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Hyperactive ACC-MDT Pathway Suppresses Prepulse Inhibition in Mice.
Yangsik Kim1,2,3, Young Woo Noh4, Kyungdeok Kim4
1Mental Health Research Institute, National Center for Mental Health, Seoul, South Korea.
Schizophrenia Bulletin
|July 5, 2020
Summary
Altered prepulse inhibition (PPI) in mice lacking IRSp53 suggests this protein is crucial for regulating brain circuits. Inhibiting specific neuronal pathways normalized PPI, revealing a potential therapeutic target for brain disorders.
Area of Science:
- Neuroscience
- Molecular Biology
- Psychiatry
Background:
- Altered prepulse inhibition (PPI) is a key endophenotype in brain disorders like schizophrenia.
- IRSp53, an excitatory postsynaptic scaffold, is linked to schizophrenia, autism, and ADHD.
- Circuit mechanisms regulating PPI remain incompletely understood.
Purpose of the Study:
- To investigate the role of IRSp53 in regulating PPI.
- To elucidate the circuit mechanisms underlying PPI deficits associated with IRSp53 deficiency.
Main Methods:
- Generated mice lacking IRSp53 in cortical excitatory neurons.
- Utilized chemogenetics to manipulate neuronal activity in the anterior cingulate cortex (ACC) and mediodorsal thalamus (MDT) pathway.
- Measured PPI and neuronal excitability in wild-type and mutant mice.
Main Results:
- Mice lacking IRSp53 exhibited decreased PPI and increased neuronal excitability in ACC layer 6 neurons.
- Hyperactivity in the ACC-MDT pathway was observed in IRSp53-mutant mice.
- Chemogenetic inhibition of ACC-MDT neurons normalized PPI in mutant mice, while activation decreased PPI in wild-type mice.
Conclusions:
- IRSp53 is critical for regulating excitatory synaptic input and neuronal excitability in the ACC.
- The hyperactive ACC-MDT pathway suppresses PPI, offering a mechanistic link between IRSp53 and PPI deficits.
- Targeting the ACC-MDT pathway may represent a therapeutic strategy for brain disorders characterized by altered PPI.
