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Molecular mechanisms of synaptic specificity in developing neural circuits - PubMed

  • ️Fri Jan 01 2010

Review

Molecular mechanisms of synaptic specificity in developing neural circuits

Megan E Williams et al. Neuron. 2010.

Abstract

The function of the brain depends on highly specific patterns of connections between populations of neurons. The establishment of these connections requires the targeting of axons and dendrites to defined zones or laminae, the recognition of individual target cells, the formation of synapses on particular regions of the dendritic tree, and the differentiation of pre- and postsynaptic specializations. Recent studies provide compelling evidence that transmembrane adhesion proteins of the immunoglobulin, cadherin, and leucine-rich repeat protein families, as well as secreted proteins such as semaphorins and FGFs, regulate distinct aspects of neuronal connectivity. These observations suggest that the coordinated actions of a number of molecular signals contribute to the specification and differentiation of synaptic connections in the developing brain.

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Figures

Figure 1
Figure 1. Specificity of synaptic connections in the central nervous system

Diagramatic representation of specificity of neuronal connections at the laminar, cellular, subcellular, and synaptic levels. Precise regulation of connectivity at each of these levels contributes to the establishment of functional neural circuits.

Figure 2
Figure 2. Cellular specificity in the spinal cord is disrupted in Pea3 and Sema3E knockout mice

A) Cutaneous maximus (CM) and triceps brachii (Tri) afferents make polysynaptic connections to CM motor neurons in wildtype mice. However, in Pea3 -/- mice, CM dendrites grow toward the center of the spinal cord allowing Tri afferents to synapse directly onto CM dendrites and altering this motor circuit. B) Expression of Sema3E causes motor neurons to make polysynaptic connections with their propriceptive afferents.

Figure 3
Figure 3. Subcellular specificity of cerebellar Purkinje neurons is dependent on the cell adhesion molecules Neurofascin and CHL1

Schematics showing the wildtype (A) connectivity patterns for Purkinje neurons and those of ankyrin-G (B) and CHL1 (C) knockout mice. In Ankyrin-G -/- mice, a gradient of Neurofascin is no longer restricted to the axon initial segment (AIS) and, consequently, basket cell axons are not properly targeted to the AIS and synapse formation is decreased. In CHL1 -/- mice, stellate cell axons are not properly targeted along Bergman glia fibers and synapse formation is decreased. SC - stellate cell, BC – basket cell, PC – Purkinje cell, BG – Bergman glia.

Figure 4
Figure 4. Alternative splicing of neurexin regulates selectivity in neurexin-ligand interactions

(A) Schematic drawing summarizing the trans-synaptic interaction between presynaptic α (long) and β (short) neurexins (NRXN) and its postsynaptic binding partner neuroligin (NLGN). Neurexins with or without a 30 amino acid insert at splice site #4 (SS#4) can bind neuroligins. Neurexins interact with the scaffolding molecule CASK and neuroligins interact with the scaffolding molecule PSD-95, which binds NMDAR receptors (NMDARs) via its PDZ domain. (B) Only neurexins lacking the SS#4 insert bind the postsynaptic adhesion molecule LRRTM2, which can recruit NMDARs and AMPARs. (C) SS#4 containing neurexins in cerebellar granule cells form a synapse-specific trans-synaptic adhesion complex with the secreted cerebellin precursor protein 1 (Cbln1) and the postsynaptic GluRδ2 receptor on Purkinje cell dendritic spines. GuK, guanylate kinase domain; CaMK, Ca2+/calmodulin-dependent kinase domain; LRR, leucine-rich repeat; LRRNT and LRRCT, N-terminal and C-terminal LRR flanking domains; PDZ BD, PDZ binding domain; AChE, acetylcholinesterase homology domain; LNS, laminin/neurexin/sex-hormone-binding protein domain; EGF, epidermal growth factor-like domain; CHO, carbohydrate attachment sequence.

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