Do transmembrane domain neuregulin 1 mutant mice exhibit a reliable sensorimotor gating deficit?

Evidence suggests that the heterozygous transmembrane domain mutant mouse model for the schizophrenia candidate gene neuregulin 1 (Nrg1 HET) exhibits a deficit in prepulse inhibition (PPI). However, not all mouse models for Nrg1 exhibit PPI deficits. Thus, our study intended to clarify the severity of the initially described PPI deficit in Nrg1 HET mice. For this, Nrg1 mutant mice and wild type-like littermates of one breeding colony were tested for PPI in four different phenotyping facilities in Australia employing a variety of different PPI protocols with fixed and variable interstimulus intervals (ISIs). Testing mutant and wild type-like mice in three Australian phenotyping facilities using PPI protocols with variable ISIs revealed no effect of mutant transmembrane domain Nrg1 on sensorimotor gating. Changes to the startle response and startle response habituation were site/protocol-specific. The employment of two different PPI protocols at the same phenotyping facility revealed a protocol-dependent and site-specific facilitation of PPI in Nrg1 mutant mice compared to wild type-like mice. In conclusion, the often-noted PPI phenotype of the transmembrane domain Nrg1 mutant mouse model is highly PPI protocol-specific and appears sensitive to the particular conditions of the test laboratory. Our study describes wild type-like PPI under most test conditions and across three different laboratories. The research suggests that analysing one of the alleged hallmarks of animal models for schizophrenia must be done carefully: to obtain reliable PPI data it seems necessary to use more than one particular PPI protocol.

Acoustic startle response and sensorimotor gating in a genetic mouse model for the Y1 receptor.

Recent research has highlighted a potential role for neuropeptide Y (NPY) and its Y(1) receptor in the development of schizophrenia. Genetic as well as molecular biological studies have demonstrated reduced levels of NPY in schizophrenia patients. Importantly, Y(1) receptors may mediate some of the potential effects of NPY on schizophrenia, as decreased Y(1) receptor expression has been found in the lymphocytes of schizophrenia patients. To clarify NPY's role in schizophrenia, we investigated a genetic animal model for Y(1) deficiency in regard to (i) acoustic startle response (ASR), (ii) habituation to ASR and (iii) sensorimotor gating [i.e. prepulse inhibition (PPI)] using two different PPI protocols. Mutant and wild type-like mice were screened for baseline behaviours and after pharmacological challenge with the psychotropic drugs dexamphetamine (DEX) and MK-801. Y(1) knockout mice (Y(1)(-/-)) showed a moderate reduction of the ASR and an impaired ASR habituation at baseline and after DEX treatment. The baseline PPI performance of Y(1) mutant mice was unaltered their response to DEX and MK-801 challenge was moderately different compared to control mice, which was dependent on the PPI protocol used. MK-801 challenge had a protocol-dependent differential effect in Y(1)(-/-) mice and DEX a more pronounced impact at the highest prepulse intensities. In conclusion, it appears that the Y(1) receptor influences the acoustic startle response and its habituation but does not play a major role in sensorimotor gating. Further explorations into the effects of Y(1) deficiency seem valid.