Role of the Group I metabotropic glutamate receptors in prepulse inhibition of the startle response.

摘要

This dissertation describes experiments assessing the influences of Group I metabotropic glutamate receptors (mGluRs) and the N-methyl-D-aspartate (NMDA) NR3A subunit on the modulation of prepulse inhibition (PPI) of the startle response in rodents. Sensorimotor gating, measured by PPI, is a fundamental form of information processing that is deficient in patients with schizophrenia and a subset of other psychiatric disorders. As such, PPI is widely used to study the neurobiology of schizophrenia and identify antipsychotic drugs in animals.; The studies presented herein demonstrate that both mGluR5 and mGluR1 KO mice exhibit PPI deficits but that NR3A KO mice do not. The PPI deficit of mGluR5 KO mice is not modality-specific nor is it due to an alteration in either startle threshold or startle magnitude. In fact, the PPI deficit of mGluR5 KO mice is dissociable from startle magnitude, and occurs at a range of interstimulus intervals. The PPI deficit of mGluR5 KO mice is present regardless of the background strain of the mouse, and is not altered by either breeding strategy or postnatal mothering behaviors. Acute administration of typical, atypical, and putative antipsychotics as well as mood stabilizers fail to alleviate the PPI deficit of mGluR5 KO mice despite their efficacy against other PPI deficits. Administration of an mGluR5 antagonist fails to mimic the PPI deficit of mGluR5 KO mice but does exacerbate a phencyclidine (PCP)---induced PPI deficit. Similarly, the PPI deficit of mGluR1 KO mice is present as early as 6 weeks postnatal, is not affected by repeated testing, and is not alleviated by a typical antipsychotic. The PPI deficit of mGluR1 KO mice is, however, partially ameliorated by administration of the mood stabilizer lamotrigine. In contrast to the Group I mGluR KO mice, NR3A KO mice exhibit an increase in PPI. This PPI increase is present only in the male KO mice at 4 weeks postnatal. Neither the female NR3A KO mice nor the transgenic mice over-expressing NR3A in adulthood exhibit alterations in PPI. Thus, we conclude that all three of the glutamate receptors examined here are involved in the modulation of PPI.