Abstract
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.
Highlights
One key feature of the pathophysiology of Alzheimer’s disease (AD) is beta-amyloid [Aβ(1-42)], a peptide that is a fundamental component of amyloid plaques: insoluble deposits of material within the brain that appear in the late stages of AD
In this study we provide novel evidence that absence of Panx1 causes an increase in neuronal excitability and of action potential firing frequency, as well as a reduction of spike frequency adaptation (SFA) in the CA1 region of the hippocampus compared to wt controls
We provide evidence of early adaptation of the hippocampus to acute hyperexcitability effects of Aβ that have been reported by others (Lei et al, 2016): 1 week following intracerebral inoculation with Aβ(1-42) we detected no generalized changes in neuronal excitability in ko and wt compared to their respective controls
Summary
One key feature of the pathophysiology of Alzheimer’s disease (AD) is beta-amyloid [Aβ(1-42)], a peptide that is a fundamental component of amyloid plaques: insoluble deposits of material within the brain that appear in the late stages of AD. Oligomeric Aβ(1-42) elevates intracellular Ca2+-levels that impairs neuronal viability (Hardy and Higgins, 1992; Mattson et al, 1992; Kuchibhotla et al, 2008) It triggers production of reactive oxygen species (Behl et al, 1994; Hensley et al, 1994) and activation of microglia (Combs et al, 1999), that contribute to the pathophysiology of AD. Intracerebral inoculation of healthy rats with oligomeric Aβ (1-42) triggers debilitations of hippocampal LTP that are accompanied by changes in neuronal oscillations (Kalweit et al, 2015) The latter effect may be supported by Pannexin (Panx1) channels shared by hippocampal neurons (Lopatár et al, 2015). Degranulation of mast cells by Aβ(1-25) is mediated by Panx (Harcha et al, 2015), suggesting that the hemichannel plays an active role in the pathophysiology of AD
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