p38 MAP kinase-mediated NMDA receptor-dependent suppression of hippocampal hypersynchronicity in a mouse model of Alzheimer’s disease

Ittner, Arne; Gladbach, Amadeus; Bertz, Josefine; Suh, Lisa S.; Ittner, Lars M.

doi:10.1186/s40478-014-0149-z

Cited by 66 publications

(55 citation statements)

References 70 publications

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“…These results are promising since there is a strong correlation between p38 activation and development of Alzheimer disease's model (Hensley et al, ; O'Donnell, Vereker, & Lynch, ; Savage, Lin, Ciallella, Flood, & Scott, ). In fact, in both the aging process and Alzheimer disease's animal model, p38 levels are found elevated in the brain (Hensley et al, ; O'Donnell et al, ; Ittner, Gladbach, Bertz, Suh, & Ittner, ). Moreover, it has been observed that p38 activation in the brain induces the formation of senile plaques, amyloid deposits, and tau phosphorylation in animal models of Alzheimer's disease (O'Donnell et al, ; Savage et al, ).…”

Section: Discussionmentioning

confidence: 99%

Aerobic exercise reduces hippocampal ERK and p38 activation and improves memory of middle‐aged rats

et al. 2017

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Aging is often accompanied by cognitive decline, memory impairment, and an increased susceptibility to neurodegenerative disorders. Although the physiological processes of aging are not fully understood, these age-related changes have been interpreted by means of various cellular and molecular theories. Among these theories, alterations in the intracellular signaling pathways associated with cell growth, proliferation, and survival have been highlighted. Based on these observations and on recent evidence showing the beneficial effects of exercise on cognitive function in the elderly, we investigated the cell signaling pathways in the hippocampal formation of middle-aged rats (18 months old) submitted to treadmill exercise over 10 days. To do this, we evaluated the hippocampal activation of intracellular signaling proteins linked to cell growth, proliferation, and survival, such as Akt, mTOR, p70S6K, ERK, CREB, and p38. We also explored the cognitive performance (inhibitory avoidance) of middle-aged rats. It was found that physical exercise reduces ERK and p38 activation in the hippocampal formation of aged rats, when compared to the control group. The hippocampal activation and expression of Akt, mTOR, p70S6K, and CREB were not statistically different between the groups. It was also observed that aged rats from the exercise group exhibited better cognitive performance in the inhibitory avoidance task (aversive memory) than aged rats from the control group. Our results indicate that physical exercise reduces intracellular signaling pathways linked to inflammation and cell death (i.e., ERK and p38) and improves memory in middle-aged rats.

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Section: Discussionmentioning

confidence: 99%

Aerobic exercise reduces hippocampal ERK and p38 activation and improves memory of middle‐aged rats

et al. 2017

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“…Place cell abnormalities have been reported in several mouse models of AD (Cacucci et al, 2008;Cheng and Ji, 2013;Zhao et al, 2014;Cayzac et al, 2015;Booth et al, 2016). Moreover, disturbed theta and gamma oscillations in the hippocampus have been observed in transgenic and Ab injection models of AD (Villette et al, 2010;Rubio et al, 2012;Cheng and Ji, 2013;Ittner et al, 2014;Schneider et al, 2014;Cayzac et al, 2015;Ciupek et al, 2015;Gillespie et al, 2016;Iaccarino et al, 2016). However, to our knowledge, no previous study has assessed rhythmic coordination of place cells by slow and fast gamma oscillations in an AD mouse model.…”

Section: Introductionmentioning

confidence: 99%

Impairments in spatial representations and rhythmic coordination of place cells in the 3xTg mouse model of Alzheimer's disease

