Modelling the functional roles of synaptic and extra-synaptic γ-aminobutyric acid receptor dynamics in circadian timekeeping

In the suprachiasmatic nucleus (SCN), gamma-aminobutyric acid (GABA) is a primary neurotransmitter. GABA can signal through two types of GABA(A) receptor subunits, often referred to as synaptic GABA(A) (gamma subunit) and extra-synaptic GABA(A) (delta subunit). To test the functional roles of these distinct GABA(A) in regulating circadian rhythms, we developed a multicellular SCN model where we could separately compare the effects of manipulating GABA neurotransmitter or receptor dynamics. Our model predicted that blocking GABA signalling modestly increased synchrony among circadian cells, consistent with published SCN pharmacology. Conversely, the model predicted that lowering GABA(A) receptor density reduced firing rate, circadian cell fraction, amplitude and synchrony among individual neurons. When we tested these predictions, we found that the knockdown of delta GABA(A) reduced the amplitude and synchrony of clock gene expression among cells in SCN explants. The model further predicted that increasing gamma GABA(A) densities could enhance synchrony, as opposed to increasing delta GABA(A) densities. Overall, our model reveals how blocking GABA(A) receptors can modestly increase synchrony, while increasing the relative density of gamma over delta subunits can dramatically increase synchrony. We hypothesize that increased gamma GABA(A) density in the winter could underlie the tighter phase relationships among SCN cells.

Automated summary

In the SCN, different types of GABA(A) receptors have been found to regulate circadian rhythms, with blocking GABA signaling modestly increasing synchrony and increasing the relative density of gamma over delta subunits significantly increasing synchrony.