GABA Networks Destabilize Genetic Oscillations in the Circadian Pacemaker

•Functional GABA connectivity is sparse in synchronized networks of circadian neurons•Strength of millisecond-level synaptic interactions varies with time of day•Endogenous GABA signaling opposes synchrony in circadian neurons•Between sample analysis of connectivity reliably reveals functional connections

SummarySystems of coupled oscillators abound in nature. How they establish stable phase relationships under diverse conditions is fundamentally important. The mammalian suprachiasmatic nucleus (SCN) is a self-sustained, synchronized network of circadian oscillators that coordinates daily rhythms in physiology and behavior. To elucidate the underlying topology and signaling mechanisms that modulate circadian synchrony, we discriminated the firing of hundreds of SCN neurons continuously over days. Using an analysis method to identify functional interactions between neurons based on changes in their firing, we characterized a GABAergic network comprised of fast, excitatory, and inhibitory connections that is both stable over days and changes in strength with time of day. By monitoring PERIOD2 protein expression, we provide the first evidence that these millisecond-level interactions actively oppose circadian synchrony and inject jitter into daily rhythms. These results provide a mechanism by which circadian oscillators can tune their phase relationships under different environmental conditions.