The MAM Rodent Model of Schizophrenia

Lodge, Daniel J.

doi:10.1002/0471142301.ns0943s63

Cited by 41 publications

(44 citation statements)

References 20 publications

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“…As described previously (Moore et al, 2006; Lodge, 2013), MAM treatments were performed on timed pregnant female Sprague Dawley rats obtained from Harlan Laboratories on gestational day (GD) 16 and housed individually in plastic tubs. MAM (diluted in saline, 25 mg/kg, IP) was administered on GD17, while control rats received injections of saline (1ml/kg, IP).…”

Section: Methodsmentioning

confidence: 99%

Alterations in dopamine system function across the estrous cycle of the MAM rodent model of schizophrenia

Perez

Chen

Lodge

2014

Psychoneuroendocrinology

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Summary Clinical studies have reported differences in the incidence and severity of schizophrenia symptoms between male and female schizophrenia patients. Unfortunately, the cause of these differences is not currently known due, in part, to the fact that preclinical studies largely focus on male subjects. Dopamine neuron activity has been previously demonstrated to change across the estrous cycle, and may therefore be of relevance, as aberrant dopamine signaling is thought to underlie the positive symptoms of schizophrenia. Here we examine dopamine neuron activity across the estrous cycle in the MAM rodent model of schizophrenia. We demonstrate that the elevation in dopamine neuron activity, consistently observed in male MAM-treated rats, is most prominent during estrus and attenuated in met-estrus. Furthermore, this appears to be mediated, in part, by progesterone in the ventral hippocampus, as increases in dopamine neuron population activity (observed in estrus) were normalized by the intra-hippocampal administration of the progesterone receptor antagonist, mifepristone (but not the estrogen receptor antagonists, fulvestrant). Taken together, these data suggest that changes in dopamine system function occur across the estrous cycle in MAM-treated rats and may contribute to the differences in symptomatology between male and female schizophrenia patients.

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Section: Methodsmentioning

confidence: 99%

Alterations in dopamine system function across the estrous cycle of the MAM rodent model of schizophrenia

Perez

Chen

Lodge

2014

Psychoneuroendocrinology

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“…As described previously (Lodge, 2013;Moore et al, 2006), MAM treatments were performed on timed pregnant female Sprague-Dawley rats obtained from Harlan Laboratories on gestational day (GD) 16 and housed individually in plastic tubs. MAM (diluted in saline, 25 mg/kg, i.p.)…”

Section: Animalsmentioning

confidence: 99%

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

Perez

Aguilar

Neary

et al. 2015

Neuropsychopharmacol

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Both environmental and genetic factors contribute to schizophrenia; however, the exact etiology of this disorder is not known. Animal models are utilized to better understand the mechanisms associated with neuropsychiatric diseases, including schizophrenia. One of these involves gestational administration of methylazoxymethanol acetate (MAM) to induce a developmental disruption, which in turn produces a schizophrenia-like phenotype in post-pubertal rats. The mechanisms by which MAM produces this phenotype are not clear; however, we now demonstrate that MAM induces differential DNA methylation, which may be heritable. Here we demonstrate that a subset of both second (F2) and third (F3) filial generations of MAM-treated rats displays a schizophrenia-like phenotype and hypermethylation of the transcription factor, Sp5. Specifically, ventral tegmental area of dopamine neuron activity was examined using electrophysiology as a correlate for the dopamine hyperfunction thought to underlie psychosis in patients. Interestingly, only a subset of F2 and F3 MAM rats exhibited increases in dopamine neuron population activity, indicating that this may be a unique model with a susceptibility to develop a schizophrenia-like phenotype. An increase in dopamine system function in rodent models has been previously associated with decreases in hippocampal GABAergic transmission. In line with these observations, we found a significant correlation between hippocampal parvalbumin expression and dopamine neuron activity in F2 rats. These data therefore provide evidence that offspring born from MAMtreated rats possess a susceptibility to develop aspects of a schizophrenia-like phenotype and may provide a useful tool to investigate geneenvironment interactions.

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“…In rodents, by taking advantage of readiness for developmental manipulation, many studies have elucidated the connectivity of the PFC underlying cognitive functions (and nowadays, we have more sophisticated methods of circuit manipulation, e.g., optogenetics). For example, gestational administration of the mitotoxin, methyl azoxymethanol acetate (MAM), has been shown to induce developmental disruptions in the brain histologically and neurophysiologically, leading to behavioral deficits similar to those observed with schizophrenia in humans (Lodge, 2013). Anthony Grace’s group has characterized this model by in vivo recordings of stimulation-induced responses in several brain regions, and has shown that connections among the mPFC, nucleus accumbens, amygdala, and hippocampus are important for motivational drive, context-dependent decision making, and affective processing (Esmaeili and Grace, 2013).…”

Section: Neurobiological Framework For Cognitive Function: Pfcmentioning

confidence: 99%

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

Sakurai

Gamo

Hikida

et al. 2015

Progress in Neurobiology

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The prefrontal cortex (PFC) and its connections with other brain areas are crucial for cognitive function. Cognitive impairments are one of the core symptoms associated with schizophrenia, and manifest even before the onset of the disorder. Altered neural networks involving PFC contribute to cognitive impairments in schizophrenia. Both genetic and environmental risk factors affect the development of the local circuitry within PFC as well as development of broader brain networks, and make the system vulnerable to further insults during adolescence, leading to the onset of the disorder in young adulthood. Since spared cognitive functions correlate with functional outcome and prognosis, a better understanding of the mechanisms underlying cognitive impairments will have important implications for novel therapeutics for schizophrenia focusing on cognitive functions. Multidisciplinary approaches, from basic neuroscience to clinical studies, are required to link molecules, circuitry, networks, and behavioral phenotypes. Close interactions among such fields by sharing a common language on connectomes, behavioral readouts, and other concepts are crucial for this goal.

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The MAM Rodent Model of Schizophrenia

Cited by 41 publications

References 20 publications

Alterations in dopamine system function across the estrous cycle of the MAM rodent model of schizophrenia

Alterations in dopamine system function across the estrous cycle of the MAM rodent model of schizophrenia

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

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

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