Early postnatal depletion of NMDA receptor development affects behaviour and NMDA receptor expression until later adulthood in rats--a possible model for schizophrenia.
There is increasing evidence that a dysfunction of the N-methyl-d-aspartate (NMDA) receptor system plays a key role in the pathophysiology of schizophrenia. Non-competitive NMDA-antagonists induce schizophrenia-like symptoms and cognitive impairment in healthy humans as well as rodents. As receptor dysfunction precedes clinical disorder manifestation, the present study investigated whether transient perinatal NMDA antagonism constitutes a suitable long-term animal model for schizophrenia. Male Wistar rats were treated from postnatal days 6-21 with the NMDA receptor antagonist MK-801, and then subjected to behavioural analysis up to an age of 180d. Alterations in cortical NMDA receptor expression and lymphocyte cAMP-response-element-binding-protein (CREB) were assessed. In comparison to controls, MK-801-treated animals showed differences in behaviour up to an age of 180d. Western blot analysis revealed that transient perinatal application of MK-801 caused a persistent increase in cortical NMDA-R1 protein in combination with a persistent disturbance of CREB phosphorylation, a downstream target of NMDA signalling. This animal model demonstrates that early postnatal NMDA receptor blockade leads to schizophrenia-like symptoms with persistent behavioural and neurochemical disturbances throughout life. Therefore, it might provide a basis for further understanding of the disease and evaluation of new therapeutic strategies.
Baier
Paul Christian
PC
Department of Psychiatry and Psychotherapy, Christian-Albrechts-University, Niemannsweg 147, D-24105 Kiel, Germany.
Blume
Annegret
A
Koch
Jakob
J
Marx
Aljoscha
A
Fritzer
Gunther
G
Aldenhoff
Josef Bernd
JB
Schiffelholz
Thomas
T
D000375:Aging; D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology*; D001921:Brain / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000008:administration & dosage / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009483:Neuropsychological Tests; D010766:Phosphorylation / Q000187:drug effects; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D012565:Schizophrenic Psychology; D013997:Time Factors
D017362:Cyclic AMP Response Element-Binding Protein; D016291:Dizocilpine Maleate; D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate