The role of glutamate in the photic regulation of the suprachiasmatic nucleus

Endogenous circadian rhythms govern most aspects of physiology and behaviour in mammals, including body temperature, autonomic and endocrine function, and sleep-wake cycles. Such rhythms are generated by the suprachiasmatic nucleus of the hypothalamus (SCN), but are synchronised to the environmental light-dark cycle by photic cues perceived by the retina and conveyed to the SCN via the retinohypothalamic tract (RHT). This review considers many lines of evidence from diverse experimental approaches indicating that the RHT employs glutamate (or a related excitatory amino acid) as a neurotransmitter. Ultrastructural studies demonstrate the presence of glutamate in presynaptic terminals within the SCN. In situ hybridisation and immunocytochemical studies reveal the presence of several NMDA (NMDAR1, NMDAR2C), non-NMDA (GluR1, GluR2, GluR4) and metabotropic (mGluR1) glutamate receptor subunits in the SCN. Messenger RNA encoding a glutamate transporter protein is also present. In behavioural tests, glutamate antagonists can block the effects of light in phase-shifting circadian rhythms. Such treatments also block the induction of c-fos within SCN cells by light, whereas a glutamate agonist (NMDA) induces c-fos expression. In hypothalamic slice preparations in vitro, electrical stimulation of the optic nerves induces release of glutamate and aspartate, and glutamate antagonists block field potentials in the SCN evoked by stimulation of the optic nerve. Circadian rhythms of electrical activity which persist in vitro are phase shifted by application of glutamate in a manner which mimics the phase shifting effects of light in vivo. This wide range of experimental findings provides strong support for the hypothesis that glutamate is the principal neurotransmitter within the RHT, and thus conveys photic cues to the circadian timing system in the SCN.