Neuropathological and reelin deficiencies in the hippocampal formation of rats exposed to MAM; differences and similarities with schizophrenia

Julien Matricon, Alfredo Bellon, Helge Frieling, Oussama Kebir, Gwenaëlle Le Pen, Frédéric Beuvon, Catherine Daumas-Duport, Thérèse M. Jay, Marie Odile Krebs

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Abstract

Background:Adult rats exposed to methylazoxymethanol (MAM) at embryonic day 17 (E17) consistently display behavioral characteristics similar to that observed in patients with schizophrenia and replicate neuropathological findings from the prefrontal cortex of psychotic individuals. However, a systematic neuropathological analysis of the hippocampal formation and the thalamus in these rats is lacking. It is also unclear if reelin, a protein consistently associated with schizophrenia and potentially involved in the mechanism of action of MAM, participates in the neuropathological effects of this compound. Therefore, a thorough assessment including cytoarchitectural and neuromorphometric measurements of eleven brain regions was conducted. Numbers of reelin positive cells and reelin expression and methylation levels were also studied. Principal Findings:Compared to untreated rats, MAM-exposed animals showed a reduction in the volume of entorhinal cortex, hippocampus and mediodorsal thalamus associated with decreased neuronal soma. The entorhinal cortex also showed laminar disorganization and neuronal clusters. Reelin methylation in the hippocampus was decreased whereas reelin positive neurons and reelin expression were unchanged. Conclusions:Our results indicate that E17-MAM exposure reproduces findings from the hippocampal formation and the mediodorsal thalamus of patients with schizophrenia while providing little support for reelin's involvement. Moreover, these results strongly suggest MAM-treated animals have a diminished neuropil, which likely arises from abnormal neurite formation; this supports a recently proposed pathophysiological hypothesis for schizophrenia.

Original languageEnglish (US)
Article numbere10291
JournalPLoS One
Volume5
Issue number4
DOIs
StatePublished - Jan 1 2010

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hippocampus
thalamus
Rats
Hippocampus
Schizophrenia
Thalamus
rats
Entorhinal Cortex
Methylation
methylation
cortex
Animals
neurites
Neuropil
Carisoprodol
Neurites
mechanism of action
animals
Prefrontal Cortex
neurons

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Matricon, Julien ; Bellon, Alfredo ; Frieling, Helge ; Kebir, Oussama ; Le Pen, Gwenaëlle ; Beuvon, Frédéric ; Daumas-Duport, Catherine ; Jay, Thérèse M. ; Krebs, Marie Odile. / Neuropathological and reelin deficiencies in the hippocampal formation of rats exposed to MAM; differences and similarities with schizophrenia. In: PLoS One. 2010 ; Vol. 5, No. 4.
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abstract = "Background:Adult rats exposed to methylazoxymethanol (MAM) at embryonic day 17 (E17) consistently display behavioral characteristics similar to that observed in patients with schizophrenia and replicate neuropathological findings from the prefrontal cortex of psychotic individuals. However, a systematic neuropathological analysis of the hippocampal formation and the thalamus in these rats is lacking. It is also unclear if reelin, a protein consistently associated with schizophrenia and potentially involved in the mechanism of action of MAM, participates in the neuropathological effects of this compound. Therefore, a thorough assessment including cytoarchitectural and neuromorphometric measurements of eleven brain regions was conducted. Numbers of reelin positive cells and reelin expression and methylation levels were also studied. Principal Findings:Compared to untreated rats, MAM-exposed animals showed a reduction in the volume of entorhinal cortex, hippocampus and mediodorsal thalamus associated with decreased neuronal soma. The entorhinal cortex also showed laminar disorganization and neuronal clusters. Reelin methylation in the hippocampus was decreased whereas reelin positive neurons and reelin expression were unchanged. Conclusions:Our results indicate that E17-MAM exposure reproduces findings from the hippocampal formation and the mediodorsal thalamus of patients with schizophrenia while providing little support for reelin's involvement. Moreover, these results strongly suggest MAM-treated animals have a diminished neuropil, which likely arises from abnormal neurite formation; this supports a recently proposed pathophysiological hypothesis for schizophrenia.",
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Neuropathological and reelin deficiencies in the hippocampal formation of rats exposed to MAM; differences and similarities with schizophrenia. / Matricon, Julien; Bellon, Alfredo; Frieling, Helge; Kebir, Oussama; Le Pen, Gwenaëlle; Beuvon, Frédéric; Daumas-Duport, Catherine; Jay, Thérèse M.; Krebs, Marie Odile.

