Kleysen Institute for Advanced Medicine, Health Sciences Centre, Winnipeg, MB, Canada.
Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, MB, Canada.
Mol Psychiatry. 2021 Nov;26(11):6912-6925. doi: 10.1038/s41380-021-01146-6. Epub 2021 May 12.
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.
中脑背内侧核（MD）活性降低以及 MD 与前额叶皮层（PFC）之间的异常功能连接导致精神分裂症患者认知功能障碍。然而，精神分裂症中 MD 功能低下的分子基础尚不清楚。在这里，我们确定富含亮氨酸的重复跨膜神经元蛋白 1（LRRTM1）作为 MD 中兴奋性突触功能和兴奋-抑制平衡的关键调节因子，LRRTM1 与精神分裂症密切相关，并且在丘脑中有很高的表达。在成年小鼠中条件性敲除 MD 中的 Lrrtm1 会降低兴奋性突触功能，并导致 PFC 的传入突触活动平行减少，而在 MD 中重新引入 LRRTM1 则可逆转这种减少。我们的研究结果表明，通过靶向敲除 Lrrtm1 导致 MD 中突触强度的慢性降低，使 MD 与 PFC 功能脱钩，这可能导致认知、社会和感觉运动门控缺陷，类似于精神分裂症。
