GABAergic cell types: ASD models
The goal of the Cell Counts project is to generate brainwide maps of inhibitory neuron sub-populations and inhibitory long-range projections in these Autism Spectrum Disorder (ASD) models, and in wildtype controls in order to determine the neuroanatomy of dysfunctional inhibition relevant to autism. We will characterize these alterations through key postnatal developmental stages and will further characterize alterations in chandelier cell development in ASD mice.
Over a hundred genes have been implicated in the etiology of ASD. The challenge is to understand how gene mutations alter brain circuits leading to deficient social interaction, communication, and repetitive behaviors. Although numerous mouse models of genetic etiology are being generated, there are two obstacles to studying their impact on neural circuits. First, neural circuits consist of diverse cell types that are intricately connected, but there are no robust methods to identify the spatial distribution of cell types and their connections brainwide, and thus to pinpoint where the pathology is. Secondly, genes often regulate the development of neural circuits by controlling the making and wiring of specific cell populations, but there are no reliable methods to track the development of cell types, and thus to determine when and how mutations alter circuit assembly and plasticity.
Among the many GABAergic cell types in the cerebral cortex, the chandelier cell type (CHCs) is arguably the most powerful in terms of its control over cortical activity. Conserved from mouse to human, chandelier cell axon terminals exclusively innervate pyramidal cells at axon initial segments (AIS), the site of action potential initiation. Each CHC innervates hundreds of pyramidal cells, and CHCs are the only cell type that innervates AIS. CHCs thus likely exert decisive control over the firing of pyramidal cell ensembles that support motor and cognitive functions. Deficient CHCs in prefrontal cortex is a well-replicated pathology in schizophrenia (SZ). Given the shared genetic etiology of SZ and ASD, alteration of CHCs, either as a direct consequence of mutations or indirectly through developmental compensation and maladaptive plasticity, is likely a sensitive probe for detecting aberrant cortical circuitry in ASD models.