Diversity of GABAergic inhibitory synapses in health and disease
GABAergic inhibitory circuits and synapses play a central role in shaping the flow of information through neuronal networks and hence the behavioral output of the brain. Not surprisingly, therefore, alterations in GABAergic synaptic transmission have been observed in a wide range of psychiatric and neurodevelopmental disorders, including anxiety disorders, autism spectrum disorders, schizophrenia, epilepsy, and others. Accordingly, therapeutic strategies targeting the GABAergic system hold great promise, and indeed, numerous pharmacological modulators of GABA receptor function are already in clinical use for the treatment of these disorders.
A key limiting aspect of most existing pharmacotherapies, however, is their lack of specifity for those GABA receptors that mediate the pathophysiologically relevant behaviours. GABA receptors are are present throughout the central nervous system, and most available drugs modulate GABA receptor function in both disease-related and disease-unrelated neural circuits, often resulting in debilitating side effects that pose significant challenges for their chronic use. To overcome these challenges, an essential step will be to identify strategies to selectively target GABA receptores in defined, pathophysiologically relevant neural circuits.
In our laboratory we aim to address this issue by investigating the diversity of GABAergic inhibitory synapses in health and disease. The GABAergic system consists of a large number of different neuronal subtypes, each of which plays a distinct role in orchestrating and finetuning information flow through the brain. Recent evidence indicates that the molecular machinery that mediates GABAergic synaptic transmission may differ both between brain regions and between GABAergic neuronal subtypes within a brain region, offering a potentially unique opportunity for circuit- and synapse-specific therapeutic interventions. To date, however, little is known about the specific molecular and functional composition of GABAergic synapses in the neural circuits of interest. By combining molecular and functional studies of GABAAR-containing postsynaptic protein complexes with analysis of the GABAergic circuits underlying psychiatrically relevant behaviors in mouse models, we aim to identify circuit-specific intervention strategies based on the diversity of GABAergic postsynaptic complexes. Our particular focus lies on GABAergic synapses in the amygdala, hippocampus and prefrontal cortex and their involvement in anxiety, fear and social behaviours.