Dendritic Structural Degeneration Is Functionally Linked to Cellular Hyperexcitability in a Mouse Model of Alzheimer’s Disease

Šišková, Zuzana; Justus, Daniel; Kaneko, Hiroshi; Friedrichs, Detlef; Henneberg, Niklas; Beutel, Tatjana; Pitsch, Julika; Schoch, Susanne; Becker, Albert; Kammer, H. von der; Remy, Stefan

doi:10.1016/j.neuron.2014.10.024

Cited by 259 publications

(296 citation statements)

References 53 publications

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“…Furthermore, there were no differences in input resistance in our dendritic patchclamp recordings in hAPPJ20 mice. Thus, the dendritic hyperexcitability we observed is likely due to functional changes in channels, including Kv4.2, rather than structural changes, although the dendritic simplification that occurs with aging (Moolman et al, 2004;Šišková et al, 2014) likely adds to these effects. The dendritic hyperexcitability we observed in hAPPJ20 mice is not likely to be related directly to amyloid plaques, as it was observed at 3 months; initial amyloid plaques form at ϳ4 months of age in hAPPJ20 mice.…”

Section: Discussionmentioning

confidence: 80%

Tau-Dependent Kv4.2 Depletion and Dendritic Hyperexcitability in a Mouse Model of Alzheimer's Disease

Hall¹,

et al. 2015

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Neuronal hyperexcitability occurs early in the pathogenesis of Alzheimer's disease (AD) and contributes to network dysfunction in AD patients. In other disorders with neuronal hyperexcitability, dysfunction in the dendrites often contributes, but dendritic excitability has not been directly examined in AD models. We used dendritic patch-clamp recordings to measure dendritic excitability in the CA1 region of the hippocampus. We found that dendrites, more so than somata, of hippocampal neurons were hyperexcitable in mice overexpressing A␤. This dendritic hyperexcitability was associated with depletion of Kv4.2, a dendritic potassium channel important for regulating dendritic excitability and synaptic plasticity. The antiepileptic drug, levetiracetam, blocked Kv4.2 depletion. Tau was required, as crossing with tau knock-out mice also prevented both Kv4.2 depletion and dendritic hyperexcitability. Dendritic hyperexcitability induced by Kv4.2 deficiency exacerbated behavioral deficits and increased epileptiform activity in hAPP mice. We conclude that increased dendritic excitability, associated with changes in dendritic ion channels including Kv4.2, may contribute to neuronal dysfunction in early stages AD.

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Section: Discussionmentioning

confidence: 80%

Tau-Dependent Kv4.2 Depletion and Dendritic Hyperexcitability in a Mouse Model of Alzheimer's Disease

Hall¹,

et al. 2015

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“…Interestingly, the relative decrease in inhibition caused not only hyperactivity but, often, also an abnormal synchronization of neuronal firing, which may underlie the previously reported higher incidence of epileptiform activity in mouse models as compared to wild-type mice [22,23]. Meanwhile, neuronal hyperactivity has been observed in various transgenic mouse models of AD, including APP23 Â PS45 [18,24], APP23 [25], PDAPP [26], Tg2576 [26], APPswe/PS1D9 [27] and ARTE 10 [28] mice. Furthermore, hyperactivity can be induced by direct application of exogenous Ab into the rstb.royalsocietypublishing.org Phil.…”

Section: Impairment Of Cortical Neurons By Amyloid Plaquesmentioning

confidence: 97%

Impairments of neural circuit function in Alzheimer's disease

Busche

Konnerth

2016

Phil. Trans. R. Soc. B

270

240

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An essential feature of Alzheimer's disease (AD) is the accumulation of amyloid-β (Aβ) peptides in the brain, many years to decades before the onset of overt cognitive symptoms. We suggest that during this very extended early phase of the disease, soluble Aβ oligomers and amyloid plaques alter the function of local neuronal circuits and large-scale networks by disrupting the balance of synaptic excitation and inhibition ( E / I balance) in the brain. The analysis of mouse models of AD revealed that an Aβ-induced change of the E / I balance caused hyperactivity in cortical and hippocampal neurons, a breakdown of slow-wave oscillations, as well as network hypersynchrony. Remarkably, hyperactivity of hippocampal neurons precedes amyloid plaque formation, suggesting that hyperactivity is one of the earliest dysfunctions in the pathophysiological cascade initiated by abnormal Aβ accumulation. Therapeutics that correct the E / I balance in early AD may prevent neuronal dysfunction, widespread cell loss and cognitive impairments associated with later stages of the disease. This article is part of the themed issue ‘Evolution brings Ca 2+ and ATP together to control life and death’.

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“…Note, however, that some data do not support decreased excitation in AD. For instance, in the parietal cortex and hippocampus of mice expressing human amyloid precursor protein, nonconvulsive seizure activity resulting from an aberrant increase in network excitability was detected (Palop et al, 2007), and increased excitability of hippocampal CA1 pyramidal neurons was detected in APP/PS1 AD model mice (Siskova et al, 2014). …”

Section: Introductionmentioning

confidence: 99%

Effects of memantine on the excitation-inhibition balance in prefrontal cortex

Povysheva

Johnson

2016

Neurobiology of Disease

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Memantine is one of the few drugs currently approved for treatment of Alzheimer’s disease (AD). The clinical effects of memantine are thought to be associated with inhibition of NMDA receptors (NMDARs). Surprisingly, other open-channel NMDAR blockers have unacceptable side effects that prevent their consideration for AD treatment. One of the mechanisms proposed to explain the therapeutic benefits of memantine involves preferential decrease of excitatory drive to inhibitory neurons in the cortical circuitry and consequent changes in balance between excitation and inhibition (E/I). In this study we addressed effects of memantine on E/I balance in the prefrontal cortex (PFC). We found that a moderate concentration of memantine shifted E/I balance away from inhibition in the PFC circuitry. Indeed, memantine decreased the frequency and amplitude of spontaneous inhibitory postsynaptic currents in pyramidal neurons while leaving spontaneous excitatory postsynaptic currents unaffected. These circuitry effects of memantine were occluded by the competitive NMDAR inhibitor AP-5, and thus are associated with NMDAR inhibition. We also found that memantine decreased feed-forward disynaptic inhibitory input to pyramidal neurons, which is thought to be mediated by parvalbumin (PV)-positive interneurons. Accordingly, memantine caused a greater decrease of the amplitude of NMDAR-mediated synaptic responses in PV-positive interneurons than in pyramidal neurons. Finally, memantine reduced firing activity in PV-positive interneurons while increasing firing in pyramidal neurons. This study elucidates a novel mechanism of action of memantine associated with shifting of the E/I balance away from inhibition in neocortical circuitry, and provides important insights for AD drug development.

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Dendritic Structural Degeneration Is Functionally Linked to Cellular Hyperexcitability in a Mouse Model of Alzheimer’s Disease

Cited by 259 publications

References 53 publications

Tau-Dependent Kv4.2 Depletion and Dendritic Hyperexcitability in a Mouse Model of Alzheimer's Disease

Tau-Dependent Kv4.2 Depletion and Dendritic Hyperexcitability in a Mouse Model of Alzheimer's Disease

Impairments of neural circuit function in Alzheimer's disease

Effects of memantine on the excitation-inhibition balance in prefrontal cortex

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