Enhancing GABAergic signaling ameliorates aberrant gamma oscillations of olfactory bulb in AD mouse models

Abstract

Background Before the deposition of amyloid-beta plaques and the onset of learning memory deficits, patients with Alzheimer’s disease (AD) experience olfactory dysfunction, typified by a reduced ability to detect, discriminate, and identify odors. Rodent models of AD, such as the Tg2576 and APP/PS1 mice, also display impaired olfaction, accompanied by aberrant in vivo or in vitro gamma rhythms in the olfactory pathway. However, the mechanistic relationships between the electrophysiological, biochemical and behavioral phenomena remain unclear. Methods To address the above issues in AD models, we conducted in vivo measurement of local field potential (LFP) with a combination of in vitro electro-olfactogram (EOG), whole-cell patch and field recordings to evaluate oscillatory and synaptic function and pharmacological regulation in the olfactory pathway, particularly in the olfactory bulb (OB). Levels of protein involved in excitation and inhibition of the OB were investigated by western blotting and fluorescence staining, while behavioral studies assessed olfaction and memory function. Results LFP measurements demonstrated an increase in gamma oscillations in the OB accompanied by altered olfactory behavior in both APP/PS1 and 3xTg mice at 3–5 months old, i.e. an age before the onset of plaque formation. Fewer olfactory sensory neurons (OSNs) and a reduced EOG contributed to a decrease in the excitatory responses of M/T cells, suggesting a decreased ability of M/T cells to trigger interneuron GABA release indicated by altered paired-pulse ratio (PPR), a presynaptic parameter. Postsynaptically, there was a compensatory increase in levels of GABAAR α1 and β3 subunits and subsequent higher amplitude of inhibitory responses. Strikingly, the GABA uptake inhibitor tiagabine (TGB) ameliorated abnormal gamma oscillations and levels of GABAAR subunits, suggesting a potential therapeutic strategy for early AD symptoms. These findings reveal increased gamma oscillations in the OB as a core indicator prior to onset of AD and uncover mechanisms underlying aberrant gamma activity in the OB. Conclusions This study suggests that the concomitant dysfunction of both olfactory behavior and gamma oscillations have important implications for early AD diagnosis: in particular, awareness of aberrant GABAergic signaling mechanisms might both aid diagnosis and suggest therapeutic strategies for olfactory damage in AD.

Pelvic Pain Alters Functional Connectivity Between Anterior Cingulate Cortex and Hippocampus in Both Humans and a Rat Model

“…We next evaluated ACC-HIPP connectivity in the frequency domain ( Figure 5E ) by coherence analysis ( Chen et al, 2021 ), and observed significantly increased coherence in the gamma range in model rats ( Figure 5F ). To better understand the connectivity in more precise phase ranges, we next used WPLI analysis ( Vinck et al, 2011 ) which can reduce the contingency caused by the bidirectional connection.…”

“…Recent animal and human studies provide converging evidence that gamma oscillations are closely related to pain perception ( Hu and Iannetti, 2019 ; Tan et al, 2019 ). In addition, cross-frequency phase-amplitude coupling (PAC), in which the amplitude of higher (e.g., gamma) rhythms is particularly modulated by the phase of lower (e.g., theta) rhythms, indicates a more complex regulatory feature through interactions between different frequency bands, such as long-range theta and local gamma communication ( Wirt and Hyman, 2019 ; Chen et al, 2021 ). However, the possible abnormalities induced by PDM in ACC-HIPP connectivity and the underlying mechanisms of the condition remain unclear.…”

Increased oscillatory power in a computational model of the olfactory bulb due to synaptic degeneration

“…W. Li et al and Chen et al measured OB activity in mice expressing amyloid precursor protein and presenilin 1 (APP/PS1) and found significant increases in gamma band power associated with synaptic deficits [18, 19]. Both groups found that treatment with a GABA agonist decreased the heightened gamma power, suggesting that increases in the gamma band may have been due to a decrease in GABA-induced inhibition to the MCs.…”

“…While they also found an increase in gamma power and impaired synaptic function, MC firing rates were decreased rather than elevated, suggesting other mechanisms at play. Note also that because AD-like pathology was induced by gene expression in all of these studies [18–21], it is more relevant to the FD modeled here rather than to SD.…”

“…In both AD and PD, olfactory deficits occur years before diagnosis and often before other symptoms [2,[4][5][6][7][8][9]. Furthermore, the OB is a site of early pathology in both diseases [7,[10][11][12][13][14][15], with resulting aberrant neural activity [16][17][18][19][20][21]. We hope that computationally modeling olfactory bulb activity in diseaselike conditions can help to further shed light on mechanisms of dysfunction, identify markers of disease, and bring attention to the opportunity the OB presents for earlier diagnosis of neurodegenerative illnesses.…”