The Functional Significance of the Excitatory Effects of GABA in the Suprachiasmatic Nucleus

Circadian rhythms are found in most all organisms and represent an evolutionary adaptation to environmental cycles resulting from the earth’s rotation. One of the most important functions of a circadian clock is to ensure that biological functions occur at appropriate times of the day. The suprachiasmatic nucleus (SCN) is a circadian clock that controls a host of rhythms such as sleep/wake cycles, hormone release, blood pressure, liver function, and neuronal activity. The SCN synchronizes circadian rhythms with the day-night cycle through a process known as entrainment. Entrainment is the process by which light resets the clock to match the 24-hr day/night cycle. γ-aminobutyric acid (GABA) is found in nearly all SCN neurons and contributes to the entrainment of circadian rhythms to the day-night cycle and plays a critical role in the ability of non-photic cues to reset the clock. GABA is the primary inhibitory neurotransmitter in the brain, but a growing body of literature indicates that GABA also acts as an excitatory neurotransmitter in many brain regions. These excitatory responses to GABA are dependent on chloride ion gradients maintained by chloride cotransporters (CCCs), and especially the chloride influx Na+/K+/Cl- cotransporter (NKCC1). Researchers have observed these excitatory responses to GABA in the SCN for over 20 years, yet surprisingly little work has addressed the functional role of these responses in entrainment or determined if the changes in excitatory GABA signaling throughout the day are due to fluctuations in NKCC1 expression. This dissertation seeks to address the lack of knowledge regarding these excitatory responses to GABA by: (1) characterizing the functional effects of excitatory GABA responses in the resetting of the clock by light; (2) investigating the role of excitatory responses in the resetting effects of non-photic stimuli; (3) determining if light duration alters NKCC1 protein; and (4) determining if the levels of NKCC1 occur in a circadian and/or daily rhythm in the SCN. These experiments together provide evidence of a functional role for GABA excitation in entrainment of the SCN and also contribute to our understanding of CNS GABA signaling mechanisms, in general