Regulation of light's action in the mammalian circadian clock: role of the extrasynaptic GABAA receptor

Abstract

GABAA receptor agonists act in the suprachiasmatic nucleus (SCN) to reset circadian rhythms during the day but inhibit the ability of light to reset rhythms during the night. In the present study, we examined whether these paradoxical differences in the effect of GABAA receptor stimulation on the circadian system are mediated by separate GABAA receptor subtypes. 4,5,6,7-Tetrahydroisoxazolo[5,4- c]pyridin-3-ol (THIP), a GABAA receptor agonist, preferentially activates GABAA receptors in extrasynaptic locations. THIP, muscimol (a GABAA agonist), or vehicle were microinjected into the SCN region of Syrian hamsters free-running in constant darkness during the mid-subjective day, early subjective night, or late subjective night. The subjective night injections were followed by a light pulse or sham control. Behavioral phase shifts of wheel running rhythms and both Period1 ( Per1) and Per2 mRNA levels in the SCN were assessed. Animals that received THIP during the subjective day did not exhibit significant phase alterations. During the early and late subjective night, however, THIP abolished the phase-shifting effects of light and the ability of light to increase Per1 and Per2 mRNA levels. The ability of N-methyl-d-aspartic acid to phase-shift wheel running rhythms was also attenuated by THIP. Together these data demonstrate that THIP does not produce phase shifts during the subjective day, but does inhibit the ability of light to produce phase shifts. Thus, extrasynaptic GABAA receptors appear to play a role in regulating light input to the SCN, while a different population of GABAA receptors appears to be responsible for daytime effects of GABA.