Histone Deacetylase Inhibitor Improves the Dysfunction of Hippocampal Gamma Oscillations and Fast Spiking Interneurons in Alzheimer’s Disease Model Mice

The hippocampal gamma oscillation is important for cognitive function, and its deficit is related to cognitive impairment in Alzheimer’s disease (AD). Recently, it has been recognized that post-translational modification via histone acetylation is a fundamental molecular mechanism for regulating synaptic plasticity and cognitive function. However, little is known regarding the regulation of hippocampal gamma oscillation by histone acetylation. We investigated whether histone acetylation regulated kainate-induced gamma oscillations and their important regulator, fast-spiking interneurons, using acute hippocampal slices of AD model mice (PSAPP transgenic mice). We found a decrease in kainate-induced gamma oscillations in slices from PSAPP mice, accompanied with the increased activity of fast spiking interneurons in basal state and the decreased activity in activated state. The histone deacetylase (HDAC) inhibitor (SAHA, named vorinostat) restored deficits of gamma oscillation in PSAPP mice, accompanied with rescue of activity of fast spiking interneurons in basal and activated state. The effect of SAHA was different from that of the clinical AD drug donepezil, which rescued only function of fast spiking interneurons in basal state. Besides, activator of nuclear receptor family 4a (NR4a) receptor (cytosporone B), as one of the epigenetic modification related to HDAC inhibition, rescued the deficits in gamma oscillations in PSAPP mice. These results suggested a novel mechanism in which HDAC inhibition improved impairment of gamma oscillations in PSAPP mice by restoring the activity of fast spiking interneurons both in basal and activated state. The reversal of gamma oscillation deficits by HDAC inhibition and/or NR4a activation appears to be a potential therapeutic target for treating cognitive impairment in AD patients.

Sensory-Evoked 40-Hz Gamma Oscillation Improves Sleep and Daily Living Activities in Alzheimer’s Disease Patients

Pathological proteins contributing to Alzheimer’s disease (AD) are known to disrupt normal neuronal functions in the brain, leading to unbalanced neuronal excitatory-inhibitory tone, distorted neuronal synchrony, and network oscillations. However, it has been proposed that abnormalities in neuronal activity directly contribute to the pathogenesis of the disease, and in fact it has been demonstrated that induction of synchronized 40 Hz gamma oscillation of neuronal networks by sensory stimulation reverses AD-related pathological markers in transgenic mice carrying AD-related human pathological genes. Based on these findings, the current study evaluated whether non-invasive sensory stimulation inducing cortical 40 Hz gamma oscillation is clinically beneficial for AD patients. Patients with mild to moderate AD (n = 22) were randomized to active treatment group (n = 14; gamma sensory stimulation therapy) or to sham group (n = 8). Participants in the active treatment group received precisely timed, 40 Hz visual and auditory stimulations during eye-closed condition to induce cortical 40 Hz steady-state oscillations in 1-h daily sessions over a 6-month period. Participants in the sham group were exposed to similar sensory stimulation designed to not evoke cortical 40 Hz steady-state oscillations that are observed in the active treatment patients. During the trial, nighttime activities of the patients were monitored with continuous actigraphy recordings, and their functional abilities were measured by Alzheimer’s Disease Cooperative Study – Activities of Daily Living (ADCS-ADL) scale. Results of this study demonstrated that 1-h daily therapy was well tolerated throughout the 6-month treatment period by all subjects. Patients receiving gamma sensory stimulation showed significantly reduced nighttime active periods, in contrast, to deterioration in sleep quality in sham group patients. Patients in the sham group also showed the expected, significant decline in ADCS-ADL scores, whereas patients in the gamma sensory stimulation group fully maintained their functional abilities over the 6-month period. These findings confirm the safe application of 40 Hz sensory stimulation in AD patients and demonstrate a high adherence to daily treatment. Furthermore, this is the first time that beneficial clinical effects of the therapy are reported, justifying expanded and longer trials to explore additional clinical benefits and disease-modifying properties of gamma sensory stimulation therapy.Clinical Trial Registration:clinicaltrials.gov, identifier: NCT03556280.

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-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.

Distinct effects of heterogeneity and noise on gamma oscillation in a model of neuronal network with different reversal potential

Gamma oscillation is crucial in brain functions such as attentional selection, and is inextricably linked to both heterogeneity and noise (or so-called stochastic fluctuation) in neuronal networks. However, under coexistence of these factors, it has not been clarified how the synaptic reversal potential modulates the entraining of gamma oscillation. Here we show distinct effects of heterogeneity and noise in a population of modified theta neurons randomly coupled via GABAergic synapses. By introducing the Fokker-Planck equation and circular cumulants, we derive a set of two-cumulant macroscopic equations. In bifurcation analyses, we find a stabilizing effect of heterogeneity and a nontrivial effect of noise that results in promoting, diminishing, and shifting the oscillatory region, and is largely dependent on the reversal potential of GABAergic synapses. These findings are verified by numerical simulations of a finite-size neuronal network. Our results reveal that slight changes in reversal potential and magnitude of stochastic fluctuations can lead to immediate control of gamma oscillation, which would results in complex spatio-temporal dynamics for attentional selection and recognition.

