TrpV1 receptor activation rescues neuronal function and network gamma oscillations from Aβ-induced impairment in mouse hippocampus in vitro

Abstract

Amyloid-β peptide (Aβ) forms plaques in Alzheimer’s disease (AD) and is responsible for early cognitive deficits in AD patients. Advancing cognitive decline is accompanied by progressive impairment of cognition-relevant EEG patterns such as gamma oscillations. The endocannabinoid anandamide, a TrpV1-receptor agonist, reverses hippocampal damage and memory impairment in rodents and protects neurons from Aβ-induced cytotoxic effects. Here, we investigate a restorative role of TrpV1-receptor activation against Aβ-induced degradation of hippocampal neuron function and gamma oscillations. We found that the TrpV1-receptor agonist capsaicin rescues Aβ-induced degradation of hippocampal gamma oscillations by reversing both the desynchronization of AP firing in CA3 pyramidal cells and the shift in excitatory/inhibitory current balance. This rescue effect is TrpV1-receptor-dependent since it was absent in TrpV1 knockout mice or in the presence of the TrpV1-receptor antagonist capsazepine. Our findings provide novel insight into the network mechanisms underlying cognitive decline in AD and suggest TrpV1 activation as a novel therapeutic target.

TRPV1 Tunes Optic Nerve Axon Excitability in Glaucoma

“…Recent evidence shows widespread TRPV1 expression in the central nervous system (CNS) tissues, including the cortex, hippocampus, hypothalamus, and retina (Mezey et al, 2000;Roberts et al, 2004;Cristino et al, 2006;Sappington et al, 2009Sappington et al, , 2015Jo et al, 2017;Lakk et al, 2018). TRPV1 has also been implicated in neurodegenerative disorders such as Alzheimer's disease (Jayant et al, 2016;Balleza-Tapia et al, 2018), Parkinson's disease (Marinelli et al, 2003;Morgese et al, 2007;Nam et al, 2015;Chung et al, 2017), Huntington's disease (Lastres-Becker et al, 2003), and glaucomatous optic neuropathy, or glaucoma (Ward et al, 2014;Weitlauf et al, 2014). Glaucoma is the leading cause of irreversible blindness (Quigley and Broman, 2006), involving sensitivity to intraocular pressure (IOP) that stresses retinal ganglion cell (RGC) axons as they form the optic nerve (Calkins, 2012).…”

TRP Channels as Emerging Therapeutic Targets for Neurodegenerative Diseases

“…Cell damage is attenuated by an intracellular Ca 2+ -chelator. In a recent study, the activity of TRPV1 was reported to decrease Aβ-induced cytotoxicity (Balleza-Tapia et al, 2018). Treatment with a TRPV1 agonist rescued Aβ-induced degradation of hippocampal neuron function (Figure 2A).…”

“…TRPM2 expression is involved in synapse loss, microglial activation, and spatial memory deficits in APP/PS1 mice (Ostapchenko et al, 2015). Activation of TRPV1 channels is required to trigger longterm depression at interneuronal synapses (Gibson et al, 2008) and prevents Aβ-involved impairment of functional networks in the hippocampus (Balleza-Tapia et al, 2018). Astrocytic Ca 2+ hyperactivity is induced by Aβ oligomers via TRPA1 in the hippocampus.…”

Single amyloid‐beta injection exacerbates 4‐aminopyridine‐induced seizures and changes synaptic coupling in the hippocampus

“…Direct application of Aβ can disrupt spontaneous oscillatory network activity in vitro (Adaya‐Villanueva, Ordaz, Balleza‐Tapia, Márquez‐Ramos, & Peña‐Ortega, ; Balleza‐Tapia, Huanosta‐Gutiérrez, Márquez‐Ramos, Arias, & Peña, ; Gutiérrez‐Lerma, Ordaz, & Peña‐Ortega, ; Peña et al, ; Peña‐Ortega, Solis‐Cisneros, Ordaz, Balleza‐Tapia, & Javier, ) and in vivo (Colom et al, ; Cornejo‐Montes‐de‐Oca, Hernández‐Soto, Isla, Morado‐Urbina, & Peña‐Ortega, ; Peña‐Ortega & Bernal‐Pedraza, ; Villette et al, ). The cellular mechanisms involved in Aβ‐induced disruption of neural network activity comprise changes in synaptic transmission (Balleza‐Tapia et al, ; Mura et al, ; Peña et al, ; Salamone et al, ; Satoh et al, ) and in intrinsic neuronal properties (Chen, ; Hou, Cui, Yu, & Zhang, ; Mondragón‐Rodríguez, Gu, et al, ; Peña et al, ; Rovira, Arbez, & Mariani, ; Shankar & Walsh, ; Ye, Selkoe, & Hartley, ), which involve direct actions of Aβ on ion channels (Balleza‐Tapia et al, ; Chen, ; Hou et al, ; Rovira et al, ; Shankar & Walsh, ; Ye et al, ) and/or their modulation through the activation of intracellular transduction pathways (Ekinci, Malik, & Shea, ; Wildburger & Laezza, ; Zhu et al, ). At the synaptic level, Aβ produces alterations at both presynaptic (Balleza‐Tapia et al, ; Cuevas et al, ; Dougherty, Wu, & Nichols, ; Nimmrich & Ebert, ; Peña et al, ; Ting, Kelley, Lambert, Cook, & Sullivan, ) and postsynaptic levels (Dinamarca, Ríos, & Inestrosa, ; Gylys et al, ; Harigaya, Shoji, Shirao, & Hirai, ; Hatanpaa, Isaacs, Shirao, Brady, & Rapoport, ; Ting et al, ).…”