The methylazoxymethanol acetate (MAM-E17) rat model: molecular and functional effects in the hippocampus
Eva Hradetzky1, Thomas M Sanderson, Tsz M Tsang
1Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge, UK.
Abstract:
Administration of the DNA-alkylating agent methylazoxymethanol acetate (MAM) on embryonic day 17 (E17) produces behavioral and anatomical brain abnormalities, which model some aspects of schizophrenia. This has lead to the premise that MAM rats are a neurodevelopmental model for schizophrenia. However, the underlying molecular pathways affected in this model have not been elucidated. In this study, we investigated the molecular phenotype of adult MAM rats by focusing on the frontal cortex and hippocampal areas, as these are known to be affected in schizophrenia. Proteomic and metabonomic analyses showed that the MAM treatment on E17 resulted primarily in deficits in hippocampal glutamatergic neurotransmission, as seen in some schizophrenia patients. Most importantly, these results were consistent with our finding of functional deficits in glutamatergic neurotransmission, as identified using electrophysiological recordings. Thus, this study provides the first molecular evidence, combined with functional validation, that the MAM-E17 rat model reproduces hippocampal deficits relevant to the pathology of schizophrenia.
Insights
Methylazoxymethanol acetate (MAM) exposure in early development creates neurodevelopmental deficits in rats, modeling schizophrenia. This study reveals molecular and functional evidence of hippocampal glutamatergic dysfunction in the MAM rat model.
Area of Science:
- Neuroscience
- Molecular Biology
- Psychiatry
Background:
- Schizophrenia is a complex psychiatric disorder with neurodevelopmental origins.
- The methylazoxymethanol acetate (MAM) rat model, induced by exposure on embryonic day 17 (E17), exhibits behavioral and anatomical brain abnormalities relevant to schizophrenia.
- The molecular underpinnings of the MAM rat model remain largely uncharacterized.
Purpose of the Study:
- To elucidate the molecular pathways affected in adult MAM rats.
- To investigate the frontal cortex and hippocampus, brain regions implicated in schizophrenia.
- To provide molecular and functional validation for the MAM rat model of schizophrenia.
Main Methods:
- Proteomic and metabonomic analyses were performed on adult MAM rats.
- Electrophysiological recordings were used to assess functional deficits in neurotransmission.
- Comparative analysis focused on frontal cortex and hippocampal tissues.
Main Results:
- MAM treatment on E17 led to significant deficits in hippocampal glutamatergic neurotransmission.
- Proteomic and metabonomic data indicated molecular alterations consistent with impaired glutamatergic function.
- Electrophysiological findings corroborated the molecular evidence, demonstrating functional deficits.
Conclusions:
- The MAM-E17 rat model exhibits molecular and functional hippocampal deficits.
- These findings provide the first molecular evidence supporting the MAM rat model's relevance to schizophrenia pathology.
- The study validates the MAM rat model for investigating schizophrenia-related glutamatergic dysfunction.