In: PLoS One, Vol. 5, No. 4, e10291, 01.01.2010.

Research output: Contribution to journalArticle

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T1 - Neuropathological and reelin deficiencies in the hippocampal formation of rats exposed to MAM; differences and similarities with schizophrenia

AU - Matricon, Julien

AU - Bellon, Alfredo

AU - Frieling, Helge

AU - Kebir, Oussama

AU - Le Pen, Gwenaëlle

AU - Beuvon, Frédéric

AU - Daumas-Duport, Catherine

AU - Jay, Thérèse M.

AU - Krebs, Marie Odile

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N2 - Background:Adult rats exposed to methylazoxymethanol (MAM) at embryonic day 17 (E17) consistently display behavioral characteristics similar to that observed in patients with schizophrenia and replicate neuropathological findings from the prefrontal cortex of psychotic individuals. However, a systematic neuropathological analysis of the hippocampal formation and the thalamus in these rats is lacking. It is also unclear if reelin, a protein consistently associated with schizophrenia and potentially involved in the mechanism of action of MAM, participates in the neuropathological effects of this compound. Therefore, a thorough assessment including cytoarchitectural and neuromorphometric measurements of eleven brain regions was conducted. Numbers of reelin positive cells and reelin expression and methylation levels were also studied. Principal Findings:Compared to untreated rats, MAM-exposed animals showed a reduction in the volume of entorhinal cortex, hippocampus and mediodorsal thalamus associated with decreased neuronal soma. The entorhinal cortex also showed laminar disorganization and neuronal clusters. Reelin methylation in the hippocampus was decreased whereas reelin positive neurons and reelin expression were unchanged. Conclusions:Our results indicate that E17-MAM exposure reproduces findings from the hippocampal formation and the mediodorsal thalamus of patients with schizophrenia while providing little support for reelin's involvement. Moreover, these results strongly suggest MAM-treated animals have a diminished neuropil, which likely arises from abnormal neurite formation; this supports a recently proposed pathophysiological hypothesis for schizophrenia.

AB - Background:Adult rats exposed to methylazoxymethanol (MAM) at embryonic day 17 (E17) consistently display behavioral characteristics similar to that observed in patients with schizophrenia and replicate neuropathological findings from the prefrontal cortex of psychotic individuals. However, a systematic neuropathological analysis of the hippocampal formation and the thalamus in these rats is lacking. It is also unclear if reelin, a protein consistently associated with schizophrenia and potentially involved in the mechanism of action of MAM, participates in the neuropathological effects of this compound. Therefore, a thorough assessment including cytoarchitectural and neuromorphometric measurements of eleven brain regions was conducted. Numbers of reelin positive cells and reelin expression and methylation levels were also studied. Principal Findings:Compared to untreated rats, MAM-exposed animals showed a reduction in the volume of entorhinal cortex, hippocampus and mediodorsal thalamus associated with decreased neuronal soma. The entorhinal cortex also showed laminar disorganization and neuronal clusters. Reelin methylation in the hippocampus was decreased whereas reelin positive neurons and reelin expression were unchanged. Conclusions:Our results indicate that E17-MAM exposure reproduces findings from the hippocampal formation and the mediodorsal thalamus of patients with schizophrenia while providing little support for reelin's involvement. Moreover, these results strongly suggest MAM-treated animals have a diminished neuropil, which likely arises from abnormal neurite formation; this supports a recently proposed pathophysiological hypothesis for schizophrenia.

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