Inhibition of connexin hemichannels alleviates neuroinflammation and hyperexcitability in temporal lobe epilepsy.

Temporal lobe epilepsy (TLE) is one of the most common types of epilepsy, yet approximately one-third of patients are refractory to current anticonvulsive drugs, which target neurons and synapses. Astrocytic and microglial dysfunction is commonly found in epileptic foci and has been shown to contribute to neuroinflammation and hyperexcitability in chronic epilepsy. Accumulating evidence points to a key role for glial hemichannels in epilepsy, but inhibiting both connexin (Cx) gap junctions and hemichannels can lead to undesirable side effects because the former coordinate physiological functions of cell assemblies. It would be a great benefit to use an orally available small molecule to block hemichannels to alleviate epileptic symptoms. Here, we explored the effect of D4, a newly developed compound that inhibits the Cx hemichannels but not Cx gap junctions using the pilocarpine mouse model of TLE. In vitro application of D4 caused a near-complete reduction in the pilocarpine-induced cell membrane permeability associated with increased Cx hemichannel activity. Moreover, preadministration of D4 in vivo effectively reduced neuroinflammation and altered synaptic inhibition, which then enhanced the animal survival rate. Posttreatment with a single dose of D4 in vivo has prolonged effects on suppressing the activation of astrocytes and microglia and rescued the changes in neuroinflammatory and synaptic gene expression induced by pilocarpine. Collectively, these results indicate that targeting Cx hemichannels by D4 is an effective and promising strategy for treating epilepsy in which neuroinflammation plays a critical role.

The connexin hemichannel inhibitor D4 produces rapid antidepressant-like effects in mice.

Depression is a common mood disorder characterized by a range of clinical symptoms, including prolonged low mood and diminished interest. Although many clinical and animal studies have provided significant insights into the pathophysiology of depression, current treatment strategies are not sufficient to manage this disorder. It has been suggested that connexin (Cx)-based hemichannels are candidates for depression intervention by modifying the state of neuroinflammation. In this study, we investigated the antidepressant-like effect of a recently discovered selective Cx hemichannel inhibitor, a small organic molecule called D4. We first showed that D4 reduced hemichannel activity following systemic inflammation after LPS injections. Next, we found that D4 treatment prevented LPS-induced inflammatory response and depressive-like behaviors. These behavioral effects were accompanied by reduced astrocytic activation and hemichannel activity in depressive-like mice induced by repeated low-dose LPS challenges. D4 treatment also reverses depressive-like symptoms in mice subjected to chronic restraint stress (CRS). To test whether D4 broadly affected neural activity, we measured c-Fos expression in depression-related brain regions and found a reduction in c-Fos+ cells in different brain regions. D4 significantly normalized CRS-induced hypoactivation in several brain regions, including the hippocampus, entorhinal cortex, and lateral septum. Together, these results indicate that blocking Cx hemichannels using D4 can normalize neuronal activity and reduce depressive-like symptoms in mice by reducing neuroinflammation. Our work provides evidence of the antidepressant-like effect of D4 and supports glial Cx hemichannels as potential therapeutic targets for depression.

Target-specific control of piriform cortical output via distinct inhibitory circuits.

Information represented by principal neurons in anterior piriform cortex (APC) is regulated by local, recurrent excitation and inhibition, but the circuit mechanisms remain elusive. Two types of layer 2 (L2) principal neurons, semilunar (SL), and superficial pyramidal (SP) cells, are parallel output channels, and the control of their activity gates the output of APC. Here, we examined the hypothesis that recurrent inhibition differentially regulates SL and SP cells. Patterned optogenetic stimulation revealed that the strength of recurrent inhibition is target- and layer-specific: L1 > L3 for SL cells, but L3 > L1 for SP cells. This target- and layer-specific inhibition was largely attributable to the parvalbumin (PV), but not somatostatin, interneurons. Intriguingly, olfactory experience selectively modulated the PV to SP microcircuit while maintaining the overall target and laminar specificity of inhibition. Together, these results indicate the importance of target-specific inhibitory wiring for odor processing, implicating these mechanisms in gating the output of piriform cortex.

Modified photoanode by in situ growth of covalent organic frameworks on BiVO4 for oxygen evolution reaction.

The development of efficient oxygen evolution reaction (OER) catalysts is of great significance because the water oxidation reaction at the photoanode is the rate-determining step in photoelectrocatalytic (PEC) water splitting. Herein, two hybrid photoanodes named BiVO4/COF-Azo and BiVO4/COF-Ben were prepared by in situ solvothermal growth on a modified BiVO4 photoanode. Characterization results revealed that the Azo and Ben COFs could match with BiVO4 well to form heterojunctions, which could effectively enhance the separation efficiency of photogenerated carriers. Also, the smaller impedance of the composite photoanodes and faster kinetics of the water oxidation reaction promoted the charge transmission and enhanced the reaction efficiency of the surface-reaching holes, respectively. As a result, the composite photoanodes exhibited a larger photocurrent and more negative onset potential compared to the pristine BiVO4. This work not only provides a new strategy to construct efficient hybrid photoanodes, but also expands the applications of COFs.

TNF-α Orchestrates Experience-Dependent Plasticity of Excitatory and Inhibitory Synapses in the Anterior Piriform Cortex.

Homeostatic synaptic plasticity, which induces compensatory modulation of synapses, plays a critical role in maintaining neuronal circuit function in response to changing activity patterns. Activity in the anterior piriform cortex (APC) is largely driven by ipsilateral neural activity from the olfactory bulb and is a suitable system for examining the effects of sensory experience on cortical circuits. Pro-inflammatory cytokine tumor necrosis factor-α (TNF-α) can modulate excitatory and inhibitory synapses, but its role in APC is unexplored. Here we examined the role of TNF-α in adjusting synapses in the mouse APC after experience deprivation via unilateral naris occlusion. Immunofluorescent staining revealed that activity deprivation increased excitatory, and decreased inhibitory, synaptic density in wild-type mice, consistent with homeostatic regulation. Quantitative RT-PCR showed that naris occlusion increased the expression of Tnf mRNA in APC. Critically, occlusion-induced plasticity of excitatory and inhibitory synapses was completely blocked in the Tnf knockout mouse. Together, these results show that TNF-α is an important orchestrator of experience-dependent plasticity in the APC.