Decrease in parvalbumin‐expressing neurons in the hippocampus and increased phencyclidine‐induced locomotor activity in the rat methylazoxymethanol (MAM) model of schizophrenia

Abstract

Treatment of rats with methylazoxymethanol (MAM) on gestational day (GD)17 disrupts corticolimbic development in the offspring (MAM-GD17 rats) and leads to abnormalities in adult MAM-GD17 rats resembling those described in schizophrenic patients. The underlying changes in specific cortical and limbic cell populations remain to be characterised. In schizophrenia, decreases in inhibitory c-aminobutyric acid (GABA)-containing interneurons that express the calcium-binding protein parvalbumin have been reported in the prefrontal cortex and hippocampus. In this study we analysed the expression of parvalbumin (PV), calretinin (CR) and calbindin (CB) in the prefrontal cortex and hippocampus of MAM-GD17 rats. Exposure in utero to MAM led to a significant decrease in the number of neurons expressing PV in the hippocampus, but not the prefrontal cortex. Neurons expressing CR or CB were not affected in either structure. The neurochemical changes in MAM-GD17 rats were accompagnied by increased hyperlocomotion after administration of phencyclidine (PCP), analogous to the hypersensitivity of schizophrenic patients to PCP. Therefore, the developmental MAM-GD17 model reproduces key neurochemical and behavioural features that reflect cortical and subcortical dysfunction in schizophrenia, and could be a useful tool in the development of new antipsychotic drugs.

Selective Remediation of Reversal Learning Deficits in the Neurodevelopmental MAM Model of Schizophrenia by a Novel mGlu5 Positive Allosteric Modulator

“…MAM treatment at E17 reproduces many of the neural and neurochemical changes observed in schizophrenia, including changes in hippocampal and prefrontal volume (Flagstad et al, 2004;Moore et al, 2006), prefrontal cortex organization (Moore et al, 2006) and up-regulation of striatal dopamine (Flagstad et al, 2004;see Lodge and Grace, 2009). Earlier studies had reported PV changes in the ventral hippocampus and medial prefrontal cortex (Penschuck et al, 2006;, while the present study extends these findings to both the OFC and the mPFC, mirroring histological changes in schizophrenia (Lewis, 2000). Also, down-regulation of mGlu5 receptors in the OFC might be consistent with the reversal learning deficit in the MAM model being mediated by orbitofrontal dysfunction.…”

Changes in parvalbumin immunoreactivity with aging in the central auditory system of the rat

“…Parallel studies were performed in animal models: In the LPA1-deficient mice model of schizophrenia, a significant decrease in PV and GABA immunoreactivity was present in the entorhinal cortex, associated with a dramatic decrease in the power of gamma oscillations at the same location (Cunningham et al, 2006). In the rat methylazoxymethanol model of schizophrenia, the number of PV-ir neurons was significantly decreased in the prefrontal cortex but not in the hippocampus (Penschuck et al, 2006). In both animal studies, no changes in the number of CB-ir or CR-ir cells were found.…”

Schizophrenia-Like Phenotype Inherited by the F2 Generation of a Gestational Disruption Model of Schizophrenia

“…Post-mortem studies on schizophrenia patients report a decreased PV expression in the prefrontal cortex and hippocampus (Beasley et al, 2002;Hashimoto et al, 2003;Knable et al, 2004). In addition, numerous animal models also report region-specific decreases in PV expression (Amitai et al, 2012;Chen et al, 2014;Francois et al, 2009;Jenkins et al, 2010;Lodge et al, 2009a;Penschuck et al, 2006;Wang et al, 2008). Moreover, we have recently demonstrated that a decrease in PV interneuron function is sufficient to augment hippocampal signaling and produce downstream changes in dopamine system function and behavior (Boley et al, 2014;Shah and Lodge, 2013).…”