Mechanisms Underlying Target Selectivity for Cell Types and Subcellular Domains in Developing Neocortical Circuits

Abstract

The cerebral cortex contains numerous neuronal cell types, distinguished by their molecular identity as well as their electrophysiological and morphological properties. Cortical function is reliant on stereotyped patterns of synaptic connectivity and synaptic function among these neuron types, but how these patterns are established during development remains poorly understood. Selective targeting not only of different cell types but also of distinct postsynaptic neuronal domains occurs in many brain circuits and is directed by multiple mechanisms. These mechanisms include the regulation of axonal and dendritic guidance and fine-scale morphogenesis of pre- and postsynaptic processes, lineage relationships, activity dependent mechanisms and intercellular molecular determinants such as transmembrane and secreted molecules, many of which have also been implicated in neurodevelopmental disorders. However, many studies of synaptic targeting have focused on circuits in which neuronal processes target different lamina, such that cell-type-biased connectivity may be confounded with mechanisms of laminar specificity. In the cerebral cortex, each cortical layer contains cell bodies and processes from intermingled neuronal cell types, an arrangement that presents a challenge for the development of target-selective synapse formation. Here, we address progress and future directions in the study of cell-type-biased synaptic targeting in the cerebral cortex. We highlight challenges to identifying developmental mechanisms generating stereotyped patterns of intracortical connectivity, recent developments in uncovering the determinants of synaptic target selection during cortical synapse formation, and current gaps in the understanding of cortical synapse specificity.

Cell-type specific transcriptomic signatures of neocortical circuit organization and their relevance to autism

“…Thus, we could not identify a specific set of neuronal subtypes that may be uniquely vulnerable in autism. In summary, we identified circuit-related genes that are conserved between ALM and VISp for each neuronal subclass and may act as molecular mechanisms underlying stereotyped “canonical circuits” found across the cortex (Kubota, 2014;Harris and Shepherd, 2015b;Gutman-Wei and Brown, 2021). Furthermore, many of them are candidates to disrupt the balance between excitation and inhibition throughout the cortex in developmental disorders (Sohal and Rubenstein, 2019).…”

“…There is evidence of cell-types forming local synaptic connections according to their subclass identity (Harris and Shepherd, 2015;Ye et al, 2015;Wester et al, 2019). A prominent example is that across diverse cortical regions, intratelencephalic projection neurons preferentially form local synapses onto pyramidal tract projection neurons (Harris and Shepherd, 2015;Gutman-Wei and Brown, 2021). Among interneurons, stereotyped connections between pre- and post-synaptic cell-types have also been revealed (Harris and Shepherd, 2015;Gutman-Wei and Brown, 2021).…”

“…A prominent example is that across diverse cortical regions, intratelencephalic projection neurons preferentially form local synapses onto pyramidal tract projection neurons (Harris and Shepherd, 2015;Gutman-Wei and Brown, 2021). Among interneurons, stereotyped connections between pre- and post-synaptic cell-types have also been revealed (Harris and Shepherd, 2015;Gutman-Wei and Brown, 2021). In addition to cell-type biased connections, there is evidence of neuronal subclasses preferentially targeting specific subdomains on post-synaptic cells and exhibiting unique synaptic properties dependent on their partner’s identity (Harris and Shepherd, 2015;Gutman-Wei and Brown, 2021).…”

“…Among interneurons, stereotyped connections between pre- and post-synaptic cell-types have also been revealed (Harris and Shepherd, 2015;Gutman-Wei and Brown, 2021). In addition to cell-type biased connections, there is evidence of neuronal subclasses preferentially targeting specific subdomains on post-synaptic cells and exhibiting unique synaptic properties dependent on their partner’s identity (Harris and Shepherd, 2015;Gutman-Wei and Brown, 2021). Together, these findings suggest molecular mechanisms for synaptic targeting and maintenance that are conserved within subclasses.…”

Cell-type specific transcriptomic signatures of neocortical circuit organization and their relevance to autism

“…Thus, we could not identify a specific set of neuronal classes that may be uniquely vulnerable in autism. In summary, we identified circuit-related genes that are conserved between ALM and VISp for each neuronal class and may mediate molecular mechanisms underlying stereotyped "canonical circuits" found across the cortex (Kubota, 2014;Harris and Shepherd, 2015;Gutman-Wei and Brown, 2021). Furthermore, many of them are candidates to disrupt the balance between excitation and inhibition throughout the cortex in developmental disorders (Sohal and Rubenstein, 2019).…”