Alterations in spatial memory and anxiety in the MAM E17 rat model of hippocampal pathology in schizophrenia.

Francois Gastambide,Maija Karjalainen,Clare Palmer,Mark Tricklebank,Amy M Taylor,Heta Svard,David M Bannerman,Sanna K Janhunen

doi:10.1007/s00213-014-3862-1

Francois Gastambide, Maija Karjalainen + Show 6 more

Open Access

https://doi.org/10.1007/s00213-014-3862-1

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Abstract

Adult rats exposed to methylazoxymethanol acetate (MAM) at embryonic day 17 (E17) display robust pathological alterations in the hippocampus. However, discrepancies exist in the literature regarding the behavioural effects of this pre-natal manipulation. Therefore, a systematic assessment of MAM E17-induced behavioural alterations was conducted using a battery of dorsal and ventral hippocampus-dependent tests. Compared to saline controls, MAM E17-treated rats displayed deficits in spatial reference memory in both the aversive hidden platform watermaze task and an appetitive Y-maze task. Deficits in the spatial reference memory watermaze task were replicated across three different cohorts and two laboratories. In contrast, there was little, or no, effect on the non-spatial, visible platform watermaze task or an appetitive, non-spatial, visual discrimination task, respectively. MAM rats were also impaired in the spatial novelty preference task which assesses short-term memory, and displayed reduced anxiety levels in the elevated plus maze task. Thus, MAM E17 administration resulted in abnormal spatial information processing and reduced anxiety in a number of hippocampus-dependent behavioural tests, paralleling the effects of dorsal and ventral hippocampal lesions, respectively. These findings corroborate recent pathological and physiological studies, further highlighting the usefulness of MAM E17 as a model of hippocampal dysfunction in at least some aspects of schizophrenia.

Highlights

Schizophrenia is a complex and heterogeneous disorder, associated with profound deficits in a wide variety of cognitive domains, including attention, memory and executive function (Heinrichs and Zakzanis. 1998; Nuechterlein et al 2004)
Evidence consistent with hippocampal alterations in schizophrenia comes from animal models, including neonatal ventral hippocampal damage and the embryonic day 17 methylazoxymethanol acetate (MAM E17) rodent model which exhibits robust hippocampal pathology
Through selective disturbance of proliferation and migration of neuronal precursor cells, MAM E17 treatment interferes with the development of cortical and subcortical brain regions, and results in a series of structural and functional alterations that are consistent with those observed in schizophrenia (Moore et al 2006; Lodge and Grace. 2009)

Summary

Introduction

Schizophrenia is a complex and heterogeneous disorder, associated with profound deficits in a wide variety of cognitive domains, including attention, memory and executive function (Heinrichs and Zakzanis. 1998; Nuechterlein et al 2004). 2007; Matricon et al 2010; Chin et al 2011; Hradetzky et al 2012; Phillips et al 2012a, b; Sanderson et al 2012; Snyder et al 2013) Alongside these robust anatomical and physiological alterations, a number of studies have looked at the effects of MAM E17 treatment in behavioural paradigms assessing hippocampus-dependent spatial memory (Gourevitch et al 2004; Flagstad et al 2005; Le Pen et al 2006; Featherstone et al 2009; Hazane et al 2009; Snyder et al 2013). While there appear to be consistent, robust and reliable spatial working/short-term memory deficits in MAM E17 rats (Gourevitch et al 2004; Featherstone et al 2009; Hazane et al 2009), the picture for associative, long-term spatial reference memory tasks is less clear cut

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