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

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

Published: Sept. 12, 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

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A novel enhancer-AAV approach selectively targeting dentate granule cells

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Feb. 4, 2023

The mammalian brain contains the most diverse array of cell types any organ, including dozens neuronal subtypes with distinct anatomical and functional characteristics. leverages these neuron-type-specializations to perform circuit operations thus execute different behaviors properly. Through use Cre lines, access specific neuron has steadily improved over past decades. Despite their extraordinary utility, development cross-breeding lines is time-consuming expensive, presenting a significant barrier entry for many investigators. Furthermore, cell-based therapeutics developed in mice are not clinically translatable. Recently, several AAV vectors utilizing neuron-type-specific regulatory transcriptional sequences (enhancer-AAVs) were which overcome limitations. Using publicly available RNAseq dataset, we evaluated potential candidate enhancers targeting hippocampus. Here identified promising enhancer-AAV dentate granule cells validated its selectivity wild-type adult mice.

Language: Английский

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Dysfunctional parvalbumin interneurons in a genetic mouse model of schizophrenia

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Sept. 10, 2023

Abstract The 22q11 deletion syndrome (22q11DS) is an interstitial microdeletion associated to increased risk of developing schizophrenia. In this disorder, there a dysfunction in the overall connectivity brain. Parvalbumin-expressing (PV + ) interneurons have been with multiple pre- and post-synaptic impairments that affect various brain regions. Specifically, previous results suggested alterations hippocampal networks may be related PV dysfunction. study, we used Df1 mouse model carries examine excitability cells dorsal CA1 region hippocampus, due its importance memory cognition. We found were hyperexcitable region. To understand source altered excitability, measured potassium currents, highly involved intrinsic firing properties neurons. observed voltage-gated channel subfamily A member 1 (K v 1.1) was impaired cells. Specific activation recovered some disturbances mice. Furthermore, blockade synaptic inputs also restored interneuron’s excitability. Taken together, these suggest hippocampus it partially mediated by K 1.1 22q11DS.

Language: Английский

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Entorhinal cortex vulnerability to human APP expression promotes hyperexcitability and tau pathology

Research Square (Research Square), Journal Year: 2023, Volume and Issue: unknown

Published: Nov. 6, 2023

Preventative treatment for Alzheimer’s Disease is of dire importance, and yet, cellular mechanisms underlying early regional vulnerability in remain unknown. In human patients with Disease, one the earliest observed pathophysiological correlates to cognitive decline hyperexcitability1. mouse models, hyperexcitability has been shown entorhinal cortex, first cortical region impacted by Disease2-4. The origin early-stage disease why it preferentially emerges specific regions unclear. Using cortical-region cell-type- proteomics patch-clamp electrophysiology, we uncovered differential susceptibility human-specific amyloid precursor protein (hAPP) a model sporadic Alzheimer’s. Unexpectedly, our findings reveal that may result from intrinsic parvalbumin interneurons, rather than suspected layer II excitatory neurons. This PV interneurons hAPP, as could not be recapitulated increased murine APP expression. Furthermore, Somatosensory Cortex showed no such adult-onset hAPP expression, likely resulting PV-interneuron variability between two based on physiological proteomic evaluations. Interestingly, hAPP-induced was quelled co-expression Tau at expense pathological tau species. study suggests interventions targeting non-excitatory cell types protect symptoms downstream decline.

Language: Английский

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Modelling the contributions to hyperexcitability in a mouse model of Alzheimer’s disease

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

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