Inhibitory synapses in neuropsychiatric disorders

Understanding the molecular and cellular basis of neuropsychiatric disorders is essential for the development of new therapeutic strategies in psychiatry. In recent years, the notion that many psychiatric disorders may be ‘synaptopathies’, or diseases of the synapse, has gained substantial interest, largely due to the identification of a number of mutations in synaptic proteins in individuals with autism, schizophrenia and other disorders. The vast majority of studies to date have focused on the role of excitatory synapses in this context, but it is becoming increasingly clear that alterations in inhibitory synapse function may be equally important. In support of this notion, several mutations in the proteins that compose the postsynaptic scaffold at inhibitory synapses have been recently linked to psychiatric disorders (see Krueger-Burg et al. 2017 for a review).

We study the mechanisms by which these mutations alter the function of inhibitory synapses and circuits to induce abnormal behaviors. Our work focuses on understanding the synaptic and behavioral consequences of mutations in the cell adhesion proteins Neuroligin 2, Neuroligin 4 and IgSF9b, all of which have been linked to autism and/or schizophrenia. Using a wide range of techniques, including mouse behavior, immunohistochemistry, whole-brain immediate early gene imaging, viral vector-mediated local manipulation of molecules and circuits, neuronal tracing, and (together with our collaboration partners) in vitro and in vivo electrophysiology, we investigate how deletion of these proteins in mice affects inhibitory synapses in the amygdala circuitry and alters anxiety and social behaviors. Our ultimate aim is to identify new molecular or cellular circuit-specific targets for the development of novel treatment approaches in psychiatry.

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