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Related Experiment Video

Updated: Dec 11, 2025

Isolation and Culture of Mouse Cortical Astrocytes
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Astrocyte DISC1 contributes to cognitive function in a brain region-dependent manner.

Alexey V Shevelkin1, Chantelle E Terrillion1, Yuto Hasegawa1

  • 1Departments of Psychiatry and Behavioral Sciences.

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Altering Disrupted-In-Schizophrenia-1 (DISC1) in hippocampal astrocytes impairs cognitive function and synaptic activity. This suggests DISC1

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Area of Science:

  • Neuroscience
  • Genetics
  • Cell Biology

Background:

  • Genetic risk factors for neuropsychiatric diseases primarily focus on neurodevelopment and neuronal function.
  • The role of genetic risk variants in glial cell physiology, particularly astrocytes, remains largely unexplored.
  • Previous research linked mutant Disrupted-In-Schizophrenia-1 (DISC1) to astrocyte metabolic dysfunction and cognitive deficits.

Purpose of the Study:

  • To investigate the region-specific effects of Disrupted-In-Schizophrenia-1 (DISC1) knockdown in mature astrocytes on behavior and physiology.
  • To determine if DISC1 knockdown in astrocytes impacts astrocyte bioenergetics and synaptic function.
  • To explore the potential regional differences in DISC1's influence on astrocyte function.

Main Methods:

  • Utilized a Disrupted-In-Schizophrenia-1 (DISC1) knockdown (Disc1-KD) model in mature mouse astrocytes from the prefrontal cortex (PFC) and hippocampus.
  • Assessed behavioral abnormalities, specifically trace fear conditioning, in adult mice.
  • Employed deep learning (convolutional deep neural networks - cDNNs) and single-cell analysis to examine astrocyte density, mitochondrial markers, and synaptic markers.

Main Results:

  • Disc1-KD in hippocampal astrocytes, but not PFC astrocytes, resulted in impaired trace fear conditioning.
  • Deep learning analysis revealed decreased spatial astrocyte density and altered mitochondrial marker distribution in Disc1-KD astrocytes.
  • Disc1-KD astrocytes showed reduced glutamatergic and increased GABA-ergic synaptic marker expression, linked to caspase 3 activation in nearby neurons.

Conclusions:

  • Altered Disrupted-In-Schizophrenia-1 (DISC1) expression in astrocytes can impair astrocyte bioenergetics.
  • Astrocyte DISC1 dysfunction leads to synaptic neurotransmission abnormalities and cognitive deficits in a region-dependent manner.
  • These findings highlight the critical role of astrocyte DISC1 in maintaining cognitive function and synaptic homeostasis.