Schizophrenia NMDA receptor hypofunction

Neurochemical imaging and MRS techniques have obvious, although longterm studies of neurochemistry in vivo have yet to be applied to schizophrenia. One correlate of the neurodegenerative process proposed in the NMDA receptor hypofunction hypothesis is demonstrated in the relationship between anterior cingulate NAA deficits and disease duration (Ende et al., 2000). A... 

Several lines of evidence have implicated NMDA receptor hypofunction in the pathophysiology of schizophrenia. The administration of certain, but not all, uncompetitive NMDA receptor antagonists exacerbates psychotic symptoms in schizophrenics and mimics schizophrenia in non-psychotic subjects (Coyle et al. 2003 Konradi and Heckers 2003). 

Olney JW, Newcomer JW, Farber NB. NMDA receptor hypofunction model of schizophrenia. J Psychiatry Res 1999 33 523-533. 

Jentsch JD, Roth RH. 1999. The neuropsychopharmacology of phencyclidine From NMDA receptor hypofunction to the dopamine hypothesis of schizophrenia. Neuropsychopharmacology 20 201-225. 

Hahn CG, Wang HY, Cho DS, Talbot K, Gur RE, et al. 2006. Altered neuregulin l-erbB4 signaling contributes to NMDA receptor hypofunction in schizophrenia. Nat Med 12 824-828. 

Lindsley CW, Shipe WD, Wolkenberg SE, Theberge CR, Williams DL Jr., et al. 2006. Progress towards validating the NMDA receptor hypofunction hypothesis of schizophrenia. Curr Top Med Chem 6 771-785. 

Biological Role of Glutamate and the NMDA Receptor Hypofunction Hypothesis of Schizophrenia... 

Deutsch SI, Schwartz BL, Rosse RB, Mastropaolo J, Marvel CL, et al. 2003. Adjuvant topiramate administration A pharmacologic strategy for addressing NMDA receptor hypofunction in schizophrenia. Clin Neuropharmacol 26... 

Although chronic ketamine (repeated acute administration for 14 days) reportedly has no effect on the amplitude or latency of any ERP components, there does appear to be some lasting effects of chronic ketamine exposure (Maxwell et al., 2006b). In a study by Maxwell and colleagues, mice were treated with ketamine daily for 2 weeks, and then tested 1 week later. Ketamine decreased N40 amplitude, but not latency 7 days after last ketamine dose. These data indicate that chronic NMDA receptor hypofunction can lead to auditory processing deficits similar to those seen in schizophrenia patients (Maxwell et al., 2006b). 

Phencyclidine (PCP), Ketamin, and MK-801 all block the N-methyl-D-aspartate (NMDA) receptor complex and are associated with schizophrenia-like symptoms through hypofunction of the gintamatergic nenrotransmission (Krystal et al., 1994 Olney and Farber, 1995). Other NMDA antagonists have psychotogenic properties, too (CPP, CPP-ene, CGS 19755). NMDA receptor hypofunction can explain schizophrenic positive and negative symptoms, cognitive deterioration and structural brain changes (Olney and Farber, 1995). 

Hypofunction of NMDA receptors may contribute to the endophenotype of schizophrenia 880... 

Hypofunction of NMDA receptors may contribute to the endophenotype of schizophrenia. The hypothesis that hypofunction of a subpopulation of NMDA receptors contributes to the pathophysiology of schizophrenia has gained considerable support over the last decade (see Fig. 54-1). The dissociative anesthetics including phencyclidine (PCP) and ketamine when introduced clinically 40 years ago were noted to produce a syndrome that was difficult to distinguish from schizophrenia. These agents act as noncompetitive open-channel blockers of the NMDA receptor. 

Experimental pharmacological in vitro models in which glutathione is decreased reveal a hypofunction of NMDA receptors. In vivo developmental models show a reduction of dendritic spine density and of y-aminobutyric acid (GABA)-parvalbumin immunoreactive intemeurones in prefrontal cortex, as well as memory and sensory integration impairments. These anomalies are similar to that observed in schizophrenia. 

Steullet P, Neijt HC, Cuenod M, Do KQ. 2006. Synaptic plasticity impairment and hypofunction of NMDA receptors induced by glutathione deficit Relevance to schizophrenia. Neuroscience 137 807-819. 

The glutamate hypofunction hypothesis relies on the fact that phencyclidine and ketamine, both potent noncompetitive N-methyl-D-aspartate (NMDA)-glutamate receptor antagonists, induce schizophrenia-like symptoms in healthy individuals and worsen some symptoms in schizophrenia patients... 

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