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.

Early cognitive deficit characteristic of early Alzheimer's disease seems to be produced by the soluble forms of beta-amyloid protein. Such cognitive deficit correlates with neuronal network dysfunction that is reflected as alterations in the electroencephalogram of both Alzheimer patients and transgenic murine models of such disease. Correspondingly, recent studies have demonstrated that chronic exposure to betaAP affects hippocampal oscillatory properties. However, it is still unclear if such neuronal network dysfunction results from a direct action of betaAP on the hippocampal circuit or it is secondary to the chronic presence of the protein in the brain. Therefore, we aimed to explore the effect of acute exposure to betaAP(25-35) on hippocampal network activity both in vitro and in vivo, as well as on intrinsic and synaptic properties of hippocampal neurons. We found that betaAP(25-35), reversibly, affects spontaneous hippocampal population activity in vitro. Such effect is not produced by the inverse sequence betaAP(35-25) and is reproduced by the full-length peptide betaAP(1-42). Correspondingly betaAP(25-35), but not the inverse sequence betaAP(35-25), reduces theta-like activity recorded from the hippocampus in vivo. The betaAP(25-35)-induced disruption in hippocampal network activity correlates with a reduction in spontaneous neuronal activity and synaptic transmission, as well as with an inhibition in the subthreshold oscillations produced by pyramidal neurons in vitro. Finally, we studied the involvement of Fyn-kinase on the betaAP(25-35)-induced disruption in hippocampal network activity in vitro. Interestingly, we found that such phenomenon is not observed in slices obtained from Fyn-knockout mice. In conclusion, our data suggest that betaAP acutely affects proper hippocampal function through a Fyn-dependent mechanism. We propose that such alteration might be related to the cognitive impairment observed, at least, during the early phases of Alzheimer's disease.

In Alzheimer’s disease (AD) the accumulation of amyloid-β (Aβ) correlates with degradation of cognition-relevant gamma oscillations. The gamma rhythm relies on proper neuronal spike-gamma coupling, specifically of fast-spiking interneurons (FSN). Here we tested the hypothesis that decrease in gamma power and FSN synchrony precede amyloid plaque deposition and cognitive impairment in AppNL-G-F knock-in mice (AppNL-G-F). The aim of the study was to evaluate the amyloidogenic pathology progression in the novel AppNL-G-F mouse model using in vitro electrophysiological network analysis. Using patch clamp of FSNs and pyramidal cells (PCs) with simultaneous gamma oscillation recordings, we compared the activity of the hippocampal network of wild-type mice (WT) and the AppNL-G-F mice at four disease stages (1, 2, 4, and 6 months of age). We found a severe degradation of gamma oscillation power that is independent of, and precedes Aβ plaque formation, and the cognitive impairment reported previously in this animal model. The degradation correlates with increased Aβ1-42 concentration in the brain. Analysis on the cellular level showed an impaired spike-gamma coupling of FSN from 2 months of age that correlates with the degradation of gamma oscillations. From 6 months of age PC firing becomes desynchronized also, correlating with reports in the literature of robust Aβ plaque pathology and cognitive impairment in the AppNL-G-F mice. This study provides evidence that impaired FSN spike-gamma coupling is one of the earliest functional impairment caused by the amyloidogenic pathology progression likely is the main cause for the degradation of gamma oscillations and consequent cognitive impairment. Our data suggests that therapeutic approaches should be aimed at restoring normal FSN spike-gamma coupling and not just removal of Aβ.

Soluble amyloid beta (Abeta) oligomers might trigger early cognitive impairment in Alzheimer's Disease (AD) through the impairment of proper neuronal network function. We have recently shown that the short sequence Abeta(25-35) affects the spontaneous activity in hippocampal slices, when was added to the bath, at high nanomolar concentrations. In the present study, we aimed to characterize the effects of the oligomerized full length sequence Abeta(1-42) on the spontaneous network activity in the CA1 hippocampal area testing whether such effects are age dependent. By performing extracellular field recordings of spontaneous network activity of hippocampal slices, we found that an oligomerized solution of Abeta(1-42) (osAbeta) potently inhibit, in a dose-dependent manner, the spontaneous hippocampal network activity with an IC(50) of 0.4 +/- 3.2 nM and a maximal effect reached around 10 nM. While spontaneous hippocampal network activity is unaffected by age, the sensitivity of spontaneous hippocampal network activity to osAbeta (10 nM) appears to be increased in slices from older animals. Moreover, to see a significant reduction in spontaneous network activity in slices from animals in their second week of life 100nM osAbeta was needed. The osAbeta-induced reduction in hippocampal network activity is accompanied by a presynaptic reduction in both spontaneous and miniature synaptic potentials. Finally, we demonstrated that the effect produced by osAbeta on spontaneous network activity was specific, reversible and unrelated with cell death. In conclusion, our data show that osAbeta alters hippocampal network activity at concentrations commonly observed in AD patients and that such effect of osAbeta increase with age.

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