Mutant mouse models implicate a role for mGluR1/5, prolyl isomerase (Pin1) and Homer1a interactions in wakefulness

Brendan T. Keenan¹Ewa Strus¹Raozhou Lin²May Chan¹Jie Lian¹Raymond Galante¹Paul Worley²Allan Pack¹Nirinjini Naidoo^1*

• ¹University of Pennsylvania, Philadelphia, Pennsylvania, United States
• ²Johns Hopkins University, Baltimore, Maryland, United States

Healthy sleep and wake are integral to good health and occur when an organism is able to maintain long bouts of both sleep and wakefulness. Homer proteins, which function as adaptors for group I metabotropic glutamate receptors, have been shown to be important for sleep in both Drosophila and mice. For example, genetic deletion of Homer1a in mice results in failure to sustain long bouts of wakefulness. Homer1a, which is upregulated by neural activity and prolonged waking/sleep loss, has been shown to amplify mGluR activity by facilitating binding of the prolyl isomerase Pin1 to mGluR. This study evaluates the hypothesis that the Homer1a null sleep phenotype may be dependent on the mGluR-Pin1 interaction and examines sleep/wake behavior in mGluR(TS-AA) knock-in mice that have the Pin1 binding site altered. Knock-in mGluR(TS-AA) mice display a reduced ability to sustain long bouts of wakefulness during the active lights off period, recapitulating part of the previously observed wake phenotype of the Homer1a knock-out mouse. Alteration of the Homer binding site to mGluR in mGluR(F-R) knock-in mice has no effect on the sleep phenotype, whereas crossing the mGluR(F-R) knock-in into the Homer null background resulted in increased duration of long wake bouts. These studies highlight the role of Pin1 binding to mGluR as a potential mechanism in the control of sleep/wake behavior.