Impaired pattern separation in Tg2576 mice is associated with hyperexcitable dentate gyrus caused by Kv4.1 downregulation

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that causes memory loss. Most AD researches have focused on neurodegeneration mechanisms. Considering that neurodegenerative changes are not reversible, understanding early functional changes before neurodegeneration is critical to develop new strategies for early detection and treatment of AD. We found that Tg2576 mice exhibited impaired pattern separation at the early preclinical stage. Based on previous studies suggesting a critical role of dentate gyrus (DG) in pattern separation, we investigated functional changes in DG of Tg2576 mice. We found that granule cells in DG (DG-GCs) in Tg2576 mice showed increased action potential firing in response to long depolarizations and reduced 4-AP sensitive K+-currents compared to DG-GCs in wild-type (WT) mice. Among Kv4 family channels, Kv4.1 mRNA expression in DG was significantly lower in Tg2576 mice. We confirmed that Kv4.1 protein expression was reduced in Tg2576, and this reduction was restored by antioxidant treatment. Hyperexcitable DG and impaired pattern separation in Tg2576 mice were also recovered by antioxidant treatment. These results highlight the hyperexcitability of DG-GCs as a pathophysiologic mechanism underlying early cognitive deficits in AD and Kv4.1 as a new target for AD pathogenesis in relation to increased oxidative stress.

Rescue of astrocyte activity by the calcium sensor STIM1 restores long-term synaptic plasticity in female mice modelling Alzheimer’s disease

“…Noteworthy, the classic version of ORT could not detect a memory deficit even at this age. On the one hand, such observation could spring from different pattern separation abilities required by the different pairs of stimuli utilized in the ORT with respect to tORT, taking into account that in FAD pattern separation is impaired in both mice 58 and humans 59 . On the other hand, the stimuli utilized in the classic ORT activate different sensory areas, i.e., they are objects with different shapes, colors, and textures, with respect to tactile-only stimuli.…”

Dentate Granule Cells Are Hyperexcitable in the TgF344-AD Rat Model of Alzheimer's Disease

“…Increased DGC excitability has been reported in other transgenic rodent models of AD (Hazra et al, 2013 ; Nenov et al, 2015 ; Kim et al, 2021 ). We recently reported increased steady-state postsynaptic depolarization of DGCs during high-frequency stimulation and heightened LTP magnitude at MPP-DGC synapses in 6-month-old TgF344-AD rats (Smith and McMahon, 2018 ; Goodman et al, 2021 ).…”

“…While our somatic recordings did not reveal a difference in AHP, whether the threshold for local dendritic I A current is altered or if a downregulation of K + current is responsible for the increased excitability is not known. An elegant study by Kim et al ( 2021 ) in Tg2576 mice shows that decreased expression of Kv4.1 causes DGC hyperexcitability that is associated with impaired pattern recognition. It is possible that loss of Kv4.1 is also occurring in TgF344-AD DG that is leading to increased excitability.…”

Novel Approaches Used to Examine and Control Neurogenesis in Parkinson′s Disease

“…This mechanism underlies the ability of young dentate gyrus cells to support pattern separation and the ability of old dentate gyrus cells to support rapid recall and pattern completion [16]. That is why hyperexcitable dentate gyrus results in cognitive deficits and the impairment of pattern separation in mice [17].…”