Homeostatic Maintenance of Neocortical Excitation-inhibition Balance by Ciliary Neuropeptidergic Signaling

2022 Scientific Innovations Award
Gina Turrigiano, Ph.D.
Brandeis University

Brain circuit wiring is adjusted during adolescence to generate fully functional circuits, and this process depends on an interaction between genetics and experience. During this period of experience-dependent development, excitatory and inhibitory synapses must be carefully balanced so that circuits do not become either too excitable or not excitable enough, but the mechanisms that allow excitation and inhibition within brain circuits to be dynamically adjusted are poorly understood. Here we will examine the role of a small subcellular organelle, the primary neuronal cilium, in this process. Cilia concentrate a number of neurotransmitter and neuropeptide receptors, and couple these receptors to signaling pathways that we recently found are able to adjust excitatory synapse formation. In this proposal we aim to test the hypothesize that release of the neuropeptide somatostatin from inhibitory neurons acts as a network-wide signal of circuit excitability, that then activates somatostatin receptors within cilia to adjust excitatory synapse number. This would act as a novel form of network-wide homeostatic compensation that would adjust excitatory synaptic drive to keep network activity stable. These experiments will have relevance for a wide range of neurological disorders characterized by imbalances in network activity (e.g.. autism-spectrum disorders, epilepsies), as well as human ciliopathies that lead to intellectual disability.

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