Effect of connexin 36 blockers on the neuronal cytoskeleton and synaptic plasticity in kainic acid-kindled rats

Abstract

In this study we investigated the potential anti-epileptogenic effect of neuronal connexin Cx36 gap junction blockage via inhibition of microtubule-associated protein 2 (MAP-2) and synaptophysin (SYP) overexpression. Thirty adult male Wistar rats were divided into five groups (six animals per group): control, sham, carbenoxolone (CBX), quinine (QN), and quinidine (QND). An epilepsy model was produced by injecting kainic acid (KA) into the rat amygdala. Broad-spectrum and selective blockers of the Cx36 channel (CBX, QN, and QND) were administered via intraperitoneal injection. Expression of MAP-2 and SYP was assessed by immunofluorescent and immunohistochemical examination. Expression of MAP-2 and SYP was significantly increased after KA administration in the sham group compared with the control group. Expression of MAP-2 and SYP was significantly decreased in the CBX, QN, and QND groups compared with the sham group. The results provide new evidence regarding the key role of MAP-2 and SYP overexpression in three important mechanisms: the modulation of neuronal plasticity, hyperexcitability of the hippocampal neuronal network, and persistent seizure discharge. Furthermore, the reversal of MAP-2 and SYP overexpression following administration of Cx36 channel blockers indicates a potential role for Cx36 channel blockers in anti-epileptogenic treatment and in doing so, highlights a critical need for further investigation of these compounds.

Clozapine Normalizes a Glutamatergic Transmission Abnormality Induced by an Impaired NMDA Receptor in the Thalamocortical Pathway via the Activation of a Group III Metabotropic Glutamate Receptor

“…Interestingly, an inhibitor of hemichannels and gap-junctions, CBX was reported to prevent hyperexcitability of the hippocampal neuronal network and persistent seizure discharge in a kainate-kindled epilepsy model. [37,38]. Therapeutically relevant concentrations of CLZ (lower than 3 μM) did not affect the astroglial l -glutamate release inhibited by CBX, whereas toxic concentrations of CLZ (higher than 10 μM) increased astroglial release.…”

“…However, pathological conditions, including ischemia and excessive depolarization, generate persistent gap-junction and hemichannel opening, which leads to the disruption of several homeostasis systems [36,37]. In particular, inhibitors of gap-junctions and hemichannels can prevent the onset of epileptic seizures [37,38,39]. In the context of our previous research, we primarily aimed to explore the detailed mechanisms of MK801-induced glutamate release in the mPFC to determine the regulatory mechanisms of glutamatergic transmission in the RTN–MDTN–mPFC pathway.…”

Brain-Region Specific Metabolic Abnormalities in Parkinson’s Disease and Levodopa-Induced Dyskinesia

“…It was noticed that there was a disorder of neurotransmitters in the PD and LID rats, we wondered if the synaptic plasticity, which controls the release and recycle of neurotransmitters was also involved in the PD and LID disease. SYP, a standard presynaptic marker, which was responsible for synapse formation and neurotransmitter recycle (Wu et al, 2015). Immunofluorescence staining was performed to visually evaluate the expression of SYP in the right cortex of PD and LID rats.…”

Activation of Astroglial Connexin Is Involved in Concentration-Dependent Double-Edged Sword Clinical Action of Clozapine

“…Furthermore, the expression of Cx43 is increased in glia but not neuron in animal models and patients with epilepsy [34]. Exactly, inhibitors of Cxs can prevent the onset of epileptic seizures [29,35,36]. Although there have not been studies of Cx43 alterations in brains from subjects with schizophrenia, the dysfunction of Cxs contributes to attenuated information processing and cognitive impairment, which is a major symptom of schizophrenia [8].…”