Abstract
The neurodevelopmental factor dysbindin is required for synapse function and GABA interneuron development. Dysbindin protein levels are reduced in the hippocampus of schizophrenia patients. Mouse dysbindin genetic defects and other mouse models of neurodevelopmental disorders share defective GABAergic neurotransmission and, in several instances, a loss of parvalbumin-positive interneuron phenotypes. This suggests that mechanisms downstream of dysbindin deficiency, such as those affecting GABA interneurons, could inform pathways contributing to or ameliorating diverse neurodevelopmental disorders. Here we define the transcriptome of developing wild type and dysbindin null Bloc1s8sdy/sdy mouse hippocampus in order to identify mechanisms downstream dysbindin defects. The dysbindin mutant transcriptome revealed previously reported GABA parvalbumin interneuron defects. However, the Bloc1s8sdy/sdy transcriptome additionally uncovered changes in the expression of molecules controlling cellular excitability such as the cation-chloride cotransporters NKCC1, KCC2, and NCKX2 as well as the potassium channel subunits Kcne2 and Kcnj13. Our results suggest that dysbindin deficiency phenotypes, such as GABAergic defects, are modulated by the expression of molecules controlling the magnitude and cadence of neuronal excitability.
Highlights
Dysbindin (Bloc1s8) is a subunit of the cytosolic heterooctamer known as the biogenesis of lysosome-related organelles complex 1 (BLOC-1)
We explored the ontological and anatomical penetrance of interneuron phenotypes in mouse mutants affecting three subunits of the dysbindin-BLOC-1 complex: dysbindin, muted, and pallid; which are encoded by the genes Bloc1s8, Bloc1s5, and Bloc1s6, respectively, in mouse (Larimore et al, 2014)
We propose that changes in the expression of NKCC1, KCC2, NCKX2, Kcne2, and Kcnj13 represent developmental adaptive responses to a reduced GABAergic tone induced by genetic defects in a neurodevelopmental gene, Bloc1s8
Summary
Dysbindin is a neurodevelopmental gene product encoded by DTNBP1, a gene whose polymorphisms influence cognitive and neuroanatomical traits in non-disease individuals. (Straub et al, 2002; Van Den Bogaert et al, 2003; Bray et al, 2005; Luciano et al, 2009; Markov et al, 2009, 2010; Mechelli et al, 2010; Cerasa et al, 2011; Tognin et al, 2011; Wolf et al, 2011; Ayalew et al, 2012; Trost et al, 2013). DTNBP1 polymorphisms have been considered risk factors for schizophrenia onset (Straub et al, 2002; Van Den Bogaert et al, 2003), Dysbindin Hippocampus Transcriptome yet this is not a consensus view (Schizophrenia Working Group of the Psychiatric Genomics Consortium, 2014; Farrell et al, 2015). The reduction of dysbindin in the hippocampus of patients with schizophrenia, alterations in excitatory/inhibitory signaling in the mouse, and changes in neurotransmission impacting short term memory in Drosophila demonstrate that dysbindin-dependent pathways provide insight into mechanisms of schizophrenia and other neurodevelopmental disorders. The focus of this work is the characterization of these dysbindin-dependent mechanisms and pathways in the developing mouse brain
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