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

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.

Case Studies in Neuroscience: Evidence of motor thalamus reorganization following bilateral forearm amputations.

Following injury, functional improvement can result from central nervous system plasticity. Use-dependent plasticity of motor systems is evident, for example, in recovery of function resulting from rehabilitative interventions. Here, we present a single patient who underwent bilateral microelectrode-guided stereotactic implantation of deep brain stimulating leads for the treatment of essential tremor 52 yr following bilateral arm amputations. The tremor affected his upper extremities and had rendered him unable to perform fine motor tasks with his prostheses, significantly reducing his independence. We found a large territory of neurons in the ventral intermediate nucleus of his thalamus that responded to shoulder protraction, the movement that he used to control fine motor movements of his terminal hook prostheses. We propose that reorganization of this motor nucleus may have occurred secondary to a use-dependent gain of function in neurons that were previously involved in hand movement. NEW & NOTEWORTHY We had a unique opportunity to record neurons in the ventrointermediate (Vim) motor nucleus of thalamus in a patient with essential tremor, decades following bilateral forearm amputations. We demonstrate that a large region of Vim is active during shoulder protraction-the movement used to operate the patient's mechanical prostheses. We suggest that this provides evidence of human motor thalamic plasticity.