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Dominant-Negative DISC1 Alters the Dopaminergic Modulation of Inhibitory Interneurons in the Mouse Prefrontal Cortex
Ross A Cardarelli1, Rolicia Martin2, Hanna Jaaro-Peled3
1Program in Neuroscience, University of Maryland Medical School, Baltimore, Maryland, USA.
Molecular Neuropsychiatry
|July 13, 2018
Summary
A truncated Disrupted in Schizophrenia 1 (DISC1) gene impacts fast-spiking interneurons in mice, altering their function and dopamine modulation. This dysfunction contributes to psychiatric disorder pathophysiology.
Area of Science:
- Neuroscience
- Genetics
- Psychiatry
Background:
- A truncated Disrupted in Schizophrenia 1 (DISC1) gene is linked to increased psychiatric disorder risk.
- Cortical interneurons are implicated in the pathophysiology of psychiatric disorders.
Purpose of the Study:
- To investigate the effects of a truncated DISC1 allele (DN-DISC1) on cortical interneurons in mice.
- To assess electrophysiological properties and dopamine modulation in fast-spiking (FS) and low threshold-spiking (LTS) interneurons.
Main Methods:
- Whole-cell recordings were used to analyze electrophysiological properties.
- Dopamine modulation was assessed in FS and LTS interneurons from wild-type and DN-DISC1 mice.
- Morphology of perineuronal nets surrounding FS interneurons was examined.
Main Results:
- DN-DISC1 mice showed altered action potentials in FS interneurons, but not LTS interneurons.
- Abnormal morphology of perineuronal nets was observed around FS interneurons in DN-DISC1 mice.
- Dopamine modulation of FS interneurons was altered in DN-DISC1 mice.
Conclusions:
- Early-life manipulation of DISC1 leads to dysfunction, not loss, of specific GABAergic interneurons.
- Altered excitatory-inhibitory balance due to DISC1 dysfunction is a key factor in psychiatric pathophysiology.
- Findings highlight the role of specific interneuron subtypes in DISC1-associated psychiatric risks.
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