The clock gene Period2 influences the glutamatergic system and thereby modulates alcohol consumption

NM A22834 (Albrecht) 2 Period (Per) genes are involved in the regulation of the circadian clock and are thought to modulate several brain functions. We show that Per2 Brdm1 mutant mice display alterations in the glutamatergic system. Lowered expression of the glutamate transporter Eaat1 is observed in these animals, leading to reduced uptake of glutamate by astrocytes. As a consequence, glutamate levels increase in the extra-cellular space of Per2 Brdm1 mutant mouse brains. This is accompanied by increased alcohol intake in these animals. In humans, variations of the PER2 gene are associated with the regulation of alcohol consumption. Acamprosate, a medication used in the prevention of craving and relapse in alcoholic patients is thought to act by dampening a hyper-glutamatergic state. This drug reduced augmented glutamate levels and normalized the drinking behavior in Per2 Brdm1 mutant mice. Collectively, these data establish glutamate as a link between the dysfunction of the circadian clock gene Per2 and enhanced alcohol consumption. 3 Across a spectrum of living organisms, ranging from cyanobacteria to humans, it has been observed that biological functions follow a pattern of circadian rhythmicity. These endogenous rhythms display a periodicity close to 24 hours in the absence of environmental cues, thus reflecting the existence of an intrinsic biological clock. In mammals, circadian rhythms in different tissues are coordinated by a master clock located in the suprachiasmatic nucleus (SCN) of the anterior hypothalamus 1. This circadian clock is thought to be advantageous in synchronising physiological and biochemical pathways, allowing the organism to anticipate daily changes, thus ensuring better adaptation to the environment 2. The oscillatory mechanism of the circadian clock has been unraveled by means of genetic analysis in Drosophila and mammals 3-5. In the latter, the heterodimeric complex of two transcriptional activators, CLOCK and BMAL1 (MOP3), induce the expression of several genes by interacting with the enhancer elements, termed E-boxes, of their promoters. Amongst these genes are Per1, Per2, Cry1 and Cry2, whose protein products, upon entering the nucleus, inhibit the activity of the CLOCK/BMAL1 complex, and thereby generating an inhibitory feedback loop driving recurrent rhythms in mRNA and protein levels of their own genes. This molecular mechanism seems to be present in the local clocks of most tissues and brain regions. Furthermore, these different clocks may then be synchronized by the SCN via neural and endocrine outputs 6. Several lines of evidence implicate glutamate in the activation of receptors on …