The Methylazoxymethanol Acetate (MAM-E17) Rat Model: Molecular and Functional Effects in the Hippocampus

Hradetzky, Eva; Sanderson, Thomas M.; Tsang, Tsz M.; Sherwood, J. L.; Fitzjohn, Stephen M.; Lakics, Viktor; Malik, Nadia; Schoeffmann, Stephanie; O’Neill, Michael; Cheng, Tammy M.K.; Harris, Laura W.; Rahmoune, Hassan; Guest, Paul C.; Sher, Emanuele; Collingridge, Graham L.; Holmes, Elaine; Tricklebank, Mark D.; Bahn, Sabine

doi:10.1038/npp.2011.219

Cited by 55 publications

(48 citation statements)

References 73 publications

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“…Consistent with the proteomic data, pathway analysis of the hippocampal metabolites demonstrated that the most significant canonical pathway affected by prenatal MAM administration was the glutamatergic system. Specifically, changes in glutamate, N-acetyl aspartyl glutamate and overlapping spectra of glutamate/glutamine were observed.Taken together, the study by Bahn and colleagues (Hradetzky et al, 2011) further validates the MAM-treated rat as a model relevant to human disease, and extends this work to demonstrate that gestational MAM administration significantly alters glutamatergic markers throughout the hippocampus, in accord with human studies demonstrating alterations in hippocampal function (Konradi et al, 2011; …”

supporting

confidence: 62%

supporting

confidence: 62%

“…Taken together, the study by Bahn and colleagues (Hradetzky et al, 2011) further validates the MAM-treated rat as a model relevant to human disease, and extends this work to demonstrate that gestational MAM administration significantly alters glutamatergic markers throughout the hippocampus, in accord with human studies demonstrating alterations in hippocampal function (Konradi et al, 2011;Lahti et al, 2006) and glutamatergic signaling (Tsai and Coyle, 2002). Given similar deficits in anatomical, behavioral, neurophysiological, and now molecular markers, the MAM model is an exceptionally well-validated model with the potential to aid in preclinical drug discovery and development.…”

mentioning

confidence: 66%

“…In the current issue, Bahn and colleagues (Hradetzky et al, 2011) describe important and relevant molecular effects of gestational MAM administration that further validate the MAM-treated rat as a model relevant to human disease. Using proteomic and metabolomic analyses, the authors report that gestational MAM administration induces molecular alterations that are largely localized to the hippocampus.…”

mentioning

confidence: 91%

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Gestational Methylazoxymethanol Acetate Administration Alters Proteomic and Metabolomic Markers of Hippocampal Glutamatergic Transmission

Lodge

Grace

2011

Neuropsychopharmacol

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Gestational methylazoxymethanol acetate (MAM) administration produces deficits consistent with those observed in schizophrenia patients, including anatomical changes, behavioral deficits, and altered neuronal information processing (for review see Lodge and Grace (2009b)). Behaviorally, MAM-treated rats display deficits in prepulse inhibition of startle, latent inhibition, working memory, social interaction, and an enhanced response to psychomotor stimulants. The mechanisms underlying these deficits have not been conclusively demonstrated; however, neurophysiological studies have confirmed that MAMtreated rats display an augmented dopamine system function, consistent with the enhanced dopamine signaling proposed to underlie the positive symptoms of schizophrenia in humans. These deficits in dopamine system regulation can be attributed to a lack of interneuron function within the ventral hippocampus (Lodge et al, 2009a), a finding consistent with postmortem (Konradi et al, 2011) and imaging studies (Lahti et al, 2006) in human schizophrenia patients. Although gestational MAM administration recapitulates a pathodevelopmental process leading to a schizophrenia-like phenotype, the molecular changes underlying these neurophysiological and behavioral alterations have not previously been examined.In the current issue, Bahn and colleagues (Hradetzky et al, 2011) describe important and relevant molecular effects of gestational MAM administration that further validate the MAM-treated rat as a model relevant to human disease. Using proteomic and metabolomic analyses, the authors report that gestational MAM administration induces molecular alterations that are largely localized to the hippocampus. Specifically, LC-MS analysis of hippocampal tissue demonstrated 38 (out of 673) proteins that were altered by MAM-treatment. Interestingly these alterations were restricted to the hippocampus with no significant differences observed for the 743 proteins identified from the frontal cortex. The candidate proteins with the greatest statistical significance were verified by immunoblot analysis, and three proteins demonstrated a significant correlation with LC-MS analysis, namely AMPA1, PMCA1, and HPCA. In addition, the AMPA1 immunoblots identified two distinct bands, corresponding to phosphorylated and nonphosphorylated forms of the receptor. These bands were differentially altered by MAM treatment, indicating a potential reduction in phosphorylation of the AMPA1 subunit of the receptor.To characterize the pathways associated with the proteomic changes, analyses using in silico modeling were performed on the proteins identified by LC-MS. Thus, pathway analysis of the 38 differentially expressed hippocampal proteins demonstrated a significant association with glutamatergic signaling. Of particular relevance to glutamatergic transmission were changes in AMPA-receptor subunit expression and phosphorylation that suggest MAM-treated rats may display alterations in hippocampal synaptic transmission and synaptic plasticity. Indeed, electroph...

