Increased excitatory to inhibitory synaptic ratio in parietal cortex samples from individuals with Alzheimer’s disease

Julie C. Lauterborn (), Pietro Scaduto, Conor D. Cox, Anton Schulmann, Gary Lynch, Christine M. Gall, C. Dirk Keene and Agenor Limon ()
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Julie C. Lauterborn: University of California at Irvine
Pietro Scaduto: University of Texas Medical Branch at Galveston
Conor D. Cox: University of California at Irvine
Anton Schulmann: Human Genetics Branch
Gary Lynch: University of California at Irvine
Christine M. Gall: University of California at Irvine
C. Dirk Keene: University of Washington School of Medicine
Agenor Limon: University of Texas Medical Branch at Galveston

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: Abstract Synaptic disturbances in excitatory to inhibitory (E/I) balance in forebrain circuits are thought to contribute to the progression of Alzheimer’s disease (AD) and dementia, although direct evidence for such imbalance in humans is lacking. We assessed anatomical and electrophysiological synaptic E/I ratios in post-mortem parietal cortex samples from middle-aged individuals with AD (early-onset) or Down syndrome (DS) by fluorescence deconvolution tomography and microtransplantation of synaptic membranes. Both approaches revealed significantly elevated E/I ratios for AD, but not DS, versus controls. Gene expression studies in an independent AD cohort also demonstrated elevated E/I ratios in individuals with AD as compared to controls. These findings provide evidence of a marked pro-excitatory perturbation of synaptic E/I balance in AD parietal cortex, a region within the default mode network that is overly active in the disorder, and support the hypothesis that E/I imbalances disrupt cognition-related shifts in cortical activity which contribute to the intellectual decline in AD.

Date: 2021
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DOI: 10.1038/s41467-021-22742-8

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