Brain-derived neurotrophic factor rescues and prevents chronic intermittent hypoxia-induced impairment of hippocampal long-term synaptic plasticity

Post-stroke cognitive impairment is a major cause of long-term neurological disability. The prevalence of post-stroke cognitive deficits varies between 20% and 80% depending on brain region, country, and diagnostic criteria. The biochemical mechanisms underlying post-stroke cognitive impairment are not known in detail. Cyclin-dependent kinase 5 is involved in neurodegeneration, and its dysregulation contributes to cognitive disorders and dementia. Here, we administered cyclin-dependent kinase 5-targeting gene therapy to the right hippocampus of ischemic rats after transient right middle cerebral artery occlusion. Cyclin-dependent kinase 5 RNA interference prevented the impairment of reversal learning four months after ischemia as well as neuronal loss, tauopathy, and microglial hyperreactivity. Additionally, cyclin-dependent kinase 5 silencing increased the expression of brain-derived neurotrophic factor in the hippocampus. Furthermore, deficits in hippocampal long-term potentiation produced by excitotoxic stimulation were rescued by pharmacological blockade of cyclin-dependent kinase 5. This recovery was blocked by inhibition of the TRKB receptor. In summary, these findings demonstrate the beneficial impact of cyclin-dependent kinase 5 reduction in preventing long-term post-ischemic neurodegeneration and cognitive impairment as well as the role of brain-derived neurotrophic factor/TRKB in the maintenance of normal synaptic plasticity.

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The Association of Brain-Derived Neurotrophic Factor with Long-Term Potentiation

Shiraz E-Medical Journal ◽

10.5812/semj.112278 ◽

2021 ◽

Vol In Press (In Press) ◽

Author(s):

Zahra Salimi ◽

Farshad Moradpour ◽

Zahra Rashidi ◽

Fatemeh Zarei ◽

Mohammad Rasool Khazaei ◽

...

Keyword(s):

Synaptic Plasticity ◽

Learning And Memory ◽

Neurotrophic Factor ◽

Synapse Formation ◽

Long Term Potentiation ◽

Brain Derived Neurotrophic Factor ◽

Synaptic Efficacy ◽

Term Potentiation ◽

The Central Nervous System

: Long-term potentiation (LTP) is one of the most important topics in neuroscience. It refers to a long-lasting increase in synaptic efficacy and is considered as a molecular and cellular mechanism of learning and memory. Neurotrophins play essential roles in different processes in the central nervous system (CNS), such as synaptogenesis, survival of specific populations of neurons, and neuroplasticity. Some evidence suggests that neurotrophins also participate in the synaptic plasticity related to learning and memory formation. Brain-derived neurotrophic factor (BDNF) is an important neurotrophic factor that is extensively expressed in the hippocampus and cerebral cortex, where it promotes neuroprotection, increases synaptogenesis and neurotransmission, and mediates synapse formation and synaptic plasticity. In this review, we first focused on the research investigating the effects of BDNF on synaptic plasticity and LTP induction and then reviewed the neuronal signaling molecules employed by BDNF to promote its effects on these processes.

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Selected Contribution: Chronic intermittent hypoxia enhances respiratory long-term facilitation in geriatric female rats

Journal of Applied Physiology ◽

10.1152/japplphysiol.00476.2003 ◽

2003 ◽

Vol 95 (6) ◽

pp. 2614-2623 ◽

Cited By ~ 37

Author(s):

A. G. Zabka ◽

G. S. Mitchell ◽

E. B. Olson ◽

M. Behan

Keyword(s):

Intermittent Hypoxia ◽

Young Female ◽

Time Dependent ◽

Female Rats ◽

Chronic Intermittent Hypoxia ◽

Middle Aged ◽

Short Term ◽

Hypoxic Response ◽

Long Term Facilitation

Age and the estrus cycle affect time-dependent respiratory responses to episodic hypoxia in female rats. Respiratory long-term facilitation (LTF) is enhanced in middle-aged vs. young female rats ( 72 ). We tested the hypothesis that phrenic and hypoglossal (XII) LTF are diminished in acyclic geriatric rats when fluctuating sex hormone levels no longer establish conditions that enhance LTF. Chronic intermittent hypoxia (CIH) enhances LTF ( 41 ); thus we further predicted that CIH would restore LTF in geriatric female rats. LTF was measured in young (3-4 mo) and geriatric (20-22 mo) female Sasco Sprague-Dawley rats and in a group of geriatric rats exposed to 1 wk of nocturnal CIH (11 vs. 21% O2 at 5-min intervals, 12 h/night). In anesthetized, paralyzed, vagotomized, and ventilated rats, time-dependent hypoxic phrenic and XII responses were assessed. The short-term hypoxic response was measured during the first of three 5-min episodes of isocapnic hypoxia (arterial Po2 35-45 Torr). LTF was assessed 15, 30, and 60 min postepisodic hypoxia. Phrenic and XII short-term hypoxic response was not different among groups, regardless of CIH treatment ( P > 0.05). LTF in geriatric female rats was smaller than previously reported for middle-aged rats but comparable to that in young female rats. CIH augmented phrenic and XII LTF to levels similar to those of middle-aged female rats without CIH ( P < 0.05). The magnitude of phrenic and XII LTF in all groups was inversely related to the ratio of progesterone to estradiol serum levels ( P < 0.05). Thus CIH and sex hormones influence the magnitude of LTF in geriatric female rats.

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