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


RESULTS
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.
Matricon
Julien
J
INSERM U894, Laboratoire de Physiopathologie des Maladies Psychiatriques, Centre de Psychiatrie et Neurosciences, Paris, France.
Bellon
Alfredo
A
Frieling
Helge
H
Kebir
Oussama
O
Le Pen
Gwenaëlle
G
Beuvon
Frédéric
F
Daumas-Duport
Catherine
C
Jay
Thérèse M
TM
Krebs
Marie-Odile
MO
D000818:Animals; D001931:Brain Mapping; D015816:Cell Adhesion Molecules, Neuronal / Q000172:deficiency*; D047108:Embryonic Development / Q000187:drug effects; D016326:Extracellular Matrix Proteins / Q000172:deficiency*; D006624:Hippocampus / Q000187:drug effects* / Q000473:pathology; D006801:Humans; D001523:Mental Disorders / Q000139:chemically induced*; D008745:Methylation; D008746:Methylazoxymethanol Acetate / Q000031:analogs & derivatives* / Q000633:toxicity; D009419:Nerve Tissue Proteins / Q000172:deficiency*; D009474:Neurons / Q000473:pathology / Q000648:ultrastructure; D051381:Rats; D000091042:Reelin Protein; D012559:Schizophrenia / Q000473:pathology; D012697:Serine Endopeptidases / Q000172:deficiency*; D013723:Teratogens / Q000633:toxicity; D013788:Thalamus / Q000473:pathology
D015816:Cell Adhesion Molecules, Neuronal; D016326:Extracellular Matrix Proteins; D009419:Nerve Tissue Proteins; D000091042:Reelin Protein; C000717129:Reln protein, rat; D013723:Teratogens; D008746:Methylazoxymethanol Acetate; C000717127:RELN protein, human; D012697:Serine Endopeptidases; C030667:methylazoxymethanol