Decrease in parvalbumin-expressing neurons in the hippocampus and increased phencyclidine-induced locomotor activity in the rat methylazoxymethanol (MAM) model of schizophrenia.
Treatment of rats with methylazoxymethanol (MAM) on gestational day (GD)17 disrupts corticolimbic development in the offspring (MAM-GD17 rats) and leads to abnormalities in adult MAM-GD17 rats resembling those described in schizophrenic patients. The underlying changes in specific cortical and limbic cell populations remain to be characterised. In schizophrenia, decreases in inhibitory gamma-aminobutyric acid (GABA)-containing interneurons that express the calcium-binding protein parvalbumin have been reported in the prefrontal cortex and hippocampus. In this study we analysed the expression of parvalbumin (PV), calretinin (CR) and calbindin (CB) in the prefrontal cortex and hippocampus of MAM-GD17 rats. Exposure in utero to MAM led to a significant decrease in the number of neurons expressing PV in the hippocampus, but not the prefrontal cortex. Neurons expressing CR or CB were not affected in either structure. The neurochemical changes in MAM-GD17 rats were accompagnied by increased hyperlocomotion after administration of phencyclidine (PCP), analogous to the hypersensitivity of schizophrenic patients to PCP. Therefore, the developmental MAM-GD17 model reproduces key neurochemical and behavioural features that reflect cortical and subcortical dysfunction in schizophrenia, and could be a useful tool in the development of new antipsychotic drugs.
Penschuck
Silke
S
Department of Neuroscience, 900, Lundbeck Research USA, Inc., 215 College Road, Paramus, NJ 07652-1431, USA. SILP@lundbeck.com
Flagstad
Peter
P
Didriksen
Michael
M
Leist
Marcel
M
Michael-Titus
Adina T
AT
D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002452:Cell Count / Q000379:methods; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology*; D007150:Immunohistochemistry / Q000379:methods; D008746:Methylazoxymethanol Acetate / Q000031:analogs & derivatives*; D009043:Motor Activity / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010320:Parvalbumins / Q000378:metabolism*; D010622:Phencyclidine / Q000494:pharmacology*; D017397:Prefrontal Cortex / Q000187:drug effects / Q000473:pathology; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D051381:Rats; D017208:Rats, Wistar; D012559:Schizophrenia / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D013997:Time Factors
D018691:Excitatory Amino Acid Antagonists; D010320:Parvalbumins; D008746:Methylazoxymethanol Acetate; D010622:Phencyclidine; C030667:methylazoxymethanol