Role of histone deacetylases in the development of GABAergic interneuron connectivity and function

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GABAergic neurons form an important subset of the neuronal population in the brain, which powerfully control the dynamics of brain circuits. In addition, they strongly regulate brain development by modulating several processes including experience-dependent neuronal wiring. The complexity of brain circuitry and the non-homogeneity of the GABAergic cell population has so far made the study of how these neurons develop and form synaptic connections very difficult. We have recently developed techniques to label and manipulate parvalbumin positive GABAergic cells (PV cells), which constitute the most numerous types of cortical GABAergic neurons. PV cells form dense axonal arborisations that innervate hundreds of target neurons, each with multiple, clustered synapses onto their soma and proximal dendrites. Such precise subcellular location of PV cell synapses, in conjunction with their striking ability to fire sustained trains of brief action potentials at remarkably high frequency, allows them to powerfully control the output of their target cells and influence large network activities in the brain. My long-term goal is to understand the mechanisms underlying the formation of cortical PV cell connectivity and how they modulate experience-dependent cortical plasticity in the young and adult brain. Molecular mechanisms involved in synapse formation and strengthening include the activation and repression of specific genes by stable epigenetic modifications. Chromatin remodeling, especially through histone-tail acetylation, which alters the compact chromatin structure and changes the accessibility of DNA to regulatory proteins, is emerging as a fundamental mechanism for regulating gene expression. In particular, Histones Deacetylase 2 (HDAC2) has been shown to regulate excitatory synapse formation and plasticity. Interestingly, HDAC2 binding to chromatic is strongly regulated by the brain-derived neurotrophic factor BDNF, which is one of the most powerful factors promoting PV cell synapse formation. Here, we propose to use a unique combination of single-cell genetics, conditional knockout mice, high-resolution imaging, mouse behavioural testing, ex vivo and in vivo electrophysiology to investigate the role of HDAC2 in PV cell circuit development. Our working hypothesis is that HDAC2 is a critical molecular determinant of the postnatal development of PV cell circuits and that, in its absence, PV cell connectivity and function remain immature. The proposed experiments will shed light on the epigenetic mechanisms controlling the development of cortical PV cell connectivity and, in turn, developmental plasticity. The multidisciplinary core of the proposed approaches and the use of in vitro and in vivo experimental models will provide excellent training opportunities for HQPs at both the graduate and undergraduate levels.