Modelling the contributions to hyperexcitability in a mouse model of Alzheimer’s disease DOI Creative Commons
Martin Mittag, Laura Mediavilla, Stefan Remy

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2022, Volume and Issue: unknown

Published: July 2, 2022

Abstract Neuronal hyperexcitability is a feature of Alzheimer’s disease (AD). Three main mechanisms have been proposed to explain it: i), dendritic degeneration leading increased input resistance, ii), ion channel changes enhanced intrinsic excitability, and iii), synaptic excitation-inhibition ( E/I ) imbalance. However, the relative contribution these not fully understood. Therefore, we performed biophysically realistic multi-compartmental modelling excitability in reconstructed CA1 pyramidal neurons wild-type APP/PS1 mice, well-established animal model AD. We show that, for activation, promoting effects are cancelled out by decreasing loss. find an interesting balance regulation with basal dendrites cells potentially excitation apical but decreased Schaffer collateral pathway. Furthermore, our simulations reveal that three additional pathomechanistic scenarios can account experimentally observed increase firing bursting mice. Scenario 1: excitatory burst input; scenario 2: ratio 3: alteration channels I AHP down-regulated; Nap , Na CaT up-regulated) addition ratio. Our work supports hypothesis pathological network major contributors neuronal Overall, results line concept multi-causality degeneracy according which multiple different disruptions separately sufficient no single disruption necessary hyperexcitability. In brief Using computational model, extrinsic biophysical properties rather than alone altered behaviour Highlights Simulations synaptically driven responses PCs AD-related degeneration. Dendritic alters PC layer-specific required Possible Burst hyperactivity surrounding hyper-excitability during together inhibitory imbalance) lead PCs. Changes combined

Language: Английский

Epilepsy and epileptiform activity in late-onset Alzheimer disease: clinical and pathophysiological advances, gaps and conundrums DOI
Anita Kamondi, Madeleine Grigg‐Damberger, Wolfgang Löscher

et al.

Nature Reviews Neurology, Journal Year: 2024, Volume and Issue: 20(3), P. 162 - 182

Published: Feb. 14, 2024

Language: Английский

Citations

33
Native-state proteomics of Parvalbumin interneurons identifies unique molecular signatures and vulnerabilities to early Alzheimer’s pathology DOI Creative Commons
Prateek Kumar, Annie M Goettemoeller, Claudia Espinosa‐García

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: April 1, 2024

Abstract Dysfunction in fast-spiking parvalbumin interneurons (PV-INs) may represent an early pathophysiological perturbation Alzheimer’s Disease (AD). Defining proteomic alterations PV-INs can provide key biological and translationally-relevant insights. We used cell-type-specific in-vivo biotinylation of proteins (CIBOP) coupled with mass spectrometry to obtain native-state PV-IN proteomes. signatures include high metabolic translational activity, over-representation AD-risk cognitive resilience-related proteins. In bulk proteomes, were associated decline humans, progressive neuropathology humans the 5xFAD mouse model Aβ pathology. CIBOP stages pathology revealed increased mitochondria metabolism, synaptic cytoskeletal disruption decreased mTOR signaling, not apparent whole-brain Furthermore, we demonstrated pre-synaptic defects PV-to-excitatory neurotransmission, validating our findings. Overall, this study present proteomes PV-INs, revealing molecular insights into their unique roles resiliency AD pathogenesis.

Language: Английский

Citations

22
Parvalbumin Interneuron Dysfunction in Neurological Disorders: Focus on Epilepsy and Alzheimer’s Disease DOI Open Access
Beulah Leitch

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(10), P. 5549 - 5549

Published: May 19, 2024

Parvalbumin expressing (PV+) GABAergic interneurons are fast spiking neurons that provide powerful but relatively short-lived inhibition to principal excitatory cells in the brain. They play a vital role feedforward and feedback synaptic inhibition, preventing run away excitation neural networks. Hence, their dysfunction can lead hyperexcitability increased susceptibility seizures. PV+ also key players generating gamma oscillations, which synchronized oscillations associated with various cognitive functions. interneuron particularly vulnerable aging degeneration has been decline memory impairment dementia Alzheimer’s disease (AD). Overall, of disrupts normal excitatory/inhibitory balance within specific neurocircuits brain thus linked wide range neurodevelopmental neuropsychiatric disorders. This review focuses on dysfunctional inhibitory generation epileptic seizures potential as targets design future therapeutic strategies treat these Recent research using cutting-edge optogenetic chemogenetic technologies demonstrated they be selectively manipulated control restore activity brains animal models. suggests could important developing treatments for patients epilepsy comorbid disorders, such AD, where directly deficits.

