Dysbindin Deficiency Modifies the Expression of GABA Neuron and Ion Permeation Transcripts in the Developing Hippocampus

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.

Inhibitory control of the excitatory/inhibitory balance in psychiatric disorders

“…Family-based association data have identified dysbindin ( DTNBP1 ) as a susceptibility gene for schizophrenia 172 , whose dominant circuit impact is impaired inhibition 173 . Dysbindin KO mice show a reduced number of PV interneurons in hippocampal CA1 173 , 174 , and transcriptome changes of various proteins involved the regulation of intrinsic properties 174 . Recordings from PV interneurons in dysbindin KO mice show a reduction in action potential frequency resulting in a reduced inhibitory drive 126 .…”

Developmental Genes and Regulatory Proteins, Domains of Cognitive Impairment in Schizophrenia Spectrum Psychosis and Implications for Antipsychotic Drug Discovery: The Example of Dysbindin-1 Isoforms and Beyond

“…Investigation of transcriptional responses of developing hippocampal neurons in sdy/B6 mutants revealed not only the characteristic GABAergic interneuron deficiency but also changes in expression of the cation-chloride cotransporters NKCC1 and KCC2 during hippocampal development (Larimore et al, 2017). NKCC1 and KCC2 expression changes have been documented in the brains of patients with schizophrenia (Hyde et al, 2011;Sullivan et al, 2015) and NKCC1 agents, including the NKCC1 chloride antagonist bumetanide, have been studied in schizophrenia.…”

Sleep/Wake Disruption in a Mouse Model of BLOC-1 Deficiency

“…BLOC-1 expression in the mouse central nervous system is developmentally regulated with higher expression during perinatal periods ( Ghiani et al, 2010 ), and in its absence, hippocampal neurones in cultures exhibit defective neurite outgrowth ( Ghiani et al, 2010 ; Ito et al, 2010 ; Ma et al, 2011 ). Behavioural and neurophysiological abnormalities have been reported in the sandy mouse, a naturally occuring mutant carrying an in-frame deletion in the gene encoding dysbindin (reviewed by Ghiani and Dell’Angelica, 2011 , for examples see Bhardwaj et al, 2009 ; Cox et al, 2009 ; Ryder and Faundez, 2009 ; Talbot, 2009 ; Papaleo et al, 2012 ; Carr et al, 2013 ; Glen et al, 2014 ; Larimore et al, 2014 , 2017 ; Bhardwaj et al, 2015a ; Yuan et al, 2016 ) as well as in other dysbindin-mutants ( Petit et al, 2017 ; Chang et al, 2018 ). Importantly, Spiegel et al (2015) reported that the pallid and sandy lines show similar impairment of social recognition memory.…”