No abstract

theoretical and experimental work has demonstrated that excitatory (e) and inhibitory (i) currents within cortical circuits stabilize to a balanced state. This E/I balance, observed from single neuron to network levels, has a fundamental role in proper brain function and its impairment has been linked to numerous brain disorders. Over recent years, large amount of microarray and RNA-Sequencing datasets have been collected, however few studies have made use of these resources for exploring the balance of global gene expression levels between excitatory AMpA receptors (AMpARs) and inhibitory GABA A receptors. Here, we analyzed the relative relationships between these receptors to generate a basic transcriptional marker of E/I ratio. Using publicly available data from the Allen Brain Institute, we generated whole brain and regional signatures of AMpAR subunit gene expression in healthy human brains as well as the transcriptional e/i (tE/I) ratio. Then we refined the tE/I ratio to cell-type signatures in the mouse brain using data from the Gene Expression Omnibus. Lastly, we applied our workflow to developmental data from the Allen Brain institute and revealed spatially and temporally controlled changes in the te/i ratio during the embryonic and early postnatal stages that ultimately lead to the te/i balance in adults.

Individuals at distinct stages of Alzheimer’s disease (AD) show abnormal electroencephalographic activity, which has been linked to network hyperexcitability and cognitive decline. However, whether pro-excitatory changes at the synaptic level are observed in brain areas affected early in AD, and if they are emergent in MCI, is not clearly known. Equally important, it is not known whether global synaptic E/I imbalances correlate with the severity of cognitive impairment in the continuum of AD. Measuring the amplitude of ion currents of human excitatory and inhibitory synaptic receptors microtransplanted from the hippocampus and temporal cortex of cognitively normal, mildly cognitively impaired and AD individuals into surrogate cells, we found regional differences in pro-excitatory shifts of the excitatory to inhibitory (E/I) current ratio that correlates positively with toxic proteins and degree of pathology, and impinges negatively on cognitive performance scores. Using these data with electrophysiologically anchored analysis of the synapto-proteome in the same individuals, we identified a group of proteins sustaining synaptic function and those related to synaptic toxicity. We also found an uncoupling between the function and expression of proteins for GABAergic signaling in the temporal cortex underlying larger E/I and worse cognitive performance. Further analysis of transcriptomic and in situ hybridization datasets from an independent cohort across the continuum of AD confirm regional differences in pro-excitatory shifts of the E/I balance that correlate negatively with the most recent calibrated composite scores for memory, executive function, language and visuospatial abilities, as well as overall cognitive performance. These findings indicate that early shifts of E/I balance may contribute to loss of cognitive capabilities in the continuum of AD clinical syndrome.