A matter of space and time: Emerging roles of disease-associated proteins in neural development

Abstract

Recent genetic studies of neurodevelopmental disorders point to synaptic proteins and ion channels as key contributors to disease pathogenesis. Although many of these proteins, such as the L-type calcium channel Ca_v1.2 or the postsynaptic scaffolding protein SHANK3, have well-studied functions in mature neurons, new evidence indicates that they may subserve novel, distinct roles in immature cells as the nervous system is assembled in prenatal development. Emerging tools and technologies, including single-cell sequencing and human cellular models of disease, are illuminating differential isoform utilization, spatiotemporal expression, and subcellular localization of ion channels and synaptic proteins in the developing brain compared with the adult, providing new insights into the regulation of developmental processes. We propose that it is essential to consider the temporally distinct and cell-specific roles of these proteins during development and maturity in our framework for understanding neuropsychiatric disorders.

Figure 1:

Dynamic changes in CACNA1C splicing may underlie novel roles for Ca_v1.2 channels in neuronal differentiation. Utilization of the Timothy syndrome-associated exons 8 and 8a of CACNA1C in the developing brain is temporally regulated. Exon 8a-expressing transcripts are enriched in neural progenitors and immature neurons (left, center), whereas channels encoded by exon 8-containing transcripts are more highly expressed in mature neurons (right). The TS mutation promotes persistently increased expression of exon 8A transcripts containing the mutation during neuronal differentiation and maturation.

Figure 2:

Developmental reorganization of Na_v1.2 channels contributes to distinct functions at different stages of neuronal maturation. In immature neurons (left), Na_v1.2 channels decorate the axon initial segment (AIS) and entire length of the axon, underpinning their indispensable role in action potential generation and propagation at early postnatal ages. In mature neurons (right), Na_v1.2 channels display somatodendritic localization and are restricted to the proximal AIS. They are replaced in the distal AIS and Nodes of Ranvier by Na_v1.6 channels. As a consequence of this dynamic subcellular regulation of channel distribution, Scn2a inactivation yields distinct electrophysiological phenotypes in immature and mature cortical projection neurons, and SCN2A loss-of-function variants preferentially affect immature neuron excitability.

Figure 3:

Alternative splicing of Syngap1 gives rise to SynGAP isoforms with distinct, temporally-regulated subcellullar localization in immature and mature neurons. Earlier and less synaptically-enriched expression of the β isoform of SynGAP in immature neurons (left) results in a specific role for this classical synaptic protein in dendritic arborization. In mature neurons (right), SynGAP-α1 is enriched at the postsynaptic density, where it directly interacts with PSD-95 and regulates synaptic plasticity. Dendritic arborization is altered in human neurons lacking all SYNGAP1 isoforms, but it is not yet clear in human cells how this developmental reorganization of SynGAP isoforms might be influenced by SYNGAP1 mutations.