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Review
. 2017 Feb:42:102-110.
doi: 10.1016/j.conb.2016.12.004. Epub 2016 Dec 26.

Synapse biology in the 'circuit-age'-paths toward molecular connectomics

Dietmar Schreiner  1 , Jeffrey N Savas  2 , Etienne Herzog  3 , Nils Brose  4 , Joris de Wit  5
Affiliations
Review

Synapse biology in the 'circuit-age'-paths toward molecular connectomics

Dietmar Schreiner et al. Curr Opin Neurobiol. 2017 Feb.

Abstract

The neural connectome is a critical determinant of brain function. Circuits of precisely wired neurons, and the features of transmission at the synapses connecting them, are thought to dictate information processing in the brain. While recent technological advances now allow to define the anatomical and functional neural connectome at unprecedented resolution, the elucidation of the molecular mechanisms that establish the precise patterns of connectivity and the functional characteristics of synapses has remained challenging. Here, we describe the power and limitations of genetic approaches in the analysis of mechanisms that control synaptic connectivity and function, and discuss how recent methodological developments in proteomics might be used to elucidate the molecular synaptic connectome that is at the basis of the neural connectome.

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Conflict of interest statement

Conflict of Interest Statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1. Genetic dissection of Purkinje cell connectivity in the cerebellum
(A) Presynaptic neurexin molecules bind to postsynaptic neuroligin molecules to form a trans-synaptic adhesive complex that organizes the pre- and postsynaptic machinery by recruiting scaffolding proteins and neurotransmitter receptors. (B) Purkinje cells (PCs) receive excitatory input from climbing fibers (CFs) originating from the inferior olivary nucleus and from parallel fibers (PFs) originating from cerebellar granule cells. Local interneurons, stellate and basket cells, provide inhibitory input. At excitatory PF-PC synapses, Cbln1 is secreted from PFs and forms a tri-partite complex with presynaptic neurexin (Nrxn) isoforms and the postsynaptic GluD2 neurotransmitter receptor to regulate synaptogenesis. Neuroligin-3 (Nlgn3) is not required for synapse formation, but is required for long-term depression of PF-PC synapses, although this is under debate. At excitatory CF-PC synapses, C1ql1 is secreted from CFs and binds the postsynaptic adhesion GPCR BAI3 to regulate CF synapse formation. Whether C1ql1 also binds a presynaptic receptor at CF-PC synapses to form a tri-partite complex remains to be determined. Nlgn1, Nlgn2, and Nlgn3 all contribute to the specification of CF-PC synapse functional properties. At inhibitory basket cell-PC synapses, Semaphorin 3A is secreted from PCs to attract basket cell axons via its receptor Neuropilin-1 (NRP1) on these axons. NRP1 then binds in trans to Neurofascin 186 (NF186), which is expressed in a gradient on the PC soma and the axon initial segment. Both Nlgn2 and Nlgn3 contribute to stellate/basket cell inhibitory synapse function.
Figure 2
Figure 2. Overview of chemical labeling techniques and their application for targeted proteome analysis
(A) Bioorthogonal noncanonical amino acid tagging (BONCAT): the approach is based on the in vivo incorporation of non-canonical, azide containing amino acids such as L-azidohomoalanine (AHA) into newly synthesized proteins. These proteins can be subsequently labeled with biotin by ‘click-chemistry’ and isolated for further analysis. (B) In vivo proximity protein biotinylation by promiscuous biotin-ligase (BioID): biotinylation occurs through Biotinoyl-5’-Adenylate which is released by a mutated variant of E.coli biotin ligase BirA. Biotinoyl-5’-Adenylate is a highly reactive compound that quickly reacts with lysines of proximal proteins. (C) Biotin-labeling by ascorbate-peroxidase (APEX) and (D) by split-horseradish-peroxidase: both techniques utilize the ability of peroxidase enzymes to generate highly reactive species from tyramide derived compounds such as biotin-phenol. These react quickly with aromatic groups (usually tyrosine and tryptophan, but also histidine and cytosine) of proteins in close proximity. (E) Application of metabolic labeling for analysis of cell-type/compartment-specific proteomes: Selective expression of biotin-labeling enzymes in cells of interest (e.g. utilizing the Cre-Lox-system) allows isolation of proteins expressed in identified cells. Additionally, targeting these enzymes to synaptic compartments provides an opportunity for the labeling and subsequent determination of synapse-type specific protein composition in desired cell populations.
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