances in the functions of ErbBs and Ephs at the synapse, including dendritic spine morphogenesis, synapse formation and maturation, and synaptic transmission and plasticity. In addition to signaling at interneuronal synapses, communication between neuron and glia is increasingly implicated in the control of synaptic functions. Studies on RTKs and their cognate ligands in glial cells enhance our understanding on the nature of ‘tripartite synapse’. Implications of these signaling events in human diseases will be discussed.

Current concepts of invertebrate phylogeny are reviewed. Annelida and Arthropoda, previously regarded as closely related, are now placed in separate clades. Myelin, a sheath of multiple layers of membranes around nerve axons, is found in members of the Annelida, Arthropoda and Chordata. The structure, composition and function of the sheaths in Annelida and Arthropoda are examined and evidence for the separate evolutionary origins of myelin in the three clades is presented. That myelin has arisen independently at least three times, namely in Annelids, Arthropodas and Chordates, provides a remarkable example of convergent evolution.

Research on the molecular and cellular basis of learning and memory has focused on the mechanisms that underlie the induction and expression of synaptic plasticity. There is increasing evidence that structural changes at the synapse are associated with synaptic plasticity and that extracellular matrix (ECM) components and cell adhesion molecules are associated with these changes. The functions of both groups of molecules can be regulated by proteolysis. In this article we review the roles of selected proteases and protease inhibitors in perisynaptic proteolysis of the ECM and synaptic adhesion proteins and the impact of proteolysis on synaptic modification and cognitive function.

The protein composition of myelin in the central nervous system (CNS) has changed at the evolutionary transition from fish to tetrapods, when a lipid-associated transmembrane-tetraspan (proteolipid protein, PLP) replaced an adhesion protein of the immunoglobulin superfamily (P0) as the most abundant constituent. Here, we review major steps of proteolipid evolution. Three paralog proteolipids (PLP/DM20/DMα, M6B/DMγ and the neuronal glycoprotein M6A/DMβ) exist in vertebrates from cartilaginous fish to mammals, and one (M6/CG7540) can be traced in invertebrate bilaterians including the planktonic copepod Calanus finmarchicus that possess a functional myelin equivalent. In fish, DMα and DMγ are coexpressed in oligodendrocytes but are not major myelin components. PLP emerged at the root of tetrapods by the acquisition of an enlarged cytoplasmic loop in the evolutionary older DMα/DM20. Transgenic experiments in mice suggest that this loop enhances the incorporation of PLP into myelin. The evolutionary recruitment of PLP as the major myelin protein provided oligodendrocytes with the competence to support long-term axonal integrity. We suggest that the molecular shift from P0 to PLP also correlates with the concentration of adhesive forces at the radial component, and that the new balance between membrane adhesion and dynamics was favorable for CNS myelination.

Activity-dependent signaling between neurons and astrocytes contributes to experience-dependent plasticity and development of the nervous system. However, mechanisms responsible for neuron–glial interactions and the releasable factors that underlie these processes are not well understood. The pro-inflammatory cytokine, leukemia-inhibitory factor (LIF), is transiently expressed postnatally by glial cells in the hippocampus and rapidly up-regulated by enhanced neural activity following seizures. To test the hypothesis that spontaneous neural activity regulates glial development in hippocampus via LIF signaling, we blocked spontaneous activity with the sodium channel blocker tetrodotoxin (TTX) in mixed hippocampal cell cultures in combination with blockers of LIF and purinergic signaling. TTX decreased the number of GFAP-expressing astrocytes in hippocampal cell culture. Furthermore, blocking purinergic signaling by P2Y receptors contributed to reduced numbers of astrocytes. Blocking activity or purinergic signaling in the presence of function-blocking antibodies to LIF did not further decrease the number of astrocytes. Moreover, hippocampal cell cultures prepared from LIF −/− mice had reduced numbers of astrocytes and activity-dependent neuron–glial signaling promoting differentiation of astrocytes was absent. The results show that endogenous LIF is required for normal development of hippocampal astrocytes, and this process is regulated by spontaneous neural impulse activity through the release of ATP.

Extracellular matrix (ECM) in the brain is composed of molecules synthesized and secreted by neurons and glial cells in a cell-type-specific and activity-dependent manner. During development, ECM plays crucial roles in proliferation, migration and differentiation of neural cells. In the mature brain, ECM undergoes a slow turnover and supports multiple physiological processes, while restraining structural plasticity. In the first part of this review, we discuss the contribution of ECM molecules to different forms of plasticity, including developmental plasticity in the cortex, long-term potentiation and depression in the hippocampus, homeostatic scaling of synaptic transmission and metaplasticity. In the second part, we focus on pathological changes associated with epileptogenic mutations in ECM-related molecules or caused by seizure-induced remodeling of ECM. The available data suggest that ECM components regulating physiological plasticity are also engaged in different aspects of epileptogenesis, such as dysregulation of excitatory and inhibitory neurotransmission, sprouting of mossy fibers, granule cell dispersion and gliosis. At the end, we discuss combinatorial approaches that might be used to counteract seizure-induced dysregulation of both ECM molecules and extracellular proteases. By restraining ECM modification and preserving the status quo in the brain, these treatments might prove to be valid therapeutic interventions to antagonize the progression of epileptogenesis.

