The recycling of AMPA receptors/GABAa receptors is related to neuronal excitation/inhibition imbalance and may be regulated by KIF5A

Sijun Li; Hongmi Huang; Xin Wei; Lin Ye; Meigang Ma; Min Ling; Yuan Wu

doi:10.21037/atm-22-4337

The recycling of AMPA receptors/GABAa receptors is related to neuronal excitation/inhibition imbalance and may be regulated by KIF5A

Ann Transl Med. 2022 Oct;10(20):1103. doi: 10.21037/atm-22-4337.

Authors

Sijun Li¹, Hongmi Huang¹, Xin Wei¹, Lin Ye¹, Meigang Ma¹, Min Ling², Yuan Wu¹

Affiliations

¹ Department of Neurology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China.
² Department of Biotechnology, Guangxi Medical University, Nanning, China.

Abstract

Background: Excitation/inhibition imbalance (E/I imbalance), which involves an increase of alpha-amino-3-hydroxy-5-methyl-4-isoxazole (AMPA) receptors (AMPARs) and decrease of gamma-aminobutyric acid type A (GABA) type A receptors (GABAaRs) on the neuron surface, has been documented in the pathogenesis of seizures. Notably, it has been established that both the glutamate receptor subunit 2 (GluR2) of AMPARs and beta 2/3 subunits of GABAaRs (Gabrb2+3) participate in the recycling mechanism mediated by the kinesin heavy chain isoform 5A (KIF5A), which determines the number of neuron surface receptors. However, it remains unclear whether receptor recycling is involved in the pathogenesis of seizures.

Methods: Twelve adult male Sprague-Dawley rats were randomly allocated to the normal control (Ctl) group (n=6) and the pentylenetetrazol (PTZ)-induced seizure (Sez) group (n=6). The rats in the Ctl group were treated with saline. The rats in the Sez group received an intraperitoneal injection of PTZ at an initial dose of 40 mg/kg. Primary cultured neurons were obtained from newborn rats (24-hour-old). The neurons were exposed to magnesium-free (Mg²⁺-free) extracellular fluid for 3 hours to establish the seizure model in vitro. We detected the electrophysiology of the seizure model, the expression levels of KIF5A, GluR2, and Gabrb2+3, the recycling ratio of GluR2 and Gabrb2+3, the interaction between KIF5A and GluR2, and the interaction between KIF5A and Gabrb2+3.

Results: In the Sez group, the expression of GluR2 on the cell surface was increased and the expression of Gabrb2+3 on the cell surface was decreased. The amplitude and frequency of action potentials were significantly increased in the Mg²⁺-free group. The amplitude and decay time of AMPAR-mediated miniature excitatory postsynaptic currents were increased in the Mg²⁺-free group. The amplitude and decay time of miniature inhibitory postsynaptic currents were decreased in the Mg²⁺-free group. The recycling ratio of GluR2 was increased and the recycling ratio of Gabrb2+3 was decreased in the Mg²⁺-free group. The interaction between KIF5A and GluR2 was increased, and the interaction between KIF5A and Gabrb2+3 was decreased in the seizure model in vivo and in vitro.

Conclusions: The recycling of AMPA receptors/GABAa receptors is related to E/I imbalance and may be regulated by KIF5A.

Keywords: Gabrb2+3; Seizures; glutamate receptor subunit 2 (GluR2); kinesin heavy chain isoform 5A (KIF5A); recycling.