Intraoperative epileptogenic network visualization using gamma oscillation regularity correlation analysis in epilepsy surgery

Background: We have recently demonstrated that gamma oscillation (30–70 Hz) regularity (GOR) analysis accurately localized epileptogenic focus using intraoperative electrocorticographic data. In this report, we assessed whether GOR correlation analysis could depict epileptogenic networks intraoperatively. Dual foci in temporal lobe epilepsy without hippocampal structural abnormalities are difficult to diagnose. Using our GOR correlation analysis, we aimed to intraoperatively visualize such dual foci and epileptogenic networks. Case Description: A 56-year-old man suffered from pharmacoresistant focal impaired awareness seizures. Magnetic resonance imaging demonstrated an 8 × 12-mm cavernoma in the right inferior temporal gyrus without any structural changes in the hippocampus. Since ictal semiology indicated a high probability of epileptogenicity in the right hippocampus, we reached the hippocampus using a transsylvian approach and assessed intraoperative GOR correlation analysis in the lateral temporal lobe where the cavernoma was located and the hippocampus, simultaneously. High GORs suggestive of epileptogenicity were identified in both the lateral temporal lobe and the hippocampus. Furthermore, they were connected using GOR correlation networks. When the high GOR locations in the lateral temporal lobe and the cavernoma were removed, high GORs and those networks were found within the hippocampus only. After additional hippocampal transection, high GORs and these networks were absent. The patient became seizure-free after the surgery. Conclusion: Our GOR correlation analysis may be a powerful tool for intraoperative evaluation of epileptogenic networks in epilepsy surgery.

Ablation of p75NTR signaling strengthens gamma–theta rhythm interaction and counteracts Aβ-induced degradation of neuronal dynamics in mouse hippocampus in vitro

Gamma and theta brain rhythms play important roles in cognition and their interaction can affect gamma oscillation features. Hippocampal theta oscillations depend on cholinergic and GABAergic input from the medial septum-diagonal band of Broca. These projecting neurons undergo degeneration during aging and maintain high levels of neurotrophin receptor p75 (p75NTR). p75NTR mediates both apoptosis and survival and its expression is increased in Alzheimer’s disease (AD) patients. Here, we investigate the importance of p75NTR for the cholinergic input to the hippocampus. Performing extracellular recordings in brain slices from p75NTR knockout mice (p75−/−) in presence of the muscarinic agonist carbachol, we find that gamma oscillation power and rhythmicity are increased compared to wild-type (WT) mice. Furthermore, gamma activity is more phase-locked to the underlying theta rhythm, which renders a stronger coupling of both rhythms. On the cellular level, we find that fast-spiking interneurons (FSNs) fire more synchronized to a preferred gamma phase in p75−/− mice. The excitatory input onto FSN is more rhythmic displaying a higher similarity with the concomitant gamma rhythm. Notably, the ablation of p75NTR counteracts the Aβ-induced degradation of gamma oscillations and its nesting within the underlying theta rhythm. Our results show that the lack of p75NTR signaling could promote stronger cholinergic modulation of the hippocampal gamma rhythm, suggesting an involvement of p75NTR in the downregulation of cognition-relevant hippocampal network dynamics in pathologies. Moreover, functional data provided here suggest p75NTR as a suitable target in the search for efficacious treatments to counteract the loss of cognitive function observed in amyloid-driven pathologies such as AD.

Laminar Profile of Auditory Steady-State Response in the Auditory Cortex of Awake Mice

ObjectiveAuditory steady-state response (ASSR) is a gamma oscillation evoked by periodic auditory stimuli, which is commonly used in clinical electroencephalographic examination to evaluate the neurological functions. Though it has been suggested that auditory cortex is the origin of ASSR, how the laminar architecture of the neocortex contributes to the ASSR recorded from the brain surface remains unclear.MethodsWe used a 16-channel silicon probe to record the local field potential and the single-unit spike activity in the different layers of the auditory cortex of unanesthetized mice. Click-trains with a repetition rate at 40-Hz were present as sound stimuli to evoke ASSR.ResultsWe found that the LFPs of all cortical layers showed a stable ASSR synchronizing to the 40-Hz click stimuli, while the ASSR was strongest in the granular (thalamorecipient) layer. Furthermore, time-frequency analyses also revealed the strongest coherence between the signals recorded from the granular layer and pial surface.ConclusionOur results reveal that the 40-Hz ASSR primarily shows the evoked gamma oscillation of thalamorecipient layers in the neocortex, and that the ASSR may be a biomarker to detect the cognitive deficits associated with impaired thalamo-cortical connection.