Mechanisms of GABAergic Signaling in the Suprachiasmatic Nucleus Network

Project Summary/Abstract
Hypothalamic suprachiasmatic nucleus (SCN) neurons express a cell-autonomous molecular clock that
generates circadian rhythms and regulates physiological rhythms throughout the body. The molecular clock
produces a circadian pattern of neuronal activity that feeds back onto the molecular circadian clock and
strengthens its activity. Intercellular communication between SCN neurons and astrocytes further strengthens
and synchronizes these neuronal rhythms. This integrated SCN network activity is critical for generating
precise circadian timing signals, stabilizing the circadian clock, and determining an animal's behavioral
circadian phenotype. Although small in size, the SCN expresses a diverse population of neurons with unique
functional properties, spatial locations, and efferent projections that regulate different physiological and
behavioral rhythms. SCN neurons expressing vasoactive intestinal peptide (VIP+) or arginine vasopressin
(AVP+) are the most extensively studied. These neurons have distinct SCN locations and unique roles in
photic entrainment, circadian timing maintenance, and different downstream circadian rhythms. The unique
functional properties of the dorsal and ventral SCN regions reflects differences in the number and the coupling
mechanisms and strength of oscillating neurons.
Most SCN neurons utilize GABA as a neurotransmitter, and GABAergic neurotransmission in the SCN is
rhythmic at synaptic and extrasynaptic GABAA receptors and shows significant regional variation. Astrocytes
regulate GABA neurotransmission by releasing transmitters that modify GABA release and expressing GABA
transporters that control the extrasynaptic GABA concentration. Multiple small-molecule transmitters and
neuromodulators regulate GABA neurotransmission, but the cellular mechanisms of this regulation are poorly
understood. GABA refines the action potential firing pattern, a critical component in refining the SCN circadian
clock output. A complete understanding of how the SCN network generates circadian timing signals requires
more detailed knowledge of the signaling pathways that mediate communication between SCN neurons and
astrocytes and a deeper understanding of how these signaling pathways differ in different parts of the SCN.
Our research's long-term goal is to identify the signaling pathways by which neurons and astrocytes
communicate to generate and entrain circadian rhythms. Our short-term goal is to determine the mechanisms
mediating GABA neurotransmission and regulating the coupling strength between individual SCN neuronal
oscillators and SCN regions. The Specific Aims of the application are: 1) Investigate the different roles of
synaptic and tonic GABA receptor-mediated neurotransmission in regulating the activity of SCN. 2) Investigate
the mechanisms regulating GABA transporter activity in astrocytes and whether GABA released from
astrocytes contributes to the tonic GABA current. 3) Examine the role of glutamate released from astrocytes in
regulating GABA synaptic and tonic GABA currents and the activity of AVP+ and VIP+ neurons in the SCN.

Grant Number: 5R01NS103842-08
NIH Institute/Center: NIH
Principal Investigator: Charles Allen