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.
"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). "
[Show abstract][Hide abstract] 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 ) . "
"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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