et al. 2017

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Alzheimer's disease (AD) is an irreversible and highly progressive neurodegenerative disease. Clinically, patients with AD display impairments in episodic and spatial memory. However, the underlying neuronal dysfunctions that result in these impairments remain poorly understood. The hippocampus is crucial for spatial and episodic memory, and thus we tested the hypothesis that abnormal neuronal representations of space in the hippocampus contribute to memory deficits in AD. To test this hypothesis, we recorded spikes from place cells in hippocampal subfield CA1, together with corresponding rhythmic activity in local field potentials, in the 3xTg AD mouse model. We observed disturbances in place cell firing patterns, many of which were consistent with place cell disturbances reported in other rodent models of AD. We found place cell representations of space to be unstable in 3xTg mice compared to control mice. Furthermore, coordination of place cell firing by hippocampal rhythms was disrupted in 3xTg mice. Specifically, a smaller proportion of place cells from 3xTg mice were significantly phase-locked to theta and slow gamma rhythms, and the theta and slow gamma phases at which spikes occurred were also altered. Remarkably, these disturbances were observed at an age before detectable Aβ pathology had developed. Consistencies between these findings in 3xTg mice and previous findings from other AD models suggest that disturbances in place cell firing and hippocampal rhythms are related to AD rather than reflecting peculiarities inherent to a particular transgenic model. Thus, disturbed rhythmic organization of place cell activity may contribute to unstable spatial representations, and related spatial memory deficits, in AD. © 2017 Wiley Periodicals, Inc.

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“…Reduction in theta oscillation power has also been observed in other genetically modified AD mice models such as 3xTg (Mondragon-Rodriguez et al, 2018), CRND8 (Goutagny et al, 2013), and APP23 transgenic AD mice models (Ittner et al, 2014). However, in addition to the reduction of theta oscillation power, hypersynchrony and epileptic activities were also observed in transgenic AD mice models (Bezzina et al, 2015; Ittner et al, 2014; Palop and Mucke, 2010) which was absent in the AβO-injected mice in ours and other studies (Kalweit et al, 2015). Hence, long-term effects of AβO may cause differing effects on the hippocampal neural circuits, which will require further investigation.…”

Section: Discussionmentioning

confidence: 87%

Optogenetic activation of SST-positive interneurons restores hippocampal theta oscillation impairment induced by soluble amyloid beta oligomersin vivo

Chung¹,

Park²,

Jang³

et al. 2018

Preprint

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Abnormal accumulation of amyloid β oligomers (AβO) is a hallmark of Alzheimer's disease (AD), which leads to learning and memory deficits. Hippocampal theta oscillations that are critical in spatial navigation, learning and memory are impaired in AD. Since GABAergic interneurons, such as somatostatin-positive (SST+) and parvalbumin-positive (PV+)interneurons, are believed to play key roles in the hippocampal oscillogenesis, we asked whether AβO selectively impairs these SST+ and PV+ interneurons. To selectively manipulate SST+ or PV+ interneuron activity in mice with AβO pathology in vivo, we coinjected AβO and adeno-associated virus (AAV) for expressing floxed channelrhodopsin-2 (ChR2) into the hippocampus of SST-Cre or PV-Cre mice. Local field potential (LFP) recordings in vivo in these AβO-injected mice showed a reduction in the peak power of theta oscillations and desynchronization of spikes from CA1 pyramidal neurons relative to theta oscillations compared to those in control mice. Optogenetic-activation of SST+ but not PV+ interneurons in AβO-injected mice fully restored the peak power of theta oscillations and resynchronized the theta spike phases to a level observed in control mice. In vitro whole-cell voltage-clamp recordings in CA1 pyramidal neurons in hippocampal slices treated with AβO revealed that short-term plasticity of SST+ interneuron inhibitory inputs to CA1 pyramidal neurons at theta frequency were selectively disrupted while that of PV+ interneuron inputs were unaffected. Together, our results suggest that dysfunction in inputs from SST+ interneurons to CA1 pyramidal neurons may underlie the impairment of theta oscillations observed in AβO-injected mice in vivo. Our findings identify SST+ interneurons as a target for restoring theta-frequency oscillations in early AD.

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p38 MAP kinase-mediated NMDA receptor-dependent suppression of hippocampal hypersynchronicity in a mouse model of Alzheimer’s disease

Cited by 66 publications

References 70 publications

Aerobic exercise reduces hippocampal ERK and p38 activation and improves memory of middle‐aged rats

Aerobic exercise reduces hippocampal ERK and p38 activation and improves memory of middle‐aged rats

Impairments in spatial representations and rhythmic coordination of place cells in the 3xTg mouse model of Alzheimer's disease

Optogenetic activation of SST-positive interneurons restores hippocampal theta oscillation impairment induced by soluble amyloid beta oligomersin vivo

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