Phenotypic effects of maternal immune activation and early postnatal milieu in mice mutant for the schizophrenia risk gene neuregulin-1

Neuregulin-1 and schizophrenia in the genome-wide association study era

“…This distant eQTL association between a NRG1 SNP and immune markers aligns with a clinical study in Finland reporting an interaction between a NRG1 SNP (SNP8NRG221533) and a SNP (rs16944) within the interleukin 1 beta gene, a pro-inflammatory cytokine (Hanninen et al 2008) as well as a preclinical study that showed developmental stage-specific deficits in phentoypes related to schizophrenia (i.e. social behavior, spatial working memory, PPI) among TM Nrg1 mice exposed to maternal immune activation (O'Leary et al 2014). These clinical and preclinical findings are particularly relevant given evidence of an increase in pro-inflammatory cytokines in schizophrenia (Muller et al 2015) and is further supported by reports that NRG1 influences cell adhesion of immune cells (Kanakry et al 2007) and decreases the release of free radicals from microglial cells (Dimayuga et al 2003).…”

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

“…Vorhees et al also found male specific deficits in fear-potentiated memory (cue conditioned freezing) in the offspring of poly-I:C exposed rats, but only following a repeated dosing regimen of poly-I:C injections from gestational day 14-18, while a single injection at day 14 had no such effect on the offspring (Vorhees et al 2012;Vorhees et al 2015). However, spatial memory, as assessed using a spontaneous alternation paradigm in the Y-maze, was specifically disrupted in female mouse offspring exposed to poly-I:C (5mk/kg i.p., GD9, n=5-8/group) (O'Leary et al 2014). Once again, there are discrepancies in the literature, however, with others reporting no sex differences in the effect of prenatal poly-I:C exposure (5mg/kg intravenous (i.v.…”

“…O'Leary et al showed male specific effects of poly-I:C exposure on sensorimotor gating at adulthood, as measured using the pre-pulse inhibition (PPI) paradigm, with males mice exposed to poly-I:C (5mg/kg i.p., GD9) showing greater PPI disruption (O'Leary et al 2014).…”

“…PPI impaired in male mice when exposed at GD 9 (O'Leary et al 2014) PPI impaired in female rats when exposed at GD 14 (Vorhees et al 2012) Male specific deficit in cue-conditioned memory of fear (Vorhees et al 2012). …”

Converging models of schizophrenia – Network alterations of prefrontal cortex underlying cognitive impairments

“…When the NMDA receptor was specifically disrupted in PV-positive interneurons, local circuitry formation was perturbed, leading to changes in gamma oscillation and behavior (Carlen et al, 2012). In addition, many paradigms that test G x E have been applied to animal models (e.g., Ibi et al, 2010; Kannan and Pletnikov, 2012; Moreno et al, 2011; O’Leary et al, 2014). Analysis of these models should help us to establish the neurobiological alterations underlying network disturbances and cognitive impairments in the context of the developmental hypothesis of schizophrenia.…”