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

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.

The Long-Term Pannexin 1 Ablation Produces Structural and Functional Modifications in Hippocampal Neurons

“…In addition to a large pore conformation with high conductance (100–550 pS) that mediates a non-selective ionic flux and ATP release [ 6 , 11 , 17 ], Panx1 channels also show a constitutive small pore activity characterized by low conductance (50–80 pS) driving a chloride permeability at negative voltages and outwardly rectifying current-voltage relations [ 7 , 8 , 9 , 10 ], which could influence the electrical properties of the cells and that can explain the modifications in the AP threshold upon Panx1 ablation. Accordingly, a recent report revealed higher excitability in the hippocampus of Panx1-KO mice [ 89 ].…”

Extracellular vesicles enriched with amylin receptor are cytoprotective against the Aß toxicity in vitro

“…This effect is deemed to involve direct sequestration of synaptotoxic Aβ assemblies by EV surface proteins such as cellular prion protein, PrP C , that is known to bind to Aβ. Several studies have also examined the improvements in hippocampal LTP following traumatic brain injury in rats [ 35 , 36 ], but to our knowledge, our study is the first to report an improvement in Aβ-induced reduction in hippocampal LTP in mouse brain slices following perfusion with AMY3, but not Wt, derived EVs. The rapid improvement in LTP within minutes of application of EVs would also seem to support a cell surface interaction between Aβ and AMY receptors on cell membranes of EVs.…”

Long-term Pannexin 1 ablation promotes structural and functional modifications in hippocampal neurons through the regulation of actin cytoskeleton and Rho GTPases activity

“…In addition to a large pore conformation with high conductance (100-550 pS), mediating a nonselective ionic flux and ATP release (6,14,16), PANX1 channels also show a constitutive small pore activity characterized by low conductance (50-80 pS) driving a chloride permeability at negative voltages and outwardly rectifying current-voltage relations (7-10), which could influence the electrical properties of the cells and can to explain the modifications in the action potential threshold upon PANX1 ablation. Accordingly, a recent report revealed a higher excitability in the hippocampus of PANX1-KO mice (68). CA1 pyramidal neurons exhibited a more positive resting membrane potential, a lower excitatory threshold, faster action potentials and a higher firing frequency compared to control littermates.…”