GABA signaling across seconds, days, and seasons

GABA is the only signal sent and received by all cells in the suprachiasmatic nucleus (SCN), the site of the central circadian pacemaker. We discovered separate and simultaneous mechanisms by which GABA in the SCN times fast electrical signals in cells, daily rhythms in the body and the time of year.

HFSP Program Grant holders Daniel Forger, Hugh Piggins and Toru Takumi
authored on Mon, 14 September 2015

To study the role of GABA in the SCN, we coupled a molecular model of daily timekeeping with models of GABA signaling. We then used computing on graphics processing units to simulate the billions of GABA induced events that occur each day.  This was one of the most detailed simulations of a brain region ever conducted. Our experimental collaborators validated predictions about GABA’s polarity, effect on electrical firing and their heterogeneity throughout the network.

We find that fast GABA post-synaptic currents have little effect on circadian timekeeping. However, neurons within the network can show novel electrical states, which cause a low level tonic GABA signal. Excitatory tonic GABA signaling causes cells to synchronize whereas inhibitory tonic GABA signaling desynchronizes cells. This shows that two GABA signals are being simultaneously sent.

Figure: The season is encoded in the SCN through the balance between synchronization and desynchronization mediated by GABA.

We used these findings to study seasonal affective disorder (SAD), an important global challenge where depression is triggered upon the changing of seasons. Seasonal change is measured by the change in photoperiod (the number of hours of sunlight during the day). These changes are encoded by the SCN, which then triggers other parts of the body to adapt to seasonal changes. Seasonal changes are encoded by the phase difference between the dorsal and ventral SCN. The mechanism of this change has remained elusive.

We found the mechanism of seasonal encoding resides in the distribution of intracellular chloride in the SCN, which changes through the seasons. Long days, mimicking summer, cause dorsal-specific increase of chloride in the SCN, which is nullified by furosemide (Furo), a drug that blocks chloride importers on SCN cells. We verified that the increasing phase difference between the dorsal and ventral SCN was recapitulated in SCN brain slices and the chloride importer blocker could narrow the phase difference, as in the SCN entrained in the short days. The physiological consequence of the uneven chloride distribution was difficult to trace. However, using detailed mathematical modeling, we were able to explain these perplexing results. Additionally, we showed that under normal conditions, the ventral SCN sends a synchronizing signal that reflects the light-dark cycle. However, when the days become long in summer, this signal is insufficient to properly time the SCN. Thus, excitatory GABA in the dorsal SCN creates a signal independent of the ventral SCN, which actually mitigates the ventral signal by desynchronizing the cells in the ventral SCN. We could recapitulate these dynamics through balancing of synchronizing and desynchronizing forces, which leaves the SCN in a metastable state (see figure). This dynamic reprogramming of the SCN shows a richness of computation in the SCN not previously recognized.

References

[1] Distinct roles for GABA across multiple timescales in mammalian circadian timekeeping. DeWoskin D, Myung J, Belle MD, Piggins HD, Takumi T and Forger DB. 
PNAS 112 (2015) E3911-9.

[2] GABA-mediated repulsive coupling between circadian clock neurons encodes seasonal time. Myung J, Hong S, DeWoskin D, De Schutter E, Forger DB and Takumi T.
PNAS 112 (2015) E3920-9.

Pubmed link ref 1

Pubmed link ref 2

Write-up in Science Signaling