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Acute restraint stress reverses impaired LTP in the hippocampal CA1 region in mouse models of Alzheimer's disease.

ABSTRACT: Acute stress facilitates long-term potentiation (LTP) in the mouse hippocampus by modulating glucocorticoid receptors and ion channels. Here, we analysed whether this occurs in mouse models of Alzheimer's disease (AD) with impaired LTP induction. We found that a brief 30 min restraint stress protocol reversed the impaired LTP assessed with field excitatory postsynaptic potential recordings at cornu ammonis 3-1 (CA3-CA1) synapses in both Tg2576 and 5XFAD mice. This effect was accompanied by increased phosphorylation and surface expression of glutamate A1 (GluA1) -containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). Moreover, enhanced LTP induction and GluA1 phosphorylation were sustained up to 4 h after the stress. Treatment with 200 nM dexamethasone produced similar effects in the hippocampi of these mice, which supports the glucocorticoid receptor-mediated mechanism in these models. Collectively, our results demonstrated an alleviation of impaired LTP and synaptic plasticity in the hippocampal CA1 region following acute stress in the AD mouse models.

SUBMITTER: Wang M

PROVIDER: S-EPMC6662902 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Acute restraint stress reverses impaired LTP in the hippocampal CA1 region in mouse models of Alzheimer's disease.

Wang Ming M Ramasamy Vijay Sankar VS Samidurai Manikandan M Jo Jihoon J

Scientific reports 20190729 1

Acute stress facilitates long-term potentiation (LTP) in the mouse hippocampus by modulating glucocorticoid receptors and ion channels. Here, we analysed whether this occurs in mouse models of Alzheimer's disease (AD) with impaired LTP induction. We found that a brief 30 min restraint stress protocol reversed the impaired LTP assessed with field excitatory postsynaptic potential recordings at cornu ammonis 3-1 (CA3-CA1) synapses in both Tg2576 and 5XFAD mice. This effect was accompanied by incre ...[more]

PMID: 31358853

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Project description:Hippocampal sharp wave/ripple oscillations are a prominent pattern of collective activity, which consists of a strong overall increase of activity with superimposed (140 - 200 Hz) ripple oscillations. Despite its prominence and its experimentally demonstrated importance for memory consolidation, the mechanisms underlying its generation are to date not understood. Several models assume that recurrent networks of inhibitory cells alone can explain the generation and main characteristics of the ripple oscillations. Recent experiments, however, indicate that in addition to inhibitory basket cells, the pattern requires in vivo the activity of the local population of excitatory pyramidal cells. Here, we study a model for networks in the hippocampal region CA1 incorporating such a local excitatory population of pyramidal neurons. We start by investigating its ability to generate ripple oscillations using extensive simulations. Using biologically plausible parameters, we find that short pulses of external excitation triggering excitatory cell spiking are required for sharp/wave ripple generation with oscillation patterns similar to in vivo observations. Our model has plausible values for single neuron, synapse and connectivity parameters, random connectivity and no strong feedforward drive to the inhibitory population. Specifically, whereas temporally broad excitation can lead to high-frequency oscillations in the ripple range, sparse pyramidal cell activity is only obtained with pulse-like external CA3 excitation. Further simulations indicate that such short pulses could originate from dendritic spikes in the apical or basal dendrites of CA1 pyramidal cells, which are triggered by coincident spike arrivals from hippocampal region CA3. Finally we show that replay of sequences by pyramidal neurons and ripple oscillations can arise intrinsically in CA1 due to structured connectivity that gives rise to alternating excitatory pulse and inhibitory gap coding; the latter denotes phases of silence in specific basket cell groups, which induce selective disinhibition of groups of pyramidal neurons. This general mechanism for sequence generation leads to sparse pyramidal cell and dense basket cell spiking, does not rely on synfire chain-like feedforward excitation and may be relevant for other brain regions as well.

Project description:Alzheimer's disease (AD), the most common form of dementia, is characterized by neuronal degeneration and cerebrovascular dysfunction. Increasing evidence indicates that cerebrovascular dysfunction may be a key or an aggravating pathogenic factor in AD. This emphasizes the importance to investigate the tight coupling between neuronal activity and cerebral blood flow (CBF) termed neurovascular coupling (NVC). NVC depends on all cell types of the neurovascular unit within which astrocytes are important players in the progression of AD. Hence, the objective of this study was to characterize the hippocampal NVC in a mouse model of AD. Hippocampal NVC was studied in 6-month-old amyloid-beta precursor protein (APP) transgenic mice and their corresponding wild-type littermates using in vivo laser Doppler flowmetry to measure CBF in area CA1 of the hippocampus in response to Schaffer collaterals stimulation. Ex vivo two-photon microscopy experiments were performed to determine astrocytic Ca2+ and vascular responses to electrical field stimulation (EFS) or caged Ca2+ photolysis in hippocampal slices. Neuronal synaptic transmission, astrocytic endfeet Ca2+ in correlation with reactive oxygen species (ROS), and vascular reactivity in the presence or absence of Tempol, a mimetic of superoxide dismutase, were further investigated using electrophysiological, caged Ca2+ photolysis or pharmacological approaches. Whisker stimulation evoked-CBF increases and ex vivo vascular responses to EFS were impaired in APP mice compared with their age-matched controls. APP mice were also characterized by decreased basal synaptic transmission, a shorter astrocytic Ca2+ increase, and altered vascular response to elevated perivascular K+. However, long-term potentiation, astrocytic Ca2+ amplitude in response to EFS, together with vascular responses to nitric oxide remained unchanged. Importantly, we found a significantly increased Ca2+ uncaging-induced ROS production in APP mice. Tempol prevented the vascular response impairment while normalizing astrocytic Ca2+ in APP mice. These findings suggest that NVC is altered at many levels in APP mice, at least in part through oxidative stress. This points out that therapies against AD should include an antioxidative component to protect the neurovascular unit.

Dataset Information

Acute restraint stress reverses impaired LTP in the hippocampal CA1 region in mouse models of Alzheimer's disease.

Publications

Acute restraint stress reverses impaired LTP in the hippocampal CA1 region in mouse models of Alzheimer's disease.

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