Overproduction of Upper-Layer Neurons in the Neocortex Leads to Autism-like Features in Mice

• Enhanced embryonic neurogenesis leads to overproduction of excitatory neurons
• Excess excitatory neurons perturb excitatory and inhibitory neuronal development
• Excess excitatory neurons alter excitatory and inhibitory synaptic connections
• Increased cortical neuron number is associated with autism-like behavioral deficits

SummaryThe functional integrity of the neocortex depends upon proper numbers of excitatory and inhibitory neurons; however, the consequences of dysregulated neuronal production during the development of the neocortex are unclear. As excess cortical neurons are linked to the neurodevelopmental disorder autism, we investigated whether the overproduction of neurons leads to neocortical malformation and malfunction in mice. We experimentally increased the number of pyramidal neurons in the upper neocortical layers by using the small molecule XAV939 to expand the intermediate progenitor population. The resultant overpopulation of neurons perturbs development of dendrites and spines of excitatory neurons and alters the laminar distribution of interneurons. Furthermore, these phenotypic changes are accompanied by dysregulated excitatory and inhibitory synaptic connection and balance. Importantly, these mice exhibit behavioral abnormalities resembling those of human autism. Thus, our findings collectively suggest a causal relationship between neuronal overproduction and autism-like features, providing developmental insights into the etiology of autism.

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