Elsevier

Schizophrenia Research

Volume 198, August 2018, Pages 68-83
Schizophrenia Research

Sensorimotor gating deficits in “two-hit” models of schizophrenia risk factors

https://doi.org/10.1016/j.schres.2017.10.009Get rights and content

Abstract

Genetic and environmental models of neuropsychiatric disease have grown exponentially over the last 20 years. One measure that is often used to evaluate the translational relevance of these models to human neuropsychiatric disease is prepulse inhibition of startle (PPI), an operational measure of sensorimotor gating. Deficient PPI characterizes several neuropsychiatric disorders but has been most extensively studied in schizophrenia. It has become a useful tool in translational neuropharmacological and molecular genetics studies because it can be measured across species using almost the same experimental parameters. Although initial studies of PPI in rodents were pharmacological because of the robust predictive validity of PPI for antipsychotic efficacy, more recently, PPI has become standard common behavioral measures used in genetic and neurodevelopmental models of schizophrenia. Here we review “two hit” models of schizophrenia and discuss the utility of PPI as a tool in phenotyping these models of relevant risk factors. In the review, we consider approaches to rodent models of genetic and neurodevelopmental risk factors and selectively review “two hit” models of gene × environment and environment × environment interactions in which PPI has been measured.

Section snippets

Introduction: utility of prepulse inhibition in models relevant to schizophrenia

Sensorimotor gating occurs when a motor responses is gated by a sensory event. One form of sensorimotor gating that has been studied at multiple levels of biology, from its cellular mechanisms (Frost et al., 2003, Nusbaum and Contreras, 2004, Rose and Scott, 2003) to its relationship to neuropsychiatric disease (Braff, 2010, Braff, 2011, Swerdlow et al., 2008), is prepulse inhibition (PPI) of startle. PPI occurs when a weak, subthreshold stimulus presented 30–500 ms prior to an intense startling

Approaches to genetic discoveries

The two primary approaches to understanding the genetics of neuropsychiatric disease are the common disease/common allele approach (CDCA) and the common disease/rare allele approach (CDRA) (Arguello and Gogos, 2011). Candidate gene or unbiased genome-wide association studies (GWAS) focus on common genetic variants (> 5% allele frequency); whereas, the CDRA approach focuses on the hypothesis that rare variants with high penetrance can cause common disease (Arguello and Gogos, 2011). Schizophrenia

Neurodevelopmental risk factors

There is increasing evidence that schizophrenia has its roots in disrupted brain development due to both genetic and environmental risk factors, leading to psychosis emergence in adolescence and early adulthood (Cannon et al., 2003, Murray et al., 2002, Rapoport et al., 2012). Environmental risk factors are evident throughout development and include prenatal and perinatal risk factors, psychological risk factors in early life and adolescence, and exposure to drugs of abuse or trauma in

“Two hit” models of risk factors of schizophrenia

As reviewed above, early developmental factors are implicated in the pathogenesis of schizophrenia (Davis et al., 2016), and recent GWAS have identified multiple common schizophrenia risk alleles contributing small effect to disease risk (Owen et al., 2016). In addition to common variants with small effects, there is also evidence for the involvement of several large CNVs in schizophrenia (Ross et al., 2006). Additionally, there are several non-genetic second-hits (substance abuse (McKetin et

Discussion

Here we summarize schizophrenia risk factors, neurodevelopmental animal models, and the current findings from two hit models of these risk factors published in recent years. As reviewed above, we focused on PPI because of its strong relationship with schizophrenia, its heritability, and its sensitivity to developmental risk factors. Taken together, the studies suggest that some gene and environment combinations result in more pronounced PPI deficits than either manipulation alone. For example,

Conflict of interest statement

There are no financial/personal interests or beliefs that could affect the objectivity of the authors.

Contributors

Asma Khan and Susan Powell both wrote the manuscript.

Author agreement/declaration

I certify that all authors (Asma Khan and myself, Susan Powell) have seen and approved the final version of the manuscript being submitted. I warrant that this article is our (the authors') original work, hasn't received prior publication and isn't under consideration for publication elsewhere.

Funding source declaration

NIH grant ES025585 and Veteran's Affairs VISN 22 MIRECC supported the authors during the writing of this manuscript.

Acknowledgements

We thank Drs. Victoria Risbrough, Xianjin Zhou, and Tiffany Greenwood for helpful discussions and comments. This work was supported by ES025585 and by the Veterans Affairs VISN 22 Mental Illness Research, Education, and Clinical Center.

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