Synaptic Neurexin Complexes: A Molecular Code for the Logic of Neural Circuits

Abstract

Synapses are specialized junctions between neurons in brain that transmit and compute information, thereby connecting neurons into millions of overlapping and interdigitated neural circuits. Here, we posit that the establishment, properties, and dynamics of synapses are governed by a molecular logic that is controlled by diverse trans-synaptic signaling molecules. Neurexins, expressed in thousands of alternatively spliced isoforms, are central components of this dynamic code. Presynaptic neurexins regulate synapse properties via differential binding to multifarious postsynaptic ligands, such as neuroligins, cerebellin/GluD complexes, and latrophilins, thereby shaping the input/output relations of their resident neural circuits. Mutations in genes encoding neurexins and their ligands are associated with diverse neuropsychiatric disorders, especially schizophrenia, autism, and Tourette syndrome. Thus, neurexins nucleate an overall trans-synaptic signaling network that controls synapse properties, which thereby determines the precise responses of synapses to spike patterns in a neuron and circuit and which is vulnerable to impairments in neuropsychiatric disorders.

Figure 1. Synapses construct neural circuits

A, Schematic of a neural microcircuit mediating feedforward inhibition. A presynaptic pyramidal neuron (blue) forms synapses on both a postsynaptic excitatory pyramidal neuron and a postsynaptic inhibitory neuron (red), that in turn also forms a synapse the second pyramidal neuron (top, electron micrograph of an excitatory synapse). B, Schematic of neural circuit development. Neurogenesis is followed by neural migration (not shown) and elaboration of axons and dendrites, including extension of especially axons often over long distances (axon pathfinding). Guided axon-dendrite contacts then form synapses, with three proposed components of synapse formation: target recognition that causes synapse initiation, organization of the canonical components of synapses such as synaptic vesicles and active zones, and specification of synapse properties such as transmitter identity, release probability, or competence for long-term plasticity. Synapse formation is often followed by synapse elimination, resulting in continuous turnover of some synapses.

Figure 2. Overview of trans-synaptic interaction complexes

Proteins are shown schematically; arrows signify physical binding. Interactions that are specific to particular isoforms, such as neurexin splice forms or LAR-type PTPR variants, are not shown, and interactions shown may not apply to all members of a protein family. Although only selected interactions are shown that were chosen based on the level of evidence, significant uncertainty still exists about the validity of some of the interactions shown, and even the pre- vs. postsynaptic localizations of some of the proteins (shown in red typeface) have not be definitively established.

Figure 3. Domain structures, alternative splicing, and selected ligand interactions of neurexins

A, Domain structures and sites of alternative splicing of neurexins. Domains are labeled above the schematics of α-neurexins, and sites of alternative splicing (labeled SS1-SS6) are indicated below α-, β-, and γ-neurexins. B, Expression of Nrxn1, Nrxn2, and Nrxn3 (top, shown in gray) and ratio of SS4+/SS4- splice forms of these neurexins (bottom, blue and green) as determined by quantitative RT-PCR in selected brain regions dissected from adult mice (modified from Aoto et al., 2013). C, Schematic of the interactions of α- and β-neurexins with selected ligands in the context of the synapse. Requirements for neurexin splice variants are indicated; possible competition between ligands are indicated by junctions marked with a circle; Proteins are not drawn to scale (abbreviations: E, EGF-like domain; EHD, esterase homology domain; L, LNS-domain; LRRs, leucine-rich repeats; Nt and Ct, N- and C-terminal sequences surrounding LRRs; Ig, Ig-domain; F, fibronectin III domain; MAM, MAM-domain; Lc, lectin domain; O, olfactomedin-like domain; H, hormone-binding domain; GAIN, GAIN domain).

Figure 4. Phenotypes produced by genetic manipulations of neurexins, illustrated with the results obtained by genetic control of SS4 in Nrxn3

A, Schematic summary of the most salient phenotypes emerging from genetic manipulations of neurexins. A presynaptic terminal with surface-exposed neurexins are shown on the left, and a summary list of phenotypes observed with genetic manipulations on the right. B, Experimental approach for analyzing the effects of presynaptic manipulations in hippocampal CA1 neurons on synapses formed by these neurons on pyramidal neurons in the mouse subiculum. Stereotactic infection of CA1 neurons with viruses mediating genetic manipulations are performed at P21 (left). Mice are analyzed 14–16 days later by slice physiology using whole-cell recordings from subiculum neurons and extracellular stimulations of CA1 region neuron axons as indicated (right). C, Illustration of control of postsynaptic AMPAR levels by presynaptic Nrxn3 alternative splicing at SS4. Control mice (black) and SS4-knockin mice in which the the alternatively spliced SS4 exon is rendered constitutively included (SS4+) were analyzed; in the latter, the CA1 region of the hippocampus was injected with control or Cre-recombinase expressing virus as described in panel B to either retain Nrxn3-SS4+ in the CA1 to subiculum projection (blue symbols), or to convert Nrxn3-SS4+ into Nrxn3-SS4- in this projection (green symbols). Input/output curves were then used to determined the strength of AMPAR-mediated EPSCs, demonstrating that the decrease in AMPAR-mediated responses in Nrxn3-SS4+ mice can be fully reversed by presynaptic excistion of SS4 yielding presynaptic Nrxn3-SS4-. D, Illustration of the all-or-none gating of postsynaptic NMDAR-dependent LTP by presynaptic Nrxn3 alternative splicing at SS4. Experiments were performed as described in panels B and C, except that LTP as induced by 100 Hz tetani was examined. B–D were modified from Aoto et al. (2013).

Figure 5. Phenotypes produced by genetic manipulations of selected neurexin ligands

Salient effects of specific manipulations are shown next to the diagrams of the respective proteins. For references, see text.

Figure 6. Mutations in selected genes related to neurexin complexes that are implicated in neuropsychiatric disorders

Images show descriptions of the phenotypes associated with mutations in a specific gene superimposed on the schematic diagram of the neurexin-based complexes from Fig. 3C. For details, see text.