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

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.

Assessment of behavioral, morphological and electrophysiological changes in prenatal and postnatal valproate induced rat models of autism spectrum disorder

“…The statistiscal significance of the heterogeneity of interspike intervals (or spike frequency) of the pre- and post-stimulus impulse flow was analyzed by the Student's t - test and Mann–Whitney U test. Thus, we recorded single-cell spiking short-term dynamics of a large range, which are presynaptically induced by HFS and these results confirm the view, that in a large-size network, STP can greatly enrich the network's dynamical behaviors 62 .

Figure 9 ( A ) In vivo recorded spike flow of single neuron in mPFC.

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“…Intra-population variance ratio between time intervals during HFS and post-stimulation compared to baseline was calculated using Student’s t -test. The statistical significance between control and VPA-treated groups was estimated according to chi-square and Fisher’s exact tests 62 .…”

The Involvement of Insulin-Like Growth Factor 1 and Nerve Growth Factor in Alzheimer’s Disease-Like Pathology and Survival Role of the Mix of Embryonic Proteoglycans: Electrophysiological Fingerprint, Structural Changes and Regulatory Effects on Neurotrophins

“…The increased levels of endogenous Aβ enhances the initial release probability at the CA3-CA1 synapses of the hippocampus, which, in turn, destructs the vesicles and affects the synaptic short-term plasticity and the firing probability of the CA1 output neuronal synapse [15,16]. In our previous study, we have already shown the disruption of short-term plasticity in nucleus basalis magnocellularis (NBM) hippocampus and NBM-basolateral amygdala cholinergic circuits [17]. In contrast to the deficits seen in cholinergic and glutamatergic systems, the non-significant change of TD-PTD response pattern after amyloid exposure can be due to the fact that GABAergic neurons and receptors appear more resistant to neurodegeneration during AD [18].…”