Chronic exercise buffers the cognitive dysfunction and decreases the susceptibility to seizures in PTZ-treated rats

• Published in: Epilepsy & behavior Vol. 98; no. Pt A; pp. 173 - 187
• Main Authors: Lin, Xiao-Ying, Cui, Ying, Wang, Lei, Chen, Wen
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.09.2019
• Subjects: Cognitive dysfunction; Epilepsy; Hippocampus; Pentylenetetrazole; Physical exercise; Seizures; Physical exercise; Pentylenetetrazole; Epilepsy; Cognitive dysfunction; Hippocampus; Seizures
• ISSN: 1525-5050; 1525-5069; 1525-5069
• DOI: 10.1016/j.yebeh.2019.07.032

Epilepsy is a serious neurological disorder posing a severe burden to our society. Cognitive deficits are very common comorbidities of epilepsy. It is known that enhanced cognition has been demonstrated as an indicator for successful treatment of epilepsy. Physical exercise shows a positive consequence on cognition in healthy individuals and improves health and life conditions in people with epilepsy. However, there is no direct evidence to determine the role and the potential mechanism of physical exercise on the cognitive impairment and the relationship of susceptibility to seizures. The goal of the current investigation was to explore whether sustained physical exercise improves the cognitive dysfunction and simultaneously decreases the susceptibility to seizures in rats with epilepsy. Rats were treated with pentylenetetrazole (PTZ) (35 mg/kg, i.p. [intraperitoneally]) for 36 days to induce chronic epilepsy. During the induction period, rats were exposed to voluntary wheel running or forced swimming 30 min prior to each PTZ injection from the 16th day. The cognition of rats was evaluated by object recognition test and passive avoidance test. The susceptibility to seizures was evaluated by seizure frequency and duration. The levels of synaptic-related proteins including PSD95 (postsynaptic density 95), Synapsin, GluA1, and BDNF (brain-derived neurotrophic factor) were measured to evaluate the hippocampal synaptic plasticity. Furthermore, the GAD67 (glutamic acid decarboxylase) levels and GABA (γ-aminobutyric acid)ergic function in PTZ-treated rats were also determined. Finally, antagonist of GABAAR (GABAA receptors) bicuculline was used to explore the reversal effects of physical activity on seizures and cognition. The results showed that rats subjected to voluntary wheel running or forced swimming showed a significant reduction of seizure frequency and duration in PTZ-treated group relative to rats without running or swimming. In addition, both running and swimming improved cognitive function as measured by enhanced performance in object recognition test and passive avoidance test. Furthermore, the reduced levels of synaptic-related proteins and GABAergic function were reversed by exercise compared with rats without exercise. Moreover, antagonism of hippocampal CA3 (cornu ammonis 3) GABAergic neurons blocks the reversal effects of physical activity on seizures and cognition in PTZ-treated rats. These data showed that chronic physical exercise reduced the frequency of seizures and improved the cognitive function in a rat model of chronic epilepsy through normalization of CA3 synaptic plasticity and GABAergic function. Our findings suggest that chronic physical exercise has beneficial effects on controlling seizure through enhancement of cognition and highlights the possibility to translate into reduced seizure recurrence in people with epilepsy. Model illustrating the cellular pathways for the cognition and seizures regulation of physical activity. Repeated PTZ administration induced reductions of synaptic-related proteins including PSD95, Synapsin 1, GluA1, and BDNF, and decrease of GAD67 and GABAAR expression in hippocampal CA3, leading to a dysfunction of synaptic plasticity and GABAergic system. As a result, rats that receive chronic PTZ treatment showed increased sensitivity to seizures and impaired cognition. However, regular physical exercise increased synaptic-related proteins and GABAergic function. Subsequently, the seizure frequency and cognitive performance were also reversed by physical exercise. [Display omitted] •Physical exercise reduced seizure duration and improves cognition in PTZ-treated rats.•Physical exercise enhances CA3 synaptic plasticity and GABAergic function which was impaired by PTZ.•Antagonism of CA3 GABAA receptor blocked the effects of physical exercise on cognition and seizure.