Low dose of levetiracetam counteracts amyloid ß-induced alterations of hippocampal gamma oscillations by restoring fast-spiking interneuron activity.

Alzheimer's disease (AD) is characterized at an early stage by memory alterations that worsen during the development of the disease. Several clinical trials in phase 3 have failed despite being able to counteract classical AD-related alterations, possibly because of the lack of recovery of the regular neuronal network activity essential for memory including low gamma oscillations (γ-Osc). Nowadays, Levetiracetam (LEV), an SV2A modulator approved for epilepsy, is being used in trials with AD patients without further support for neurophysiological relevant effects on restoring the normal function of hippocampal neuronal network activity. Using concomitant recordings of local field potential γ-Osc and patch-clamp recordings of fast-spiking interneurons (FS-IN) on hippocampal slices of WT and AppNL-G-F AD animals, we found that LEV restores the power and rhythmicity of γ-Osc previously reduced by acute application of amyloid-ß on WT hippocampal slices, this effect is accompanied by the recovery of the synchronicity in the firing of FS-IN. In addition, we found that LEV counteracts the hippocampal γ-Osc alterations in the early prodromal stage of the disease in AppNL-G-F mice by recovering the rhythmicity of γ-Osc and the synchronicity in the firing of FS-IN. Altogether the results show that the precise modulation of neuronal circuits with LEV is a promising strategy to counteract early-stage alterations in hippocampal activity by modulating FS-IN in a memory-relevant neuronal network state like γ-Osc.

Functionally-distinct pyramidal cell subpopulations during gamma oscillations in mouse hippocampal area CA3.

Gamma oscillations (γ-oscillations) in hippocampal area CA3 are essential for memory function. Particularly, CA3 is involved in the memory related process pattern completion, which is linked with the γ-oscillations in human hippocampus. Recent studies suggest that heterogeneity in the functional properties of pyramidal cells (PCs) in CA3 plays an important role in hippocampal function. By performing concomitant recordings of PC activity and network γ-oscillations in CA3 we found three functionally-different PC subpopulations. PCs with high spike-frequency adaptation (hAPC) have the strongest action potential gamma phase-coupling, PCs with low adaptation (lAPC) show lower phase-coupling and PCs displaying a burst-firing pattern (BPC) remained quiescent. In addition, we discovered that hAPC display the highest excitatory/inhibitory drive, followed by lAPC, and lastly BPC. In conclusion, our data advance the hypothesis that PCs in CA3 are organized into subpopulations with distinct functional roles for cognition-relevant network dynamics and provide new insights in the physiology of hippocampus.

Impaired spike-gamma coupling of area CA3 fast-spiking interneurons as the earliest functional impairment in the AppNL-G-F mouse model of Alzheimer's disease.

In Alzheimer's disease (AD) the accumulation of amyloid-ß (Aß) 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 Aß plaque formation, and the cognitive impairment reported previously in this animal model. The degradation correlates with increased Aß1-42 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 Aß 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 Aß.

Efficacy of preclinical pharmacological interventions against alterations of neuronal network oscillations in Alzheimer's disease: A systematic review.

Despite the development of multiple pharmacological approaches over the years aimed at treating Alzheimer's Disease (AD) only very few have been approved for clinical use in patients. To date there still exists no disease-modifying treatment that could prevent or rescue the cognitive impairment, particularly of memory aquisition, that is characteristic of AD. One of the possibilities for this state of affairs might be that the majority of drug discovery efforts focuses on outcome measures of decreased neuropathological biomarkers characteristic of AD, without taking into acount neuronal processes essential to the generation and maintenance of memory processes. Particularly, the capacity of the brain to generate theta (θ) and gamma (γ) oscillatory activity has been strongly correlated to memory performance. Using a systematic review approach, we synthesize the existing evidence in the literature on pharmacological interventions that enhance neuronal theta (θ) and/or gamma (γ) oscillations in non-pathological animal models and in AD animal models. Additionally, we synthesize the main outcomes and neurochemical systems targeted. We propose that functional biomarkers such as cognition-relevant neuronal network oscillations should be used as outcome measures during the process of research and development of novel drugs against cognitive impairment in AD.

Early Stage Alterations in White Matter and Decreased Functional Interhemispheric Hippocampal Connectivity in the 3xTg Mouse Model of Alzheimer's Disease.