Language: Английский

Citations

11
A structurally precise mechanism links an epilepsy-associated KCNC2 potassium channel mutation to interneuron dysfunction DOI
Jérôme Clatot, Christopher Brian Currin, Qiansheng Liang

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(3)

Published: Jan. 9, 2024

De novo heterozygous variants in KCNC2 encoding the voltage-gated potassium (K + ) channel subunit Kv3.2 are a recently described cause of developmental and epileptic encephalopathy (DEE). A de variant c.374G > (p.Cys125Tyr) was identified via exome sequencing patient with DEE. Relative to wild-type Kv3.2, Kv3.2-p.Cys125Tyr induces K currents exhibiting large hyperpolarizing shift voltage dependence activation, accelerated delayed deactivation consistent relative stabilization open conformation, along increased current density. Leveraging cryogenic electron microscopy (cryo-EM) structure Kv3.1, molecular dynamic simulations suggest that strong π-π stacking interaction between Tyr125 Tyr156 α-6 helix T1 domain promotes conformation channel, which underlies observed gain function. multicompartment computational model Kv3-expressing parvalbumin-positive cerebral cortex fast-spiking γ-aminobutyric acidergic (GABAergic) interneuron (PV-IN) demonstrates how Kv3.2-Cys125Tyr impairs neuronal excitability dysregulates inhibition circuits explain resulting epilepsy.

Language: Английский

Citations

10
Reduced excitatory neuron activity and interneuron-type-specific deficits in a mouse model of Alzheimer’s disease DOI Creative Commons
Moustafa Algamal, Alyssa N. Russ, Morgan R. Miller

et al.

Communications Biology, Journal Year: 2022, Volume and Issue: 5(1)

Published: Dec. 2, 2022

Abstract Alzheimer’s disease (AD) is characterized by progressive memory loss and cognitive decline. These impairments correlate with early alterations in neuronal network activity AD patients. Disruptions the of individual neurons have been reported mouse models amyloidosis. However, impact amyloid pathology on spontaneous distinct types remains unexplored vivo. Here we use vivo calcium imaging multiphoton microscopy to monitor compare excitatory two inhibitory interneurons cortices APP/PS1 control mice under isoflurane anesthesia. We also determine relationship between accumulation deficits mice. show that somatostatin-expressing (SOM) are hyperactive, while parvalbumin-expressing hypoactive Only SOM interneuron hyperactivity correlated proximity plaque. were accompanied decreased neuron Our study identifies cell-specific firing driven pathology. findings highlight importance addressing complexity neuron-specific ameliorate circuit dysfunction disease.

Language: Английский

Citations

32
Biophysical Kv3 channel alterations dampen excitability of cortical PV interneurons and contribute to network hyperexcitability in early Alzheimer’s DOI Creative Commons
Viktor Janos Oláh, Annie M Goettemoeller, Sruti Rayaprolu

et al.

eLife, Journal Year: 2022, Volume and Issue: 11

Published: June 21, 2022

In Alzheimer’s disease (AD), a multitude of genetic risk factors and early biomarkers are known. Nevertheless, the causal responsible for initiating cognitive decline in AD remain controversial. Toxic plaques tangles correlate with progressive neuropathology, yet disruptions circuit activity emerge before their deposition models patients. Parvalbumin (PV) interneurons potential candidates dysregulating cortical excitability as they display altered action (AP) firing neighboring excitatory neurons prodromal AD. Here, we report novel mechanism PV hypoexcitability young adult familial mice. We found that biophysical modulation K v 3 channels, but not changes mRNA or protein expression, were dampened 5xFAD These + conductances could efficiently regulate near-threshold AP firing, resulting gamma-frequency-specific network hyperexcitability. Thus, ion channel alterations alone may reshape prior to expression levels. Our findings demonstrate an opportunity design class targeted therapies ameliorate hyperexcitability

