Abstract
ABSTRACTMaternal exposure to infectious agents is a predisposing factor for schizophrenia with associated cognitive deficits in offspring. A high incidence of smoking in these individuals in adulthood might be, at least in part, due to the cognitive-enhancing effects of nicotine. Here, we have used prenatal exposure to maternal lipopolysaccharide (LPS, bacterial endotoxin) at different time points as a model for cognitive deficits in schizophrenia to determine whether nicotine reverses any associated impairments. Pregnant rats were treated subcutaneously with LPS (0.5 mg/kg) at one of three neurodevelopmental time periods [gestation days (GD) 10-11, 15-16, 18-19]. Cognitive assessment in male offspring commenced in early adulthood [postnatal day (PND) 60] and included: prepulse inhibition (PPI), latent inhibition (LI) and delayed non-matching to sample (DNMTS). Following PND 100, daily nicotine injections (0.6 mg/kg, subcutaneously) were administered, and animals were re-tested in the same tasks (PND 110). Only maternal LPS exposure early during fetal neurodevelopment (GD 10-11) resulted in deficits in all tests compared to animals that had been prenatally exposed to saline at the same gestational time point. Repeated nicotine treatment led to global (PPI) and selective (LI) improvements in performance. Early but not later prenatal LPS exposure induced consistent deficits in cognitive tests with relevance for schizophrenia. Nicotine reversed the LPS-induced deficits in selective attention (LI) and induced a global enhancement of sensorimotor gating (PPI).
Highlights
Schizophrenia develops owing to an interaction of multiple factors of genetic and environmental origin (Caspi et al, 2005; Clarke et al, 2009; Fleming and Martin, 2011; Modinos et al, 2013; Mulle, 2012)
Prenatal exposure to maternal LPS treatment on gestational days (GD) 10-11 led to significant deficits in all tests compared to saline controls: reduced prepulse inhibition (PPI), latent inhibition (LI)
Specific cognitive deficits (LI) induced by maternal LPS exposure were ameliorated by repeated nicotine exposure
Summary
Schizophrenia develops owing to an interaction of multiple factors of genetic and environmental origin (Caspi et al, 2005; Clarke et al, 2009; Fleming and Martin, 2011; Modinos et al, 2013; Mulle, 2012). Maternal infection (for example, influenza, rubella, measles) has been identified as a prenatal risk factor, and the subsequent process of inflammation is thought to interfere with. Received 18 February 2016; Accepted 4 May 2016 early fetal brain development, increasing the susceptibility of the offspring to later developing schizophrenia (Brown, 2012a,b; Ellman et al, 2008; Meyer and Feldon, 2009; Miller et al, 2013)
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