Acute Pannexin 1 Blockade Mitigates Early Synaptic Plasticity Defects in a Mouse Model of Alzheimer’s Disease

Flores‐Muñoz, Carolina; Gómez, Bárbara; Mery, Elena; Mujica, Paula; Gajardo, Ivana; Córdova, Claudio; López-Espíndola, Daniela; Duran‐Aniotz, Claudia; Hetz, Claudio; Muñoz, Pablo; González‐Jamett, Arlek M.; Ardiles, Álvaro O.

doi:10.3389/fncel.2020.00046

Cited by 24 publications

(22 citation statements)

References 105 publications

(180 reference statements)

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“…Thus, inhibition of Panx1 might serve to maintain neuroprotective processes that in turn sustain hippocampal function at least in the early phases of AD. Consistent with this proposal, others have shown in a transgenic mouse model of AD, where APP and presenilin1 are overrexpressed, that blockade of Panx1 ameliorated synaptic defects in 6 months old APP/presenilin1 tg mice, and normalized LTP (Flores-Muñoz et al, 2020). Interestingly, this study also reported increased Panx1 expression in APP/presenilin1 tg mice suggesting that changes in Panx1 may contribute to the progress of AD.…”

Section: Discussionsupporting

confidence: 88%

Absence of Pannexin 1 Stabilizes Hippocampal Excitability After Intracerebral Treatment With Aβ (1-42) and Prevents LTP Deficits in Middle-Aged Mice

Südkamp

Shchyglo

Manahan‐Vaughan

2021

Front. Aging Neurosci.

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Beta-amyloid protein [Aβ(1-42)] plays an important role in the disease progress and pathophysiology of Alzheimer's disease (AD). Membrane properties and neuronal excitability are altered in the hippocampus of transgenic AD mouse models that overexpress amyloid precursor protein. Although gap junction hemichannels have been implicated in the early pathogenesis of AD, to what extent Pannexin channels contribute to Aβ(1-42)-mediated brain changes is not yet known. In this study we, therefore, investigated the involvement of Pannexin1 (Panx1) channels in Aβ-mediated changes of neuronal membrane properties and long-term potentiation (LTP) in an animal model of AD. We conducted whole-cell patch-clamp recordings in CA1 pyramidal neurons 1 week after intracerebroventricular treatments of adult wildtype (wt) and Panx1 knockout (Panx1-ko) mice with either oligomeric Aβ(1-42), or control peptide. Panx1-ko hippocampi treated with control peptide exhibited increased neuronal excitability compared to wt. In addition, action potential (AP) firing frequency was higher in control Panx1-ko slices compared to wt. Aβ-treatment reduced AP firing frequency in both cohorts. But in Aβ-treated wt mice, spike frequency adaptation was significantly enhanced, when compared to control wt and to Aβ-treated Panx1-ko mice. Assessment of hippocampal LTP revealed deficits in Aβ-treated wt compared to control wt. By contrast, Panx1-ko exhibited LTP that was equivalent to LTP in control ko hippocampi. Taken together, our data show that in the absence of Pannexin1, hippocampi are more resistant to the debilitating effects of oligomeric Aβ. Both Aβ-mediated impairments in spike frequency adaptation and in LTP that occur in wt animals, are ameliorated in Panx1-ko mice. These results suggest that Panx1 contributes to early changes in hippocampal neuronal and synaptic function that are triggered by oligomeric Aβ.

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Section: Discussionsupporting

confidence: 88%

Absence of Pannexin 1 Stabilizes Hippocampal Excitability After Intracerebral Treatment With Aβ (1-42) and Prevents LTP Deficits in Middle-Aged Mice

Südkamp

Shchyglo

Manahan‐Vaughan

2021

Front. Aging Neurosci.

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“…PANX1 is a protein involved in the modulation of neurotransmission, neurogenesis and synaptic plasticity [189] , [272] . An increase of this protein under inflammatory conditions contributes to neuronal death [273] . Aβ can also bind to several postsynaptic partners, including NMDAR and type 1 metabotropic glutamate receptor 5(mGluR5) [189] .…”

Section: Neurodevelopment and Neurotransmission Associated Processesmentioning

confidence: 99%

The biological pathways of Alzheimer disease: a review

et al. 2021

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“…To evaluate long-term potentiation (LTP), slices were subjected to a high-frequency electrical stimulation protocol or a chemical stimulation protocol. LTP using high-frequency electrical stimulation was performed using a standard theta burst (TBS) protocol, which consists of 4 trains at 100 Hz for 1 min (Flores-Muñoz et al 2020;Gajardo et al 2018). On the other hand, chemical LTP (chLTP) was induced by perfusing a glycine solution (glycine, Gly 600 µM + picrotoxin, PTX 50 µM + strychnine Stric 3 µM) (X. Y.…”

Section: Field Electrophysiological Recordingsmentioning

confidence: 99%

A centronuclear myopathy-causing mutation in dynamin-2 perturbs the actin-dependent structure of dendritic spines leading to excitatory synaptic defects in a murine model of the disease

Arriagada-Diaz

Gómez

Prado-Vega

et al. 2021

Preprint

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Dynamin-2 is a large GTP-ase, member of the dynamin superfamily, that regulates membrane remodeling and cytoskeleton dynamics. In the mammalian nervous system dynamin-2 modulates synaptic vesicle (SV)-recycling at the nerve terminals and receptor-trafficking to and from postsynaptic densities (PSDs). Mutations in dynamin-2 cause autosomal dominant centronuclear myopathy (CNM), a congenital neuromuscular disorder characterized by progressive weakness and atrophy of distal skeletal muscles. Cognitive defects have also been reported in dynamin-2-linked CNM patients suggesting a concomitant impairment of the central nervous system. Here we addressed the mechanisms that lead to cognitive defects in dynamin-2-linked CNM using a knock-in mouse model that harbors the p.R465W mutation in dynamin-2, the most common causing CNM. Our results show that these mice exhibit reduced capability to learn and acquire spatial and recognition memory, impaired long-term potentiation of the excitatory synaptic strength and perturbed dendritic spine morphology, which seem to be associated with actin defects. Together, these data reveal for the first time that structural and functional synaptic defects underlie cognitive defects in the CNM context. In addition our results contribute to the still scarce knowledge about the importance of dynamin-2 at central synapses.

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Acute Pannexin 1 Blockade Mitigates Early Synaptic Plasticity Defects in a Mouse Model of Alzheimer’s Disease

Cited by 24 publications

References 105 publications

Absence of Pannexin 1 Stabilizes Hippocampal Excitability After Intracerebral Treatment With Aβ (1-42) and Prevents LTP Deficits in Middle-Aged Mice

Absence of Pannexin 1 Stabilizes Hippocampal Excitability After Intracerebral Treatment With Aβ (1-42) and Prevents LTP Deficits in Middle-Aged Mice

The biological pathways of Alzheimer disease: a review

A centronuclear myopathy-causing mutation in dynamin-2 perturbs the actin-dependent structure of dendritic spines leading to excitatory synaptic defects in a murine model of the disease

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