Molecular mechanisms underlying glutamatergic dysfunction in schizophrenia: Therapeutic implications

Clínica Psiquiátrica Universitaria, Hospital Clínico de la Universidad de Chile, Casilla, Santiago, Chile.
Journal of Neurochemistry (Impact Factor: 4.28). 09/2009; 111(4):891-900. DOI: 10.1111/j.1471-4159.2009.06325.x
Source: PubMed


Early models for the etiology of schizophrenia focused on dopamine neurotransmission because of the powerful anti-psychotic action of dopamine antagonists. Nevertheless, recent evidence increasingly supports a primarily glutamatergic dysfunction in this condition, where dopaminergic disbalance is a secondary effect. A current model for the pathophysiology of schizophrenia involves a dysfunctional mechanism by which the NMDA receptor (NMDAR) hypofunction leads to a dysregulation of GABA fast- spiking interneurons, consequently disinhibiting pyramidal glutamatergic output and disturbing the signal-to-noise ratio. This mechanism might explain better than other models some cognitive deficits observed in this disease, as well as the dopaminergic alterations and therapeutic effect of anti-psychotics. Although the modulation of glutamate activity has, in principle, great therapeutic potential, a side effect of NMDAR overactivation is neurotoxicity, which accelerates neuropathological alterations in this illness. We propose that metabotropic glutamate receptors can have a modulatory effect over the NMDAR and regulate excitotoxity mechanisms. Therefore, in our view metabotropic glutamate receptors constitute a highly promising target for future drug treatment in this disease.

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Available from: Pablo A. Gaspar,
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    • "The glutamatergic pathway projecting from cortical pyramidal neurons to the ventral tegmental area controls dopaminergic neurons via the activity of GABA interneurons. In this regulatory neural circuit NMDAR hypofunction causes dopamine hyperfunction of the mesolimbic dopamine pathway (Gaspar et al., 2009). If NMDARs and D1/D2 receptors establish such regulatory associations, then NMDAR hypofunction would increase dopamine activity contributing to the symptoms of schizophrenia. "
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    Frontiers in Pharmacology 01/2014; 4:169. DOI:10.3389/fphar.2013.00169 · 3.80 Impact Factor
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    • "For example, glutamate-induced excitotoxicity accompanies stroke or prolonged seizures, contributes to neurodegeneration (Danysz et al, 1995), and is implicated in anxiogenesis (Mathew et al, 2008). In contrast, glutamatergic hypofunction may contribute to cognitive impairment commonly seen in schizophrenia and depression (Gaspar et al, 2009; Sharpley, 2009) that is resistant to drug treatment and a major factor preventing patient recovery. However, it is unclear how glutamate dysregulation arises and which synaptic components are involved. "
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    • "A current model for the pathophysiology of schizophrenia involves a dysfunctional mechanism by which a NMDA receptor hypofunction leads to a dysregulation of GABA fast-spiking interneurons, consequently disinhibiting pyramidal glutamatergic output, and disturbing the signal-to-noise ratio. This mechanism might explain better than other models some cognitive deficits observed in this disease, as well as the dopaminergic alterations and therapeutic effect of antipsychotics (Gaspar et al., 2009). "
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