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

Abstract

Background: Excitation/inhibition imbalance (E/I imbalance), which involves an increase of alphaamino-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 (Mg 2+ -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 Mg 2+ -free group. The amplitude and decay time of AMPAR-mediated miniature excitatory postsynaptic currents were increased in the Mg 2+ -free group. The amplitude and decay time of miniature inhibitory postsynaptic currents were decreased in the Mg 2+ -free group. The recycling ratio of GluR2 was increased and the recycling ratio of Gabrb2+3 was decreased in the Mg 2+ -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.

Drug–drug interactions between propofol and ART drugs: Inhibiting neuronal activity by affecting glucose metabolism

“…The primary neuron culture was carried out according to the method of Li et al 27 When the neurons had been cultured for 7 days, the neurons were identified and exposed to the drugs. The neurons in different wells were randomly grouped.…”

“…We used Digidata 1550B patch‐clamp amplifier to obtain electrophysiology of neurons. The neuronal action potentials were performed according to the method of Li et al 27 …”

“…We used Digidata 1550B patch-clamp amplifier to obtain electrophysiology of neurons. The neuronal action potentials were performed according to the method of Li et al 27 Miniature inhibitory postsynaptic currents (mIPSCs), mainly produced by postsynaptic gamma-aminobutyric acid (GABA) type A receptors (GABAaRs), 28 were recorded according to the method of Wyrembek et al 29 All the measurements were recorded at 25°C. The data were analyzed by Clampfit 10.7 and MiniAnal.…”

Neuroplastin exerts antiepileptic effects through binding to the α1 subunit of GABA type A receptors to inhibit the internalization of the receptors

“…GABAaRs are first assembled in the endoplasmic reticulum and then undergo palmitoylation once transported to the Golgi body, which enhances the hydrophobicity of proteins and promotes the translocation of receptors through the Golgi apparatus to the plasma membrane and synapses [ 51 ]. Previous reports have shown that the number and location of GABAaRs on the cell membrane keep changing [ 51 ] and can be dynamically regulated through neuronal excitability processes, including movement [ 52 ], internalization [ 35 ], and recycling [ 53 , 54 ] of the receptors. These processes are also referred to as GABAaR dynamics.…”

Inhibition of GABAergic neurons in the paraventricular nucleus of the hypothalamus precipitates visceral pain induced by pancreatic cancer in mice

“…Excitation/inhibition imbalance underlies numerous pathological conditions ( 5 , 9 ). Given our previous findings that inhibiting the excitability of PVN neurons can alleviate visceral pain ( 5 ), we hypothesized that GABAergic neurons—the primary inhibitory neurons—are involved in regulating visceral pain.…”