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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: 4.24). 09/2009; 111(4):891-900. DOI: 10.1111/j.1471-4159.2009.06325.x
Source: PubMed

ABSTRACT 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, Aug 25, 2015
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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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    ABSTRACT: Glutamate is the principle excitatory neurotransmitter in the mammalian brain and dysregulation of glutamatergic neurotransmission is implicated in the pathophysiology of several psychiatric and neurological diseases. This study utilized novel lentiviral short hairpin RNA (shRNA) vectors to target expression of the vesicular glutamate transporter 1 (VGLUT1) following injection into the dorsal hippocampus of adult mice, since partial reductions in VGLUT1 expression should attenuate glutamatergic signaling and similar reductions have been reported in schizophrenia. The VGLUT1-targeting vector attenuated tonic glutamate release in the dorsal hippocampus without affecting GABA, and selectively impaired novel object discrimination (NOD) and retention (but not acquisition) in the Morris water maze, without influencing contextual fear-motivated learning or causing any adverse locomotor or central immune effects. This pattern of cognitive impairment is consistent with the accumulating evidence for functional differentiation along the dorsoventral axis of the hippocampus, and supports the involvement of dorsal hippocampal glutamatergic neurotransmission in both spatial and non-spatial memory. Future use of this non-pharmacological VGLUT1 knockdown mouse model could improve our understanding of glutamatergic neurobiology and aid assessment of novel therapies for cognitive deficits such as those seen in schizophrenia.Neuropsychopharmacology accepted article preview online, 28 August 2013. doi:10.1038/npp.2013.220.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 08/2013; DOI:10.1038/npp.2013.220 · 7.83 Impact Factor
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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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    ABSTRACT: Brain-Derived Neurotrophic Factor (BDNF) is a neurotrophin that has been related not only to neurodevelopment and neuroprotection, but also to synapse regulation, learning, and memory. Research focused on the neurobiology of schizophrenia has emphasized the relevance of neurodevelopmental and neurotoxicity-related elements in the pathogenesis of this disease. Research focused on the clinical features of schizophrenia in the past decades has emphasized the relevance of cognitive deficits of this illness, considered a core manifestation and an important predictor for functional outcome. Variations in neurotrophins such as BDNF may have a role as part of the molecular mechanisms underlying these processes, from the neurodevelopmental alterations to the molecular mechanisms of cognitive dysfunction in schizophrenia patients.
    Frontiers in Psychiatry 06/2013; 4:45. DOI:10.3389/fpsyt.2013.00045
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    • "NMDA receptor trafficking is also regulated in response to neuronal activity, via both phosphorylation-dependent and phosphorylation-independent pathways (Chen and Roche, 2007; Lau et al., 2009). NMDAR antagonists reproduce both the positive and negative symptoms of schizophrenia in humans and worsen the symptoms of nonmedicated patients (Gaspar et al., 2009), suggesting that NMDAR hypofunction contributes to the symptoms of schizophrenia. Consistent with this hypothesis, enhancing NMDAR function by administering agonists acting at the NMDAR glycine site has been reported to be effective in reducing symptoms of schizophrenia (Labrie and Roder, 2010). "
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    ABSTRACT: NMDA receptors (NMDARs) mediate fast excitatory synaptic transmission and play a critical role in synaptic plasticity associated with learning and memory. NMDAR hypoactivity has been implicated in the pathophysiology of schizophrenia, and clinical studies reveal reduced negative symptoms of schizophrenia with a dose of pregnenolone that elevates serum levels of the neuroactive steroid pregnenolone sulfate (PregS). This report describes a novel process of delayed onset potentiation whereby PregS approximately doubles the cell's response to NMDA via a mechanism that is pharmacologically and kinetically distinct from rapid positive allosteric modulation by PregS. The number of functional cell surface NMDARs in cortical neurons increases 60 -100% within 10 min of exposure to PregS as shown by surface biotinylation and affinity purification. Delayed onset potentiation is reversible and selective for expressed receptors containing the NR2A or NR2B, but not NR2C or NR2D, subunits. Moreover, substitution of NR2B J-K helices and M4 domain with the corresponding region of NR2D ablates rapid allosteric potentiation of the NMDA response by PregS but not delayed onset potentiation. This demonstrates that the initial phase of rapid positive allosteric modulation is not a first step in NMDAR upregulation. Delayed onset potentiation by PregS occurs via a non- canonical, pertussis toxin sensitive G-protein coupled and Ca(2+) dependent mechanism that is independent of NMDAR ion channel activation. Further investigation into the sequelae for PregS stimulated trafficking of NMDARs to the neuronal cell surface may uncover a new target for the pharmacological treatment of disorders in which NMDAR hypofunction has been implicated.
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