Disruption of Cholinergic Circuits as an Area for Targeted Drug Treatment of Alzheimer's Disease: In Vivo Assessment of Short-Term Plasticity in Rat Brain.

Ani Soghomonyan,Karen Simonyan,Konstantin Yenkoyan,Vergine Chavushyan,Gohar Karapetyan

doi:10.3390/ph13100297

Ani Soghomonyan, Karen Simonyan + Show 3 more

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https://doi.org/10.3390/ph13100297

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Abstract

The search for new therapeutics for the treatment of Alzheimer’s disease (AD) is still in progress. Aberrant pathways of synaptic transmission in basal forebrain cholinergic neural circuits are thought to be associated with the progression of AD. However, the effect of amyloid-beta (Aβ) on short-term plasticity (STP) of cholinergic circuits in the nucleus basalis magnocellularis (NBM) is largely unknown. STP assessment in rat brain cholinergic circuitry may indicate a new target for AD cholinergic therapeutics. Thus, we aimed to study in vivo electrophysiological patterns of synaptic activity in NBM-hippocampus and NBM-basolateral amygdala circuits associated with AD-like neurodegeneration. The extracellular single-unit recordings of responses from the hippocampal and basolateral amygdala neurons to high-frequency stimulation (HFS) of the NBM were performed after intracerebroventricular injection of Aβ 25–35. We found that after Aβ 25–35 exposure the number of hippocampal neurons exhibiting inhibitory responses to HFS of NBM is decreased. The reverse tendency was seen in the basolateral amygdala inhibitory neural populations, whereas the number of amygdala neurons with excitatory responses decreased. The low intensity of inhibitory and excitatory responses during HFS and post-stimulus period is probably due to the anomalous basal synaptic transmission and excitability of hippocampal and amygdala neurons. These functional changes were accompanied by structural alteration of hippocampal, amygdala, and NBM neurons. We have thus demonstrated that Aβ 25–35 induces STP disruption in NBM-hippocampus and NBM-basolateral amygdala circuits as manifested by unbalanced excitatory/inhibitory responses and their frequency. The results of this study may contribute to a better understanding of synaptic integrity. We believe that advancing our understanding of in vivo mechanisms of synaptic plasticity disruption in specific neural circuits could lead to effective drug searches for AD treatment.

Highlights

Central cholinergic network shortfalls are one of the most persistent neuropathological footprints in Alzheimer’s disease (AD) [1,2,3]
short-term plasticity (STP) is critically important in development [23] and age-related disorders [24], including AD [25,26], but there is a lack of knowledge about its specific role, in the context of local circuits, such as the cholinergic system affected in the AD brain
Cholinesterase inhibitor-based therapy resulted in significant symptomatic improvement in patients with AD, validating the cholinergic system as an important therapeutic target in the disease

Summary

Introduction

Central cholinergic network shortfalls are one of the most persistent neuropathological footprints in Alzheimer’s disease (AD) [1,2,3]. Recent in vivo investigations revealed that intrathecal injected or virally-delivered expression of amyloid-β (Aβ) peptide induces the reorganization of the cholinergic network within selected brain regions—the cerebral cortex, septohippocampal pathway, and nucleus basalis [4,5,6,7,8,9,10]. The high density of the innervation of cholinergic type is found in the hippocampus, entorhinal cortex, and amygdala [11,12,13]. The failure of cholinergic innervation in AD is more pronounced in the entorhinal cortex, related to a serious neurofibrillary degeneration and cell depletion in the basal nucleus complex [14,15]. Even though the NBM does not transfer direct cholinergic projections to the hippocampus, NBM abrasion was found to weaken the basal synaptic responsiveness, short- and long-term neural plasticity in the rats’ hippocampus [17]. STP is critically important in development [23] and age-related disorders [24], including AD [25,26], but there is a lack of knowledge about its specific role, in the context of local circuits, such as the cholinergic system affected in the AD brain

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