Schizophrenia-associated LRRTM1 regulates cognitive behavior through controlling synaptic function in the mediodorsal...

Area of Science:

• Neuroscience
• Molecular Biology
• Psychiatry

Background:

• Schizophrenia is linked to mediodorsal thalamus (MD) hypofunction and altered MD-prefrontal cortex (PFC) connectivity, causing cognitive deficits.
• The molecular mechanisms underlying MD hypofunction in schizophrenia remain largely unknown.
• Leucine-rich-repeat transmembrane neuronal protein 1 (LRRTM1) is a postsynaptic cell-adhesion molecule implicated in synaptic function and associated with schizophrenia.

Purpose of the Study:

• To investigate the role of LRRTM1 in regulating excitatory synaptic function within the MD.
• To determine if LRRTM1 dysfunction contributes to MD hypofunction and associated cognitive deficits in schizophrenia models.

Main Methods:

• Conditional deletion of the Lrrtm1 gene in the MD of adult mice.
• Assessment of excitatory synaptic function and synaptic activity in the MD and PFC.
• Reintroduction of LRRTM1 in the MD to observe reversal of deficits.

Main Results:

• Conditional deletion of Lrrtm1 in the MD significantly reduced excitatory synaptic function.
• This reduction in synaptic function led to a parallel decrease in afferent synaptic activity from the PFC.
• Reintroducing LRRTM1 in the MD successfully reversed these synaptic deficits.

Conclusions:

• LRRTM1 is a critical regulator of excitatory synaptic function and excitation-inhibition balance in the MD.
• Targeted reduction of LRRTM1 in the MD functionally disengages the MD from the PFC.
• LRRTM1 dysfunction in the MD may underlie cognitive, social, and sensorimotor gating deficits observed in schizophrenia.