Agenor Limon from University of Texas Presented in Translational Genomics Virtual Distinguished Lecture Series
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Electrophysiology of Human Native Receptors and its Integration in Multiomic Data in Health and DiseaseAgenor Limon, PhD Tuesday, November 9, 2021 |
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Alterations in synaptic function have been found in transcriptomic, genetic, and proteomic studies of neurological and mental disorders. Clinical and preclinical studies suggest that synaptic dysfunction and behavioral abnormalities in disorders like Alzheimer’s disease and schizophrenia may be mechanistically linked to the emergence of imbalances between excitatory (E) and inhibitory (I) receptors. However, until recently, the electrophysiological E/I synaptic ratio had only been measured in animal models. Using pioneering methods developed in the lab, that include the reactivation and microtransplantation of synaptic receptors from frozen human brains, we have obtained electrophysiological metrics of global synaptic E/I ratios in cortical brain regions of subjects that were affected by Alzheimer’s Disease and synaptic measurements in schizophrenia. By integrating these functional metrics with large datasets across different levels of complexity (anatomical, transcriptomic, proteomic) we found that the global synaptic E/I ratio in the cortex of subjects without a psychiatric or neuro- logical diagnosis is remarkable stable in humans across postmortem intervals and brain banks; however, in addition to the synaptic loss found in AD, there are severe E/I imbalances in cortical regions associated to the behavioral abnormalities commonly found in these disorders. These analyses provide a window on the physiology of neurotransmitter receptors that were working in the human brain, and an opportunity to use this knowledge in the development of effective therapeutic strategies.
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