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supporting

confidence: 62%

supporting

confidence: 62%

mentioning

confidence: 66%

mentioning

confidence: 91%

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Gestational Methylazoxymethanol Acetate Administration Alters Proteomic and Metabolomic Markers of Hippocampal Glutamatergic Transmission

Lodge

Grace

2011

Neuropsychopharmacol

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“…Cellular disarray in the CA1 region of hippocampus has also been described and is thought to be analogous to hippocampal disarray seen in schizophrenia patients 120,166 . Recently, we carried out a proteomic and metabonomic investigation which showed that MAM-E17 rats have primarily deficits in hippocampal glutamatergic neurotransmission, as seen in some schizophrenia patients 167 . Most importantly, these results were consistent with our finding of functional deficits in glutamatergic neurotransmission, as identified using electrophysiological recordings.…”

Section: Interruption Of Neurogenesismentioning

confidence: 99%

Estudos traducionais de neuropsiquiatria e esquizofrenia: modelos animais genéticos e de neurodesenvolvimento

Gottschalk

Sarnyai

Guest

et al. 2012

Arch. Clin. Psychiatry (São Paulo)

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Psychiatric symptoms are subjective by nature and tend to overlap between different disorders. The modelling of a neuropsychiatric disorder therefore faces challenges because of missing knowledge of the fundamental pathophysiology and a lack of accurate diagnostics. Animal models are used to test hypotheses of aetiology and to represent the human condition as close as possible to increase our understanding of the disease and to evaluate new targets for drug discovery. In this review, genetic and neurodevelopmental animal models of schizophrenia are discussed with respect to behavioural and neurophysiological findings and their association with the clinical condition. Only specific animal models of schizophrenia may ultimately lead to novel diagnostic approaches and drug discovery. We argue that molecular biomarkers are important to improve animal to human translation since behavioural readouts lack the necessary specificity and reliability to assess human psychiatric symptoms.Gottschalk MG, et al. / Rev Psiq Clín. 2013;40(1):41-50 Keywords: Translational research, neuropsychiatry, genetic, neurodevelopment, animal model, schizophrenia. ResumoSintomas psiquiátricos são subjetivos por natureza e tendem a se sobrepor entre diferentes desordens. Sendo assim, a criação de modelos de uma desordem neuropsiquiátrica encontra desafios pela falta de conhecimento dos fundamentos da fisiopatologia e diagnósticos precisos. Modelos animais são usados para testar hipóteses de etiologia e para representar a condição humana tão próximo quanto possível para aumentar nosso entendimento da doença e avaliar novos alvos para a descoberta de drogas. Nesta revisão, modelos animais genéticos e de neurodesenvolvimento de esquizofrenia são discutidos com respeito a achados comportamentais e neurofisiológicos e sua associação com a condição clínica. Somente modelos animais específicos de esquizofrenia podem, em último caso, levar a novas abordagens diagnósticas e descoberta de drogas. Argumentamos que biomarcadores moleculares são importantes para aumentar a tradução de animais a humanos, já que faltam a especificidade e a fidelidade necessárias às leituras comportamentais para avaliar sintomas psiquiátricos humanos.Gottschalk MG, et al. / Rev Psiq Clín. 2013;40(1):41-50

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The MAM Model to Study the Role of Dopamine in Schizophrenia

Zhu¹,

Uliana²,

Grace³

2022

Dopaminergic System Function and Dysfunction: Experimental Approaches

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The Methylazoxymethanol Acetate (MAM-E17) Rat Model: Molecular and Functional Effects in the Hippocampus

Cited by 55 publications

References 73 publications

Gestational Methylazoxymethanol Acetate Administration Alters Proteomic and Metabolomic Markers of Hippocampal Glutamatergic Transmission

Gestational Methylazoxymethanol Acetate Administration Alters Proteomic and Metabolomic Markers of Hippocampal Glutamatergic Transmission

Estudos traducionais de neuropsiquiatria e esquizofrenia: modelos animais genéticos e de neurodesenvolvimento

The MAM Model to Study the Role of Dopamine in Schizophrenia

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