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


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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    • "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.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 07/2015; DOI:10.1038/npp.2015.206 · 7.05 Impact Factor
    • "Disruptions in the molecular building blocks of interneurons have also been reported ( Woo et al . , 2008 ; Marin , 2012 ; Nakazawa et al . , 2012 ) . "
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    ABSTRACT: Schizophrenia is a devastating mental illness. Although its aetiology is still largely unknown, strides have been taken throughout the last several decades to elucidate the nature of the neuropathology behind this disorder. The advent of neuroimaging technologies such as CT and MRI have progressed knowledge about the macroscopic brain changes that occur in schizophrenia, including the characteristic reduced ventricle size and reductions in gray matter volume, whole brain volume, and white matter anisotropy. Although this review presents a broad outline of current and historical neuropathological research in research, the focus is primarily on the quantitative neuropathology of the cerebral cortex in schizophrenia, which may underlie many of the larger scale changes observed. The reduced neuropil hypothesis has been suggested as a microanatomical explanation to account for these macroscopic changes, although the present review finds that evidence does not always support this. A quantitative summary of these studies, focused on neuron density, provides support for the finding of increased neuron density in schizophrenia, with variation dependent on age. This is consistent with neuroimaging data and implicates an altered aging trajectory as a factor in the pathogenesis of schizophrenia. Combined with evidence from other neuroanatomical studies reviewed here, as well as studies in childhood-onset schizophrenia the evidence converges on a progressive neurodevelopmental model of schizophrenia related to altered neuroplasticity. The evidence also supports a particular vulnerability of inhibitory cortical circuits with markers of interneurons showing some of the more consistent reductions in schizophrenia. Copyright © 2015. Published by Elsevier Ltd.
    Neuroscience 06/2015; 303. DOI:10.1016/j.neuroscience.2015.06.028 · 3.36 Impact Factor
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    • "The reciprocal connections between PV and pyramidal cells are crucial for generation of the gamma oscillation (Bartos et al. 2007). Since loss of PV expression, especially in the superficial layers of the frontal cortex, and reduction of gamma oscillations are pathophysiological hallmarks of schizophrenia, impaired PV function may contribute to this disease (Hashimoto et al. 2003; Marín 2012; Uhlhaas and Singer 2012; Lewis 2014; Cho et al. 2015). Thus, L2/3b PV cells may participate in both the fast feedforward inhibition caused by thalamocortical inputs and the generation of gamma oscillations in cooperation with nearby pyramidal cells. "
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    ABSTRACT: Most glutamatergic inputs in the neocortex originate from the thalamus or neocortical pyramidal cells. To test whether thalamocortical afferents selectively innervate specific cortical cell subtypes and surface domains, we investigated the distribution patterns of thalamocortical and corticocortical excitatory synaptic inputs in identified postsynaptic cortical cell subtypes using intracellular and immunohistochemical staining combined with confocal laser scanning and electron microscopic observations in 2 thalamorecipient sublayers, lower layer 2/3 (L2/3b) and lower layer 5 (L5b) of rat frontal cortex. The dendrites of GABAergic parvalbumin (PV) cells preferentially received corticocortical inputs in both sublayers. The somata of L2/3b PV cells received thalamic inputs in similar proportions to the basal dendritic spines of L2/3b pyramidal cells, whereas L5b PV somata were mostly innervated by cortical inputs. The basal dendrites of L2/3b pyramidal and L5b corticopontine pyramidal cells received cortical and thalamic glutamatergic inputs in proportion to their local abundance, whereas crossed-corticostriatal pyramidal cells in L5b exhibited a preference for thalamic inputs, particularly in their distal dendrites. Our data demonstrate an exquisite selectivity among thalamocortical afferents in which synaptic connectivity is dependent on the postsynaptic neuron subtype, cortical sublayer, and cell surface domain. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail:
    Cerebral Cortex 06/2015; DOI:10.1093/cercor/bhv124 · 8.67 Impact Factor
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