Dataset Information

Altered Kv2.1 functioning promotes increased excitability in hippocampal neurons of an Alzheimer's disease mouse model.

ABSTRACT: Altered neuronal excitability is emerging as an important feature in Alzheimer's disease (AD). Kv2.1 potassium channels are important modulators of neuronal excitability and synaptic activity. We investigated Kv2.1 currents and its relation to the intrinsic synaptic activity of hippocampal neurons from 3xTg-AD (triple transgenic mouse model of Alzheimer's disease) mice, a widely employed preclinical AD model. Synaptic activity was also investigated by analyzing spontaneous [Ca(2+)]i spikes. Compared with wild-type (Non-Tg (non-transgenic mouse model)) cultures, 3xTg-AD neurons showed enhanced spike frequency and decreased intensity. Compared with Non-Tg cultures, 3xTg-AD hippocampal neurons revealed reduced Kv2.1-dependent Ik current densities as well as normalized conductances. 3xTg-AD cultures also exhibited an overall decrease in the number of functional Kv2.1 channels. Immunofluorescence assay revealed an increase in Kv2.1 channel oligomerization, a condition associated with blockade of channel function. In Non-Tg neurons, pharmacological blockade of Kv2.1 channels reproduced the altered pattern found in the 3xTg-AD cultures. Moreover, compared with untreated sister cultures, pharmacological inhibition of Kv2.1 in 3xTg-AD neurons did not produce any significant modification in Ik current densities. Reactive oxygen species (ROS) promote Kv2.1 oligomerization, thereby acting as negative modulator of the channel activity. Glutamate receptor activation produced higher ROS levels in hippocampal 3xTg-AD cultures compared with Non-Tg neurons. Antioxidant treatment with N-Acetyl-Cysteine was found to rescue Kv2.1-dependent currents and decreased spontaneous hyperexcitability in 3xTg-AD neurons. Analogous results regarding spontaneous synaptic activity were observed in neuronal cultures treated with the antioxidant 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (Trolox). Our study indicates that AD-related mutations may promote enhanced ROS generation, oxidative-dependent oligomerization, and loss of function of Kv2.1 channels. These processes can be part on the increased neuronal excitability of these neurons. These steps may set a deleterious vicious circle that eventually helps to promote excitotoxic damage found in the AD brain.

SUBMITTER: Frazzini V

PROVIDER: S-EPMC5399189 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Altered Kv2.1 functioning promotes increased excitability in hippocampal neurons of an Alzheimer's disease mouse model.

Frazzini V V Guarnieri S S Bomba M M Navarra R R Morabito C C Mariggiò M A MA Sensi S L SL

Cell death & disease 20160218

Altered neuronal excitability is emerging as an important feature in Alzheimer's disease (AD). Kv2.1 potassium channels are important modulators of neuronal excitability and synaptic activity. We investigated Kv2.1 currents and its relation to the intrinsic synaptic activity of hippocampal neurons from 3xTg-AD (triple transgenic mouse model of Alzheimer's disease) mice, a widely employed preclinical AD model. Synaptic activity was also investigated by analyzing spontaneous [Ca(2+)]i spikes. Comp ...[more]

PMID: 26890139

Similar Datasets

Project description:Duchenne muscular dystrophy (DMD) is generally regarded as a muscle-wasting disease. However, human patients and animal models of DMD also frequently display non-progressive cognitive deficits and high comorbidity with neurodevelopmental disorders, suggesting impaired central processing. Previous studies have identified the cerebellar circuit, and aberrant inhibitory transmission in Purkinje cells, in particular, as a potential site of dysfunction in the central nervous system (CNS). In this work, we investigate potential dysfunction in the output of the cerebellum, downstream of Purkinje cell (PC) activity. We examined synaptic transmission and firing behavior of excitatory projection neurons of the cerebellar nuclei, the primary output of the cerebellar circuit, in juvenile wild-type and mdx mice, a common mouse model of DMD. Using immunolabeling and electrophysiology, we found a reduced number of PC synaptic contacts, but no change in postsynaptic GABAA receptor expression or clustering in these cells. Furthermore, we found that the replenishment rate of synaptic vesicles in Purkinje terminals is reduced in mdx neurons, suggesting that dysfunction at these synapses may be primarily presynaptic. We also found changes in the excitability of cerebellar nuclear neurons. Specifically, we found greater spontaneous firing but reduced evoked firing from a hyperpolarized baseline in mdx neurons. Analysis of action potential waveforms revealed faster repolarization and greater after-hyperpolarization of evoked action potentials in mdx neurons, suggesting an increased voltage- or calcium- gated potassium current. We did not find evidence of dystrophin protein or messenger RNA (mRNA) expression in wild-type nuclear neurons, suggesting that the changes observed in these cells are likely due to the loss of dystrophin in presynaptic PCs. Together, these data suggest that the loss of dystrophin reduces the dynamic range of synaptic transmission and firing in cerebellar nuclear neurons, potentially disrupting the output of the cerebellar circuit to other brain regions and contributing to cognitive and neurodevelopmental deficits associated with DMD.

Dataset Information

Altered Kv2.1 functioning promotes increased excitability in hippocampal neurons of an Alzheimer's disease mouse model.

Publications

Altered Kv2.1 functioning promotes increased excitability in hippocampal neurons of an Alzheimer's disease mouse model.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets