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

Molecular Psychiatry volume 26, pages 6912–6925 (2021)Cite this article

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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.

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Fig. 1: Conditional knockout of Lrrtm1 in the MD.
Fig. 2: Lrrtm1 deletion in mature MD neurons reduces excitatory but not inhibitory synaptic strength and reduces synaptic levels of AMPAR subunits.
Fig. 3: Lrrtm1 deletion in mature MD neurons impairs cognitive and social behavior and disrupts sensorimotor gating.
Fig. 4: LRRTM1 controls synaptic function in MD relay neurons projecting to PFC.
Fig. 5: Lrrtm1 deletion in the MD reduces afferent synaptic activity in the PFC.

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Acknowledgements

This work was supported by grants from CIHR (MOP-142209 to T.J.S., MOP-125901 to M.F.J. and MOP-89758 to G.J.K.), NSERC (RGPIN-2015-05994 to T.J.S., RGPIN-05477-2017 to M.F.J. and RGPIN-2016-05964 J.H.K.), Research Manitoba (to T.J.S. and J.H.K.) and Alzheimer’s Society of Canada (to M.F.J.).

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Authors and Affiliations

  1. Kleysen Institute for Advanced Medicine, Health Sciences Centre, Winnipeg, MB, Canada

    Benyamin Karimi, Prabhisha Silwal, Samuel Booth, Nirmala Padmanabhan, Shreya H. Dhume, Dali Zhang, Nazmeena Zahra, Michael F. Jackson, Ji Hyun Ko & Tabrez J. Siddiqui

  2. Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, MB, Canada

    Benyamin Karimi, Prabhisha Silwal, Nirmala Padmanabhan, Shreya H. Dhume, Nazmeena Zahra, Jeremy W. Chopek & Tabrez J. Siddiqui

  3. Department of Human Anatomy and Cell Science, University of Manitoba, Winnipeg, MB, Canada

    Samuel Booth, Dali Zhang & Ji Hyun Ko

  4. Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, MB, Canada

    Michael F. Jackson

  5. Department of Oral Biology and Psychiatry, University of Manitoba, Winnipeg, MB, Canada

    Gilbert J. Kirouac

  6. Biomedical Engineering Program, University of Manitoba, Winnipeg, MB, Canada

    Ji Hyun Ko & Tabrez J. Siddiqui

  7. The Children’s Hospital Research Institute of Manitoba, Winnipeg, MB, Canada

    Tabrez J. Siddiqui

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  1. Benyamin Karimi
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Contributions

T.J.S. conceived the research; B.K. and T.J.S. designed the research; B.K. performed the bulk of the experiments and analysis (85%), P.S., S.B., N.P., S.D., D.Z., and N.Z. contributed to the experiments and analysis; M.F.J. and J.W.C. advised on electrophysiology experiments; and G.K. advised on the behavior experiments; J.H.K. supervised the FDG-PET experiments; B.K. and T.J.S. wrote the paper. All authors read and approved the paper.

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Correspondence to Tabrez J. Siddiqui.

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Karimi, B., Silwal, P., Booth, S. et al. Schizophrenia-associated LRRTM1 regulates cognitive behavior through controlling synaptic function in the mediodorsal thalamus. Mol Psychiatry 26, 6912–6925 (2021). https://doi.org/10.1038/s41380-021-01146-6

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