Hyperactive ACC-MDT Pathway Suppresses Prepulse Inhibition in Mice

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Altered prepulse inhibition (PPI) is an endophenotype associated with multiple brain disorders, including schizophrenia. Circuit mechanisms that regulate PPI have been suggested, but none has been demonstrated through direct manipulations. IRSp53 is an abundant excitatory postsynaptic scaffold implicated in schizophrenia, autism spectrum disorders, and attention-deficit/hyperactivity disorder. We found that mice lacking IRSp53 in cortical excitatory neurons display decreased PPI. IRSp53-mutant layer 6 cortical neurons in the anterior cingulate cortex (ACC) displayed decreased excitatory synaptic input but markedly increased neuronal excitability, which was associated with excessive excitatory synaptic input in downstream mediodorsal thalamic (MDT) neurons. Importantly, chemogenetic inhibition of mutant neurons projecting to MDT normalized the decreased PPI and increased excitatory synaptic input onto MDT neurons. In addition, chemogenetic activation of MDT-projecting layer 6 neurons in the ACC decreased PPI in wild-type mice. These results suggest that the hyperactive ACC-MDT pathway suppresses PPI in wild-type and IRSp53-mutant mice.
Publisher
OXFORD UNIV PRESS
Issue Date
2021-01
Language
English
Article Type
Article
Citation

SCHIZOPHRENIA BULLETIN, v.47, no.1, pp.31 - 43

ISSN
0586-7614
DOI
10.1093/schbul/sbaa090
URI
http://hdl.handle.net/10203/285576
Appears in Collection
BS-Journal Papers(저널논문)
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