Biophysical K(v)3 channel alterations dampen excitability of cortical PV interneurons and contribute to network hyperexcitability in early Alzheimer's

• Type of Material: Article
• Authors: Viktor Olah, Emory University; Annie M Goettemoeller, Emory University; Sruti Rayaprolu, Emory University; Eric Dammer, Emory University; Nicholas Seyfried, Emory University; Srikant Rangaraju, Emory University; Jordane Dimidschstein, Broad Institute Cambridge; Matthew JM Rowan, Emory University
• Language: English
• Date: 2022-06-21
• Publisher: eLIFE SCIENCES PUBL LTD
• Publication Version: Final Published Version
• Copyright Statement: © 2022, Olah, Goettemoeller et al
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.7554/eLife.75316
• Title of Journal or Parent Work: ELIFE
• Volume: 11
• Grant/Funding Information: National Institutes of Health R01AG075820 to Srikant Rangaraju.; National Institutes of Health RF1AG071587 to Srikant Rangaraju, Nicholas T Seyfried.; National Institutes of Health R01AG061800 to Nicholas T Seyfried.; National Institutes of Health R01NS114130 to Srikant Rangaraju.; National Institutes of Health R56AG072473 to Matthew JM Rowan.; Alzheimer's Disease Research Center, Emory University 00100569 to Matthew JM Rowan.; This paper was supported by the following grants:; National Institutes of Health RF1AG062181 to Nicholas T Seyfried.; National Institutes of Health UG3MH120096 to Jordane Dimidschstein.; Simons Foundation 566615 to Jordane Dimidschstein.; National Institutes of Health R01MH111529 to Jordane Dimidschstein.; National Institutes of Health F32AG064862 to Sruti Rayaprolu.
• Keywords: PARVALBUMIN-POSITIVE INTERNEURONS; FAST-SPIKING; mass spectrometry; K(v)3; GABAERGIC INTERNEURONS; AXON INITIAL SEGMENT; GATED K+ CHANNELS; APP; gamma; NEURONAL HYPEREXCITABILITY; INHIBITORY INTERNEURONS; ACTION-POTENTIAL GENERATION; parvalbumin; Life Sciences & Biomedicine - Other Topics; MOUSE MODEL; action potential; Biology; Mouse; Life Sciences & Biomedicine; Science & Technology; POTASSIUM CHANNEL
• Research Categories: Biology, Cell; Chemistry, Biochemistry

Abstract

In Alzheimer’s disease (AD), a multitude of genetic risk factors and early biomarkers are known. Nevertheless, the causal factors responsible for initiating cognitive decline in AD remain controversial. Toxic plaques and tangles correlate with progressive neuropathology, yet disrup-tions in circuit activity emerge before their deposition in AD models and patients. Parvalbumin (PV) interneurons are potential candidates for dysregulating cortical excitability as they display altered action potential (AP) firing before neighboring excitatory neurons in prodromal AD. Here, we report a novel mechanism responsible for PV hypoexcitability in young adult familial AD mice. We found that biophysical modulation of Kv3 channels, but not changes in their mRNA or protein expression, were responsible for dampened excitability in young 5xFAD mice. These K+ conductances could effi-ciently regulate near-threshold AP firing, resulting in gamma-frequency-specific network hyperexcit-ability. Thus, biophysical ion channel alterations alone may reshape cortical network activity prior to changes in their expression levels. Our findings demonstrate an opportunity to design a novel class of targeted therapies to ameliorate cortical circuit hyperexcitability in early AD.