DISC1 in Astrocytes Influences Adult Neurogenesis and Hippocampus-Dependent Behaviors in Mice

Abstract

The functional role of genetic variants in glia in the pathogenesis of psychiatric disorders remains poorly studied. Disrupted-In-Schizophrenia 1 (DISC1), a genetic risk factor implicated in major mental disorders, has been implicated in regulation of astrocyte functions. As both astrocytes and DISC1 influence adult neurogenesis in the dentate gyrus (DG) of the hippocampus, we hypothesized that selective expression of dominant-negative C-terminus-truncated human DISC1 (mutant DISC1) in astrocytes would affect adult hippocampal neurogenesis and hippocampus-dependent behaviors. A series of behavioral tests were performed in mice with or without expression of mutant DISC1 in astrocytes during late postnatal development. In conjunction with behavioral tests, we evaluated adult neurogenesis, including neural progenitor proliferation and dendrite development of newborn neurons in the DG. The ameliorative effects of D-serine on mutant DISC1-associated behaviors and abnormal adult neurogenesis were also examined. Expression of mutant DISC1 in astrocytes decreased neural progenitor proliferation and dendrite growth of newborn neurons, and produced elevated anxiety, attenuated social behaviors, and impaired hippocampus-dependent learning and memory. Chronic treatment with D-serine ameliorated the behavioral alterations and rescued abnormal adult neurogenesis in mutant DISC1 mice. Our findings suggest that psychiatric genetic risk factors expressed in astrocytes could affect adult hippocampal neurogenesis and contribute to aspects of psychiatric disease through abnormal production of D-serine.

Astrocytic Regulation of Glutamate Transmission in Schizophrenia

“…The downregulation of SR resulted in a significant decline in D-serine levels, an enhanced locomotor activity, and impaired responses to pre-pulse inhibition in the mutant mice ( 88 ). Mice carrying the astrocytic specific mutation of DISC1 also exhibited increased anxiety, attenuated social interaction and preference for social novelty, and impaired cognitive behaviors ( 90 ). These behavioral abnormalities in DISC1 mutant mice were reversed by treatments of D-serine ( 88 , 90 ), indicating a strong correlation with NMDAR hypofunction.…”

Peptide Sharing Between Viruses and DLX Proteins: A Potential Cross-Reactivity Pathway to Neuropsychiatric Disorders

“…Altered human neurogenesis is linked to neuropsychiatric conditions and to impaired cognition (Aimone et al, 2014 ). Also, alterations of the SVZ and hippocampus have been specifically related to some of the pathogenic and symptomatic aspects of schizophrenia (Reif et al, 2006 , 2007 ; Duan et al, 2007 ; Toro and Deakin, 2007 ; Christian et al, 2010 ; Aimone et al, 2014 ; Allen et al, 2016 ; Kang et al, 2016 ; Yun et al, 2016 ; Iannitelli et al, 2017 ; Terrillion et al, 2017 ).…”

Parvalbumin interneurons in the nucleus accumbens regulate impairment of risk avoidance inDISC1transgenic mice

“…Although many different DISC1 models have been generated, phenotypes have not always been consistent [6,50], and as such, the influence of the DISC1 gene on mental disorders remain elusive. As an important hub protein, DISC1 can interact with a number of synaptic or cytoskeletal molecules and modulate many cellular functions, such as synaptic plasticity [51] and neurogenesis [52,53]. As such, different mutant models (e.g., DISC1 mutation overexpressed model [8]) may influence DISC1 function to varying degrees and lead to different phenotypes.…”