Interactions of the mGluR5 gene with breeding and maternal factors on startle and prepulse inhibition in mice

Abstract

Sensorimotor gating, measured by prepulse inhibition (PPI), is a fundamental form of information processing that is deficient in schizophrenia patients and mice lacking the gene for metabotropic glutamate receptor 5 (mGluR5). Both breeding strategies and mothering behaviors are capable of influencing the behavioral phenotype of knockout (KO) mice. Previous studies found a PPI deficit and increased startle magnitudes in mGluR5 KO mice derived from homozygous matings. Here we compared the PPI of mGluR5 wildtype (WT) and KO mice derived from heterozygous matings to that seen in mice derived from homozygous matings. Possible influences of postnatal mothering behaviors were examined using two different methods of cross-fostering. The potential developmental nature of the PPI deficit of the mGluR5 KO mice was also addressed via acute administration of the mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) to C57BL/6J mice. The mGluR5 KO mice exhibited reduced PPI independently of breeding strategy or postnatal mothering behavior. Startle magnitude, however, varied with breeding strategy. The PPI deficit seen in the mGluR5 KO mice is not mimicked by acute administration of an mGluR5 antagonist, and is therefore most likely due to compensatory alterations in neuronal circuitry occurring during development independent of maternal behaviors in the postnatal environment.

Group I metabotropic glutamate receptor antagonists alter select behaviors in a mouse model for fragile X syndrome

“…Given that different PPI protocols seem to confer differential Fmr1 KO responses, this may reflect varying molecular pathways underlying each protocol and therefore may be one reason why we did not observe a similar MPEP normalization of Fmr1 KO PPI behavior using our protocol. While the doses for MPEP used in this study fall within the range used by de Vrij, as well as a number of other groups reporting no effect of MPEP in mice or rats (Brody and Geyer 2004;Henry et al 2002;Hikichi et al 2010;Schulz et al 2001;Spooren et al 2000b;Zou et al 2007), we cannot discount the possibility that higher doses of JNJ might alter PPI responses considering a recent report suggesting that only high JNJ doses (3 and 10 mg/kg) alter PPI responses in mice (Hikichi et al 2010). The PPI phenotype we observe using the whole-body flinch is not only different from that reported in the de Vrij study, but it also does not reflect the same PPI deficit typically reported in FXS individuals (Frankland et al 2004); nevertheless, it represents a robust and consistent phenotype observed in multiple labs.…”

Evaluation of Four Pyridine Analogs to Characterize 6-OHDA-Induced Modulation of mGluR5 Function in Rat Brain Using microPET Studies

“…It has been reported that many neurological disorders such as Parkinson's disease (PD), Schizophrenia, mood disorders, drug addiction, and pain might be affected by the direct or indirect effects of mGluR5s. Metabotropic glutamate subtype-5 receptors have also been tested as potential neuroprotective drugs (Chiamulera et al, 2001;Marino et al, 2003;Sotgiu et al, 2003;Brody and Geyer, 2004).…”

Maternal and Genetic Effects on the Acoustic Startle Reflex and its Sensitization in C3H/HeN, DBA/2JHd and NMRI Mice Following Blastocyst Transfer

“…In another study, postnatal maternal factors influenced the ASR in mGluR5 KO mice derived from homozygous and heterozygous matings, although possible influences of the uterine environment were not studied (Brody and Geyer 2004). Other environmental postnatal factors also alter the amplitude of the ASR in the offspring.…”