Schizophrenia glutamatergic hypothesis

However, the dopamine hypothesis does not account for some important observations. If an abnormality of dopamine physiology were solely responsible for the pathogenesis of schizophrenia, antipsychotic drugs would do a much better job in treating patients. As it is, they are only partially effective for most and ineffective for some patients. Moreover, there is evidence that diminished glutamatergic activity also plays a role in... 

Coyle, J. T. The glutamatergic dysfunction hypothesis of schizophrenia. Harvard Rev. Psychiat. 3 (1996) 241-250. 

Coyle JT. 1996. The glutamatergic dysfunction hypothesis for schizophrenia. Harv Rev Psychiatry 3 241-253. 

Glutamatergic abnormalities are also a major feature of schizophrenia. They may actually cause the dopaminergic abnormalities in that disorder and then be exacerbated by them (Laruelle et al., 2005). The glutamate hypothesis simply states that NMDAR hypofunction contributes to the pathophysiology of schizophrenia (Coyle, 2006 Lindsley et al., 2006). A variant of this is the NMDA synaptic deficit hypothesis of MacDonald and Chafee (2006), which posits that each risk factor for schizophrenia impacts the NMDA glutamate synapse such that the cumulative effect drives NMDA synaptic function below a threshold for normal function. Supporting either form of the glutamate hypothesis is evidence that... 

Kim JS, Kornhuber HH, Schmid-Burgk W, Holzmuller B (1980) Low cerebrospinal fluid glutamate in schizophrenia patients and a new hypothesis of glutamatergic neuronal dysfunction. Neurosci Lett 20 379-382. 

The dopamine hypothesis of schizophrenia posits diminished dopaminergic activity in the prefrontal cortex and reciprocal dopaminergic hyperactivity in the mesolimbic pathways, associated presumably with the induction of negative and positive symptoms, respectively. The exact mechanisms responsible for such changes in dopaminergic transmissions are not yet fully understood. However, accumulated data suggest that altered (i.e. hypoactive) glutamatergic receptor expression/function may contribute to the observed abnormalities. 

The NMDA hypothesis, called the glutamatergic dysfunction hypothesis, of schizophrenia is based on the action of glutamate on NMDA receptors on GABAergic, serotonergic, and noradrenergic neurons that inhibit two major excitatory pathways in the retrosplenial cortical neurons. (Coyle, 1996). 

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