One of the special attributes of vertebrates is their myelinated nervous system. By increasing the conduction velocity of axons, myelin allows for increased body size, rapid movement and a large and complex brain. In the central nervous system (CNS), oligodendrocytes (OLs) are the myelin-forming cells. The transcription factors OLIG1 and OLIG2, master regulators of OL development, presumably also played a seminal role during the evolution of the genetic programme leading to myelination in the CNS. From the available ontogenetic and phylogenetic data we attempt to reconstruct the evolutionary events that led to the emergence of the Olig gene family and speculate about the links between Olig genes, their specific cis-regulatory elements and myelin evolution. In addition, we report a putative myelin basic protein (MBP) ancestor in the lancelet Branchiostoma floridae, which lacks compact myelin. The lancelet ‘Mbp’ gene lacks the OLIG1/2- and SOX10-binding sites that characterize vertebrate Mbp homologs, raising the possibility that insertion of cis-regulatory elements might have been involved in evolution of the myelinating programme.

All vertebrate nervous systems, except those of agnathans, make extensive use of the myelinated fiber, a structure formed by coordinated interplay between neuronal axons and glial cells. Myelinated fibers, by enhancing the speed and efficiency of nerve cell communication allowed gnathostomes to evolve extensively, forming a broad range of diverse lifestyles in most habitable environments. The axon-covering myelin sheaths are structurally and biochemically novel as they contain high portions of lipid and a few prominent low molecular weight proteins often considered unique to myelin. Here we searched genome and EST databases to identify orthologs and paralogs of the following myelin-related proteins: (1) myelin basic protein (MBP), (2) myelin protein zero (MPZ, formerly P0), (3) proteolipid protein (PLP1, formerly PLP), (4) peripheral myelin protein-2 (PMP2, formerly P2), (5) peripheral myelin protein-22 (PMP22) and (6) stathmin-1 (STMN1). Although widely distributed in gnathostome/vertebrate genomes, neither MBP nor MPZ are present in any of nine invertebrate genomes examined. PLP1, which replaced MPZ in tetrapod CNS myelin sheaths, includes a novel ‘tetrapod-specific’ exon (see also Möbius et al., 2009). Like PLP1, PMP2 first appears in tetrapods and like PLP1 its origins can be traced to invertebrate paralogs. PMP22, with origins in agnathans, and STMN1 with origins in protostomes, existed well before the evolution of gnathostomes. The coordinated appearance of MBP and MPZ with myelin sheaths and of PLP1 with tetrapod CNS myelin suggests interdependence – new proteins giving rise to novel vertebrate structures.

Many neurons and their synapses are enwrapped in a brain-specific form of the extracellular matrix (ECM), the so-called perineuronal net (PNN). It forms late in the postnatal development around the time when synaptic contacts are stabilized. It is made of glycoproteins and proteoglycans of glial as well as neuronal origin. The major organizing polysaccharide of brain extracellular space is the polymeric carbohydrate hyaluronic acid (HA). It forms the backbone of a meshwork consisting of CNS proteoglycans such as the lectican family of chondroitin sulphate proteoglycans (CSPG). This family comprises four abundant components of brain ECM: aggrecan and versican as broadly expressed CSPGs and neurocan and brevican as nervous-system-specific family members. In this review, we intend to focus on the specific role of the HA-based ECM in synapse development and function.

The evolution of a character is better appreciated if examples of convergent emergence of the same character are available for comparison. Three instances are known among invertebrates of the evolution of axonal sheaths possessing the functional properties and many of the structural properties of vertebrate myelin. Comparison of these invertebrate myelins raises the question of what structural features must a sheath possess in order to produce the two principal functional characteristics of impulse speed enhancement and energy savings. This essay reviews the features recognized by early workers as pertaining to myelin in vertebrate and invertebrate alike: osmiophilia, negative birefringence and saltatory conduction. It then examines common features revealed by the advent of electron microscopy: multiplicity of lipid membranes, condensation of those membranes, specialized marginal seals, and nodes. Next it examines the robustness of these features as essential components of a speed-enhancing sheath. Features that are not entirely essential for speed enhancement include membrane compaction, spiral wrapping of layers, glial cell involvement, non-active axonal membrane, and even nodes and perinodal sealing. This permissiveness is discussed in relation to the possible evolutionary origin of myelin.

Low-density-lipoprotein receptors (LDLRs) are an evolutionarily ancient surface protein family with the ability to activate a diversity of extracellular signals across the cellular membrane in the adult central nervous system (CNS). Their intimate roles in modulating synaptic plasticity and their necessity in hippocampal-dependent learning and memory have only recently come to light. Two known LDLR ligands, specifically apolipoprotein E (apoE) and reelin, have been the most widely investigated in this regard. Most of our understanding of synaptic plasticity comes from investigation of both pre- and postsynaptic alterations. Therefore, it is interesting to note that neurons and glia that do not contribute to the synaptic junction in question can secrete signaling molecules that affect synaptic plasticity. Notably, reelin and apoE have been shown to modulate hippocampal long-term potentiation in general, and affect NMDA receptor and AMPA receptor regulation specifically. Furthermore, these receptors and signaling molecules have significant roles in neuronal degenerative diseases such as Alzheimer's disease. The recent production of recombinant proteins, knockout and transgenic mice for receptors and ligands and the development of human ApoE targeted replacement mice have significantly expanded our understanding of the roles LDLRs and their ligands have in certain disease states and the accompanying initiation of specific signaling pathways. This review describes the role LDLRs, apoE and reelin have in the regulation of hippocampal synaptic plasticity.