Article

Interneuron dysfunction in psychiatric disorders. Nat Rev Neurosci

Instituto de Neurociencias, Consejo Superior de Investigaciones Científicas y Universidad Miguel Hernández, 03550 Sant Joan d'Alacant, Spain.
Nature Reviews Neuroscience (Impact Factor: 31.43). 02/2012; 13(2):107-20. DOI: 10.1038/nrn3155
Source: PubMed

ABSTRACT

Schizophrenia, autism and intellectual disabilities are best understood as spectrums of diseases that have broad sets of causes. However, it is becoming evident that these conditions also have overlapping phenotypes and genetics, which is suggestive of common deficits. In this context, the idea that the disruption of inhibitory circuits might be responsible for some of the clinical features of these disorders is gaining support. Recent studies in animal models demonstrate that the molecular basis of such disruption is linked to specific defects in the development and function of interneurons - the cells that are responsible for establishing inhibitory circuits in the brain. These insights are leading to a better understanding of the causes of schizophrenia, autism and intellectual disabilities, and may contribute to the development of more-effective therapeutic interventions.

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    • "It is thought that blockade of NMDA receptors preferentially acts on fast spiking GABAergic interneurons because these neurons have a more depolarized membrane potential and consequently more open NMDA receptor channels (Moghaddam & Javitt, 2012). Disinhibition of pyramidal cell firing in turn leads to breakdown of synchronised connectivity between neuronal assemblies intra-cortically and excessive cortical discharge to subcortical centres (Marin, 2012). These observations have been incorporated into the NMDA receptor hypofunction model of schizophrenia, which proposes a functional deficit of NMDA receptor predominantly affecting interneurons and resulting in a loss of GABAergic inhibitory control over glutamatergic pyramidal cells (Gordon, 2010). "
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    ABSTRACT: Evidence suggests that anomalous mismatch negativity (MMN) in schizophrenia is related to glutamatergic abnormalities, possibly involving N-methyl-D-aspartate (NMDA) receptors. Decreased cortical expressions of NMDA receptor subunits have been observed in schizophrenia, though not consistently. To aid with integration and interpretation of previous work, we performed a meta-analysis of effect sizes of mRNA or protein levels of the obligatory NR1 subunit in prefrontal cortex from people with schizophrenia. In schizophrenia compared to unaffected controls the pooled effect size was -0.64 (95% confidence interval: -1.08 to -0.20) for NR1 mRNA reduction and -0.44 (95% confidence interval: -0.80 to -0.07) for NR1 protein reduction. These results represent the first step to a deeper understanding of the region-specific, cell-specific, and stage-specific NMDA receptor hypofunction in schizophrenia, which could be linked to mismatch negativity deficits via transgenic and pharmacological animal models.
    Full-text · Article · Nov 2015 · Biological psychology
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    • "It is thought that blockade of NMDA receptors preferentially acts on fast spiking GABAergic interneurons because these neurons have a more depolarized membrane potential and consequently more open NMDA receptor channels (Moghaddam & Javitt, 2012). Disinhibition of pyramidal cell firing in turn leads to breakdown of synchronised connectivity between neuronal assemblies intra-cortically and excessive cortical discharge to subcortical centres (Marin, 2012). These observations have been incorporated into the NMDA receptor hypofunction model of schizophrenia, which proposes a functional deficit of NMDA receptor predominantly affecting interneurons and resulting in a loss of GABAergic inhibitory control over glutamatergic pyramidal cells (Gordon, 2010). "
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    ABSTRACT: There is converging evidence of involvement of N-methyl-d-aspartate (NMDA) receptor hypofunction in the pathophysiology of schizophrenia. Our group recently identified a decrease in total NR1 mRNA and protein expression in the dorsolateral prefrontal cortex in a case-control study of individuals with schizophrenia (n=37/group). The NR1 subunit is critical to NMDA receptor function at the postsynaptic density, a cellular structure rich in the scaffolding protein, PSD-95. The extent to which the NMDA receptor NR1 subunit is altered at the site of action, in the postsynaptic density, is not clear.Aims:To extend our previous results by measuring levels of NR1 and PSD-95 protein in postsynaptic density-enriched fractions of prefrontal cortex from the same individuals in the case-control study noted above.Methods:Postsynaptic density-enriched fractions were isolated from fresh-frozen prefrontal cortex (BA10) and subjected to western blot analysis for NR1 and PSD-95.Results:We found a 20% decrease in NR1 protein (t(66)=−2.874, P=0.006) and a 30% decrease in PSD-95 protein (t(63)=−2.668, P=0.010) in postsynaptic density-enriched fractions from individuals with schizophrenia relative to unaffected controls.Conclusions:Individuals with schizophrenia have less NR1 protein, and therefore potentially fewer functional NMDA receptors, at the postsynaptic density. The associated decrease in PSD-95 protein at the postsynaptic density suggests that not only are glutamate receptors compromised in individuals with schizophrenia, but the overall spine architecture and downstream signaling supported by PSD-95 may also be deficient.
    Full-text · Article · Oct 2015
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    • "Because loss of parvalbumin neurons is associated with psychiatric disorders (Marin, 2012) and CLSTN2 variants are linked to cognitive function (Jacobsen et al, 2009; Pantzar et al, 2014; Papassotiropoulos et al, 2006), we next tested Clstn2 −/− mice in an array of behavioral assays. Tests were chosen to assess locomotor activity (open field), anxiety (elevated plus maze), behavioral despair (forced swim test), and multiple forms of learning and memory (Morris water maze, Barnes maze, novel object recognition, and displaced object recognition). "
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    ABSTRACT: Calsyntenin-2 plays an evolutionarily conserved role in cognition. In a human genome-wide screen, the CLSTN2 locus was associated with verbal episodic memory, and expression of human calsyntenin-2 rescues the associative learning defect in orthologous C. elegans mutants. Other calsyntenins promote synapse development, calsyntenin-1 selectively of excitatory synapses and calsyntenin-3 of excitatory and inhibitory synapses. We found that targeted deletion of calsyntenin-2 in mice results in a selective reduction in functional inhibitory synapses. Reduced inhibitory transmission was associated with a selective reduction of parvalbumin interneurons in hippocampus and cortex. Clstn2(-/-) mice showed normal behavior in elevated plus maze, forced swim test, and novel object recognition assays. However, Clstn2(-/-) mice were hyperactive in the open field and showed deficits in spatial learning and memory in the Morris water maze and Barnes maze. These results confirm a function for calsyntenin-2 in cognitive performance and indicate an underlying mechanism that involves parvalbumin interneurons and aberrant inhibitory transmission.Neuropsychopharmacology accepted article preview online, 14 July 2015. doi:10.1038/npp.2015.206.
    Full-text · Article · Jul 2015 · Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology
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