GABAergic Interneuron Dysfunction in Developing Cortical Circuits Underlying Autism Spectrum Disorders

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Project Summary In the cerebral cortex, gamma-aminobutyric acid (GABA)ergic interneurons are the major source of inhibition. Interneuron dysfunction is strongly associated with autism and childhood epilepsy. We demonstrated that environmental influences such as electrical activity are fundamental for the maturation of GABAergic circuits. However, the identity of the activity patterns controlling interneuron development remains poorly understood. The long-term goal of this research is to uncover how early interneuron dysfunction leads to lasting neuropathologies. The objective of this proposal is to reveal the signaling pathways underlying activity- dependent development and to assess how perturbations in this process lead to aberrant brain function. To this end, we will use the murine barrel cortex as a well-established model for the study of activity-dependent circuit maturation. We will focus our studies in cortical interneurons since our previous work indicates that these neurons are exquisitely sensitive to environmental perturbations in the neonate. In the near term, this proposal is aimed at investigating the role of specific interneuron subtypes in regulating the emergence of early activity patterns (Aim 1). In addition, this project will determine the calcium-dependent signaling pathways for the functional maturation of interneuron networks. We will study the role of Cacna1c, a gene encoding for the Cav1.2 subunit of L-type calcium channels. Mutations in this gene are strongly associated with Timothy syndrome and other neurodevelopmental disorders (Aim 2). Finally, we will assess how developmental defects in interneuron number lead to abnormal brain activity during development and impaired behavior in the adult (Aim 3). With respect to the outcomes, our work is expected to identify basic mechanisms fundamental for the emergency of a healthy balance in the number of excitatory and inhibitory neurons. In addition, these results are expected to have a significant translational impact because they will expand our mechanistic knowledge on how mutations in the CACNA1C gene, strongly associated with autism, bipolar disorder, schizophrenia and Timothy syndrome, may lead to behavioral abnormalities frequently observed in these patients.