Language: Английский

Citations

25
Entorhinal cortex vulnerability to human APP expression promotes hyperexcitability and tau pathology DOI Creative Commons
Annie M Goettemoeller, Emmie Banks, Prateek Kumar

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Sept. 10, 2024

Language: Английский

Citations

5
Case Report: Targeted treatment by fluoxetine/norfluoxetine of a KCNC2 variant causing developmental and epileptic encephalopathy DOI Creative Commons
Ping Li,

Alice Butler,

Zhou Yu

et al.

Frontiers in Pharmacology, Journal Year: 2025, Volume and Issue: 15

Published: Jan. 15, 2025

The Kv3.2 subfamily of voltage activated potassium channels encoded by the KCNC2 gene is abundantly expressed in neurons that fire trains fast action potentials are a major source cortical inhibition. Gain-of-function (GOF) de novo pathogenic variants KCNC1 and KCNC2, encoding Kv3.1 respectively, cause several types epilepsy including developmental epileptic encephalopathy (DEE). Fluoxetine (Prozac) known inhibitor current was reported to improve seizure control single patient with GOF variant. Here, we describe fluoxetine treatment two siblings V473A variant associated DEE, which resulted improved control, ability wean antiepileptic medications, development. V437A showed activity as demonstrated HEK293 cells expressing subunits activating at more hyperpolarized than WT channels. reduced currents equally for both Kv3.2-V473A channels, an IC50 ∼12 µM. Further analysis this repurposed drug norfluoxetine, long-lasting metabolite produced liver accumulates brain, effective itself selectively inhibiting dominant channel allele. Norfluoxetine 7-fold greater selectivity (IC50 ∼0.4 µM) compared ∼2.9 µM). Combined previous report outcomes variant, our results suggest or its metabolite, may be beneficial patients other neuronal

Language: Английский

Citations

0
Role of Ion Channels in Alzheimer’s Disease Pathophysiology DOI Creative Commons

Ranjit Bhoi,

Tapan Mitra,

Kallam Tejaswi

et al.

The Journal of Membrane Biology, Journal Year: 2025, Volume and Issue: unknown

Published: May 1, 2025

Ion channels play an integral role in the normal functioning of brain. They regulate neuronal electrical properties like synaptic activity, generation action potentials, maintenance resting membrane potential and plasticity, modulate physiology non-neuronal cells astrocytes microglia. Dysregulation ionic homeostasis channelopathies are associated with various neurological disorders, including Alzheimer's disease (AD). Several families ion AD pathophysiology progression. In this review, we outline current research centered around channel dysregulation during discuss briefly possibility using as therapeutic targets.

Language: Английский

Citations

0
Altered firing output of VIP interneurons and early dysfunctions in CA1 hippocampal circuits in the 3xTg mouse model of Alzheimer’s disease DOI Creative Commons

Félix Michaud,

Ruggiero Francavilla,

Dimitry Topolnik

et al.

eLife, Journal Year: 2024, Volume and Issue: 13

Published: April 8, 2024

Alzheimer's disease (AD) leads to progressive memory decline, and alterations in hippocampal function are among the earliest pathological features observed human animal studies. GABAergic interneurons (INs) within hippocampus coordinate network activity, which type 3 interneuron-specific (I-S3) cells expressing vasoactive intestinal polypeptide calretinin play a crucial role. These provide primarily disinhibition principal excitatory (PCs) CA1 region, regulating incoming inputs formation. However, it remains unclear whether AD pathology induces changes activity of I-S3 cells, impacting motifs. Here, using young adult 3xTg-AD mice, we found that while density morphology remain unaffected, there were significant their firing output. Specifically, displayed elongated action potentials decreased rates, was associated with reduced inhibition INs higher recruitment during spatial decision-making object exploration tasks. Furthermore, activation PCs also impacted, signifying early disruptions functionality. findings suggest altered patterns might initiate early-stage dysfunction circuits, potentially influencing progression pathology.

Language: Английский

Citations

3