Exercise and low-level GABAA receptor inhibition modulate locomotor activity and the expression of BDNF accompanied by changes in epigenetic regulation in the hippocampus

Hiroshi Maejima; Shuta Ninuma; Akane Okuda; Takahiro Inoue; Masataka Hayashi

doi:10.1016/j.neulet.2018.07.009

Exercise and low-level GABA_A receptor inhibition modulate locomotor activity and the expression of BDNF accompanied by changes in epigenetic regulation in the hippocampus

Neurosci Lett. 2018 Oct 15:685:18-23. doi: 10.1016/j.neulet.2018.07.009. Epub 2018 Jul 6.

Authors

Hiroshi Maejima¹, Shuta Ninuma², Akane Okuda², Takahiro Inoue³, Masataka Hayashi³

Affiliations

¹ Department of Rehabilitation Science, Faculty of Health Sciences, Hokkaido University, Kita 12 Nishi 5, Kita-ku, Sapporo, 060-0812, Japan. Electronic address: maeji@hs.hokudai.ac.jp.
² Department of Health Sciences, School of Medicine, Hokkaido University, Kita 12 Nishi 5, Kita-ku, Sapporo, 060-0812, Japan.
³ Graduate School of Health Sciences, Hokkaido University, Kita 12 Nishi 5, Kita-ku, Sapporo, 060-0812, Japan.

PMID: 30037768
DOI: 10.1016/j.neulet.2018.07.009

Abstract

Aerobic exercise is known to increase expression of brain-derived neurotrophic factor (BDNF) in the hippocampus and to improve cognitive function. The inhibition of GABAergic synapses enhances hippocampal plasticity as well as learning and memory. The objective of the present study was to examine the interactive effect of low-level GABA_A receptor inhibition and exercise on behavior tests (cognitive function and locomotor activity), expression of BDNF and epigenetic regulations including the activity levels of histone acetyltransferases (HATs) and histone deacetylases (HDACs) in the hippocampus. ICR mice were divided into two groups: those who did not participate in exercise and those who participated in exercise. Each group was subdivided into two other groups: the one who received vehicle and the one who received GABA_A receptor antagonist, bicucullin. We administered saline or bicuculline intraperitoneally to the mice at a non-epileptic dose of 0.25 mg/kg, whereas the mice were exercised on a treadmill for approximately 1 h a day, 5 days a week for 4 weeks. Novel-object recognition test and locomotor activity were assessed at a rest day approximately 4 days before the euthanasia. The mice were euthanized 4 h after the last exercise session. Aerobic exercise for 4 weeks increased mRNA and protein expression of BDNF in the hippocampus, accompanied by enhanced HAT activity. Alternatively, bicuculline administration increased HDAC activity in the hippocampus. Furthermore, exercise in the presence of bicuculline administration increased locomotor activity, indicating that exercise combined with low-level GABA_A receptor inhibition potentiated the activity of the mice. Altogether, the present study suggested that exercise beneficially contributes to neuroprotection in the hippocampus accompanied by the up-regulation of BDNF expression and epigenetic regulation, whereas the chronic inhibition of GABA_A receptor potentiates exercise-induced behavioral activity.

Keywords: Epigenetics; Exercise; GABA; Neurotrophin.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Bicuculline / pharmacology*
Brain-Derived Neurotrophic Factor / metabolism*
Cognition / drug effects
Cognition / physiology
Epigenesis, Genetic / drug effects
Female
GABA-A Receptor Antagonists / pharmacology
Hippocampus / drug effects*
Hippocampus / metabolism
Locomotion / drug effects
Memory / drug effects
Mice
Mice, Inbred ICR
Motor Activity / drug effects
Physical Conditioning, Animal / physiology*
Receptors, GABA-A / drug effects*
Receptors, GABA-A / metabolism

Substances

Brain-Derived Neurotrophic Factor
GABA-A Receptor Antagonists
Receptors, GABA-A
Bicuculline