scholarly journals 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

2020 ◽  
Vol 13 (10) ◽  
pp. 297
Author(s):  
Vergine Chavushyan ◽  
Ani Soghomonyan ◽  
Gohar Karapetyan ◽  
Karen Simonyan ◽  
Konstantin Yenkoyan
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Synaptic Transmission ◽  
Rat Brain ◽  
Basolateral Amygdala ◽  
Neural Circuits ◽  
Short Term ◽  
Short Term Plasticity ◽  
Excitatory Responses

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.

scholarly journals Short-term plasticity shapes activity pattern-dependent striato-pallidal synaptic transmission

2013 ◽  
Vol 109 (4) ◽  
pp. 932-939 ◽  
Author(s):  
Juhyon Kim ◽  
Hitoshi Kita
Keyword(s):  
Synaptic Transmission ◽  
Firing Pattern ◽  
Brain Slice ◽  
Projection Neurons ◽  
Short Term ◽  
Short Term Plasticity ◽  
Pathological Conditions ◽  
Rat Brain Slice ◽  
Signal Transfer Function

The cortico-striato (Str)-globus pallidus external segment (GPe) projection plays major roles in the control of neuronal activity in the basal ganglia under both normal and pathological conditions. The present study used rat brain-slice preparations to address our hypothesis that the gain of this disynaptic projection is dynamically controlled by activations of short-term plasticity mechanisms of Str-GPe synapses. The Str-GPe projection neurons fire with very different frequency and firing patterns in vivo depending on the condition of the animal. The results show that the Str-GPe synapses have very strong short-term enhancement mechanisms and that repetitive burst activation of the Str-GPe synapses, which mimic oscillatory burst firing of Str neurons, can sustain enhanced states of synaptic transmission for tens of seconds. The results reveal that the short-term enhancement of Str-GPe synapses contributes to the generation of pauses in the firing of GPe neurons and that signal transfer function in the Str-GPe projection is highly dependent on the firing pattern of Str neurons.

scholarly journals Genetic Therapies for Alzheimer’s Disease: A Scoping Review

2021 ◽  
pp. 1-14
Author(s):  
Matthew J. Lennon ◽  
Grant Rigney ◽  
Vanessa Raymont ◽  
Perminder Sachdev
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Scoping Review ◽  
Genetic Therapy ◽  
Short Term ◽  
Exciting Opportunity ◽  
Alternative Approaches

Effective, disease modifying therapies for Alzheimer’s disease (AD) remain a quandary, following a panoply of expensive failures in human clinical trials. Given the stagnation in therapeutics, alternative approaches are needed. Recent successes of genetic therapies in other neurodegenerative diseases may highlight the way forward. This scoping review explores suggested targets of genetic therapy in AD, with a focus on vector-based approaches in pre-clinical and clinical trials. Putative targets of genetic therapies tested in pre-clinical trials include amyloid pathway intermediates and enzymes modulation, tau protein downregulation, APOE4 downregulation and APOE2 upregulation, neurotrophin expression (nerve growth factor (NGF) and brain-derived neurotrophic factor), and inflammatory cytokine alteration, among several other approaches. There have been three completed human clinical trials for genetic therapy in AD patients, all of which upregulated NGF in AD patients, showing some mixed evidence of benefit. Several impediments remain to be surpassed before genetic therapies can be successfully applied to AD, including the challenge of delivering monogenic genetic therapies for complex polygenic disorders, risks in the dominant delivery method (intracranial injection), stability of genetic therapies in vivo, poor translatability of pre-clinical AD models, and the expense of genetic therapy production. Genetic therapies represent an exciting opportunity within the world of AD therapeutics, but clinical applications likely remain a long term, rather than short term, possibility.

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