Enhanced hippocampal neuronal excitability and LTP persistence associated with reduced behavioral flexibility in the maternal immune activation model of schizophrenia

Abstract

Individuals with schizophrenia display a number of structural and cytoarchitectural alterations in the hippocampus, suggesting that other functions such as synaptic plasticity may also be modified. Altered hippocampal plasticity is likely to affect memory processing, and therefore any such pathology may contribute to the cognitive symptoms of schizophrenia, which includes prominent memory impairment. The current study tested whether prenatal exposure to infection, an environmental risk factor that has previously been associated with schizophrenia produced changes in hippocampal synaptic transmission or plasticity, using the maternal immune activation (MIA) animal model. We also assessed performance in hippocampus-dependent memory tasks to determine whether altered plasticity is associated with memory dysfunction. MIA did not alter basal synaptic transmission in either the dentate gyrus or CA1 of freely moving adult rats. It did, however, result in increased paired-pulse facilitation of the dentate gyrus population spike and an enhanced persistence of dentate long-term potentiation. MIA animals displayed slower learning of a reversed platform location in the water maze, and a similarly slowed learning during reversal in a spatial plus maze task. Together these findings are indicative of reduced behavioral flexibility in response to changes in task requirements. The results are consistent with the hypothesis that hippocampal plasticity is altered in schizophrenia, and that this change in plasticity mechanisms may underlie some aspects of cognitive dysfunction in this disorder.

Prenatal immune activation causes hippocampal synaptic deficits in the absence of overt microglia anomalies

“…In particular, the disruption of hippocampal synaptic integrity may change the electrophysiological properties of hippocampal cells, thereby altering the firing activity of hippocampal neurons. Such abnormalities have indeed been noted by numerous previous investigations using prenatal poly(I:C) models in rodents (Dickerson et al, 2010(Dickerson et al, , 2014Savanthrapadian et al, 2013;Wolff and Bilkey, 2015;Zhang and van Praag, 2015). Furthermore, the synaptic deficits may also contribute to the cognitive impairments that have frequently been observed following prenatal immune activation (reviewed in Boksa, 2010;Harvey and Boksa, 2012;Reisinger et al, 2015).…”

Behavioral alterations in rat offspring following maternal immune activation and ELR-CXC chemokine receptor antagonism during pregnancy: Implications for neurodevelopmental psychiatric disorders

“…Using the polyI:C model in rats, Zhang et al (2012) found that MIA impaired strategy set-shifting in the male, but not female, offspring. Findings on reversal learning are mixed with enhancements Zuckerman and Weiner, 2005) and impairments (Han et al, 2011;Savanthrapadian et al, 2013) observed using different task designs. We expected the offspring of polyI:C-treated dams to show impaired PPI, associative recognition memory, crossmodal recognition memory, and behavioral flexibility.…”

Association of aberrant neural synchrony and altered GAD67 expression following exposure to maternal immune activation, a risk factor for schizophrenia

“…17,18 Many of these changes have also been reported in animal models, including those involving MIA. 19,20 Much previous work in this area has, however, either tended to focus on the HPC as a whole or has focused on the ventral or dorsal regions alone. A more discriminatory approach may be worthwhile, as the dorsal and ventral poles of the HPC are functionally distinct and possess markedly different connectivity with downstream cortical targets including the mPFC.…”