Schizophrenia-associated LRRTM1 regulates cognitive behavior through controlling synaptic function in the mediodorsal thalamus.
Mol Psychiatry
; 26(11): 6912-6925, 2021 11.
Article
in En
| MEDLINE
| ID: mdl-33981006
ABSTRACT
Reduced activity of the mediodorsal thalamus (MD) and abnormal functional connectivity of the MD with the prefrontal cortex (PFC) cause cognitive deficits in schizophrenia. However, the molecular basis of MD hypofunction in schizophrenia is not known. Here, we identified leucine-rich-repeat transmembrane neuronal protein 1 (LRRTM1), a postsynaptic cell-adhesion molecule, as a key regulator of excitatory synaptic function and excitation-inhibition balance in the MD. LRRTM1 is strongly associated with schizophrenia and is highly expressed in the thalamus. Conditional deletion of Lrrtm1 in the MD in adult mice reduced excitatory synaptic function and caused a parallel reduction in the afferent synaptic activity of the PFC, which was reversed by the reintroduction of LRRTM1 in the MD. Our results indicate that chronic reduction of synaptic strength in the MD by targeted deletion of Lrrtm1 functionally disengages the MD from the PFC and may account for cognitive, social, and sensorimotor gating deficits, reminiscent of schizophrenia.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Schizophrenia
Type of study:
Risk_factors_studies
Limits:
Animals
Language:
En
Journal:
Mol Psychiatry
Journal subject:
BIOLOGIA MOLECULAR
/
PSIQUIATRIA
Year:
2021
Document type:
Article
Affiliation country:
Canada