Alzheimer's disease (AD) is characterized in the late stages by amyloid-ß (Aß) plaques and neurofibrillary tangles. Nevertheless, recent evidence has indicated that early changes in cerebral connectivity could compromise cognitive functions even before the appearance of the classical neuropathological features. Diffusion tensor imaging (DTI), resting-state functional magnetic resonance imaging (rs-fMRI) and volumetry were performed in the triple transgenic mouse model of AD (3xTg-AD) at 2 months of age, prior to the development of intraneuronal plaque accumulation. We found the 3xTg-AD had significant fractional anisotropy (FA) increase and radial diffusivity (RD) decrease in the cortex compared with wild-type controls, while axial diffusivity (AD) and mean diffusivity (MD) were similar. Interhemispheric hippocampal connectivity was decreased in the 3xTg-AD while connectivity in the caudate putamen (CPu) was similar to controls. Most surprising, ventricular volume in the 3xTg-AD was four times larger than controls. The results obtained in this study characterize the early stage changes in interhemispheric hippocampal connectivity in the 3xTg-AD mouse that could represent a translational biomarker to human models in preclinical stages of the AD.

Tolfenamic Acid Prevents Amyloid ß-induced Olfactory Bulb Dysfunction In Vivo.

BACKGROUND: Amyloid beta inhibits olfactory bulb function. The mechanisms involved in this effect must include alterations in network excitability, inflammation and the activation of different transduction pathways. Thus, here we tested whether tolfenamic acid, a drug that modulates several of these pathological processes, could prevent amyloid beta-induced olfactory bulb dysfunction. OBJECTIVE: To test whether tolfenamic acid prevents amyloid beta-induced alterations in olfactory bulb network function, olfaction and GSK3ß activity. METHOD: The protective effects of tolfenamic acid against amyloid beta-induced population activity inhibition were tested in olfactory bulb slices from adult mice, while tolfenamic acid and amyloid beta were bath-applied. We also tested the effects of amyloid-beta in slices obtained from animals pre-treated chronically (21 days) with tolfenamic acid. The effects of amyloid beta micro-injected into the olfactory bulbs were also tested, after two weeks, on olfactory bulb population activity and olfaction in control and tolfenamic acid chronically treated animals. Olfaction was assessed with the odor-avoidance and the habituation/cross-habituation tests. GSK3ß activation was evaluated with Western-blot. RESULTS: Acute bath application of tolfenamic acid does not prevent amyloid beta-induced inhibition of olfactory bulb network activity in vitro. In contrast, chronic treatment with tolfenamic acid renders the olfactory bulb resistant to amyloid beta-induced network activity inhibition in vitro and in vivo, which correlates with the inhibition of GSK3ß activation and the protection against amyloid beta-induced olfactory dysfunction. CONCLUSION: Our data further support the use of tolfenamic acid to prevent amyloid beta-induced pathology and the early symptoms of Alzheimer Disease.

Exercise Prevents Amyloid-ß-Induced Hippocampal Network Disruption by Inhibiting GSK3ß Activation.

Exercise is becoming a promising therapeutic approach to prevent alterations both in Alzheimer's disease (AD) patients and in transgenic models of AD. This neuroprotection has been associated with changes in hippocampal structure and function, as well as with the reduction of amyloid-ß (Aß) production and accumulation. However, whether exercise produces lasting changes in hippocampal population activity and renders it resistant to Aß-induced network dysfunction is still unknown. Thus, we tested whether voluntary exercise changes hippocampal population activity and prevents its alteration in the presence of Aß, which has been associated to glycogen synthase kinase-3ß (GSK3ß) activation. We found that the hippocampal population activity recorded in slices obtained from mice that exercised voluntarily (with free access to a running wheel for 21 days) exhibits higher power and faster frequency composition than slices obtained from sedentary animals. Moreover, the hippocampal network of mice that exercised becomes insensitive to Aß-induced inhibition of spontaneous population activity. This protective effect correlates with the inability of Aß to activate GSK3ß, is mimicked by GSK3ß inhibition with SB126763 (in slices obtained from sedentary mice), and is abolished by the inhibition of PI3K with LY294002 (in slices obtained from mice that exercised). We conclude that voluntary exercise produces a lasting protective state in the hippocampus, maintained in hippocampal slices by a PI3K-dependent mechanism that precludes its functional disruption in the presence of Aß by avoiding GSK3ß activation.