Role of Gi/o-Protein Inhibition of CaV2.2 Channels in Anxiety Behavior

University Of New Hampshire, Durham NH

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Abstract

This project is the ROO phase of a K99/ROO Award to be conducted in the Department of Biological Sciences at the College of Life Sciences and Agriculture at the University of New Hampshire. Here the main goal for the next 3 years is to study the role of presynaptic voltage-gated calcium channels (CaV2.2) in regulating neurotransmission in amygdala. Dysfunction of amygdala is linked to anxiety disorders . Various anxiolytics modulate the amygdala by activating Gi/o protein coupled receptors, including cannabinoid receptors CB1. Presynaptic CaV2.2 channels are major targets of CB1. Inhibition of CaV2.2 channels by CB1 is well documented in excitatory and inhibitory synapses of hippocampus. But very little is known in synapses of the amygdala. The excitability of projection-like neurons (P-cells) in the basolateral amygdala (BLA) directly correlates with anxiety-like behavior. BLA receives glutamatergic inputs from brain areas including cortex, and inhibitory inputs from local interneurons. Endocannabinoids activate CB1 to inhibit transmitter release at excitatory and inhibitory inputs of P-cells. Recent evidence shows that anxiogenic stimuli disrupt endocannabinoid metabolism and CB1 activity. However, less is known regarding the effects of anxiogenic stimuli on CB 1 signaling effectors, like presynaptic CaV2.2 channels. In this project, I hypothesize that during anxiety states, CB1 inhibition of CaV2.2-dependent transmitter release is altered in glutamatergic and GABAergic synapses of the BLA. To test this hypothesis, I will combine synaptic electrophysiology , optogenetics, and behavior. I propose the following specific aims: a) To determine if CB1 inhibition of CaV2.2-dependent glutamatergic release is reduced in the BLA during anxiety states. I hypothesize that anxiogenic stimuli impair CB1 inhibition of CaV2.2 channels in cortico-BLA synapses, thereby allowing glutamate transmitter release and enhancing excitability of P-cells. b) To determine if CB1 inhibition of CaV2.2-dependent GABAergic release in the BLA is elevated during anxiety states. I hypothesize that, during anxiety states, CB1 inhibition of CaV2.2 channels is enhanced in GABAergic inputs of P-cells, reducing GABAergic tone and enhancing excitability of the BLA.