Forebrain gene expression predicts deficits in sensorimotor gating after isolation rearing in male rats

Abstract

Compared to socially housed (SH) rats, adult isolation-reared (IR) rats exhibit phenotypes relevant to schizophrenia (SZ), including reduced prepulse inhibition (PPI) of startle. PPI is normally regulated by the medial prefrontal cortex (mPFC) and nucleus accumbens (NAC). We assessed PPI, auditory-evoked local field potentials (LFPs) and expression of 7 PPI- and SZ-related genes in the mPFC and NAC, in IR and SH rats. Buffalo (BUF) rats were raised in same-sex groups of 2–3 (SH) or in isolation (IR). PPI was measured early (d53) and later in adulthood (d74); LFPs were measured approximately on d66. Brains were processed for RT-PCR measures of mPFC and NAC expression of Comt, Erbb4, Grid2, Ncam1, Slc1a2, Nrg1 and Reln. Male IR rats exhibited PPI deficits, most pronounced at d53; male and female IR rats had significantly elevated startle magnitude on both test days. Gene expression levels were not significantly altered by IR. PPI levels (d53) were positively correlated with mPFC expression of several genes, and negatively correlated with NAC expression of several genes, in male IR but not SH rats. Late (P90) LFP amplitudes correlated significantly with expression levels of 6/7 mPFC genes in male rats, independent of rearing. After IR that disrupts early adult PPI in male BUF rats, expression levels of PPI- and SZ-associated genes in the mPFC correlate positively with PPI, and levels in the NAC correlate negatively with PPI. These results support the model that specific gene-behavior relationships moderate the impact of early-life experience on SZ-linked behavioral and neurophysiological markers.

Analysis of LINE-1 Elements in DNA from Postmortem Brains of Individuals with Schizophrenia

“…Novel L1 insertions in GRID2 and KHDRBS2 were also confirmed (Figure 1b and c). GRID2 expression is associated with pre-pulse inhibition of the acoustic startle response, an endophenotype for SZ (Swerdlow et al, 2013). A novel L1 in the serotonin 2C receptor gene HTR2C was also confirmed (data not shown; Supplementary File S3).…”

Sex differences in animal models of schizophrenia shed light on the underlying pathophysiology

“…Additional studies by this group chose to only focus on female isolated rats, based on this apparent female bias in PPI disruption (Harte et al 2004;Harte et al 2007). However, more recent studies by Powell et al describe male specific deficits in PPI in isolation reared Buffalo rats at postnatal day 53, which correlated with gene expression of COMT, Grid2, Slcla2 and Nrg1 M a n u s c r i p t 16 positively in the medial prefrontal cortex and negatively in the nucleus accumbens (n = 13-22) (Swerdlow et al 2013). …”

“…No sex diff. (Ko et al 2015) Male-specific anxiolytic phenotype (Powell et al 2002;Guo et al 2004) Male-specific alterations in COMT, Grid2, Slcla2 and Nrg1 gene expression in the MPFC and nucleus accumbens (Swerdlow et al 2013). …”

Comparison of the Heritability of Schizophrenia and Endophenotypes in the COGS-1 Family Study

“…Many endophenotypes are even amenable to translational animal model studies for revealing neurobiological substrates associated with diseases. [37][38][39][40] In the COGS-1 sample, the heritability estimates for SZ are equivalent to the mean heritability estimate for the 12 endophenotypes of 30% (range: 18%-50%) with 7 of the COGS-1 endophenotypes exhibiting higher heritability estimates than the diagnosis of SZ in the nuclear families.…”