Termination of convulsion seizures by destabilizing and perturbing seizure memory engrams.

Epileptogenesis, arising from alterations in synaptic strength, shares mechanistic and phenotypic parallels with memory formation. However, direct evidence supporting the existence of seizure memory remains scarce. Leveraging a conditioned seizure memory (CSM) paradigm, we found that CSM enabled the environmental cue to trigger seizure repetitively, and activating cue-responding engram cells could generate CSM artificially. Moreover, cue exposure initiated an analogous process of memory reconsolidation driven by mammalian target of rapamycin-brain-derived neurotrophic factor signaling. Pharmacological targeting of the mammalian target of rapamycin pathway within a limited time window reduced seizures in animals and interictal epileptiform discharges in patients with refractory seizures. Our findings reveal a causal link between seizure memory engrams and seizures, which leads us to a deeper understanding of epileptogenesis and points to a promising direction for epilepsy treatment.

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.

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.

Activation of Somatostatin-Expressing Neurons in the Lateral Septum Improves Stress-Induced Depressive-like Behaviors in Mice.

Depression is a debilitating mood disorder with highly heterogeneous pathogenesis. The limbic system is well-linked to depression. As an important node in the limbic system, the lateral septum (LS) can modulate multiple affective and motivational behaviors. However, the role of LS in depression remains unclear. By using c-Fos expression mapping, we first screened and showed activation of the LS in various depression-related behavioral tests, including the forced swim test (FST), tail suspension test (TST), and sucrose preference test. In the LS, more than 10% of the activated neurons were somatostatin-expressing (SST) neurons. We next developed a microendoscopic calcium imaging method in freely moving mice and revealed that LSSST neural activity increased during mobility in the TST but not open field test. We hypothesize that LSSST neuronal activity is linked to stress and depression. In two mouse models of depression, repeated lipopolysaccharide (LPS) injection and chronic restraint stress (CRS), we showed that LS neuronal activation was suppressed. To examine whether the re-activation of LSSST neurons can be therapeutically beneficial, we optogenetically activated LSSST neurons and produced antidepressant-like effects in LPS-injected mice by increasing TST motility. Moreover, chemogenetic activation of LSSST neurons increased FST struggling in the CRS-exposed mice. Together, these results provide the first evidence of a role for LSSST neurons in regulating depressive-like behaviors in mice and identify them as a potential therapeutic target for neuromodulation-based intervention in depression.

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.

Deletion of TrkB in parvalbumin interneurons alters cortical neural dynamics.

Signaling by neurotrophins such as the brain-derived neurotrophic factor (BDNF) is known to modulate development of interneurons, but the circuit effects of this modulation remain unclear. Here, we examined the impact of deleting TrkB, a BDNF receptor, in parvalbumin-expressing (PV) interneurons on the balance of excitation and inhibition (E-I) in cortical circuits. In the mouse olfactory cortex, TrkB deletion impairs multiple aspects of PV neuronal function including synaptic excitation, intrinsic excitability, and the innervation pattern of principal neurons. Impaired PV cell function resulted in aberrant spiking patterns in principal neurons in response to stimulation of sensory inputs. Surprisingly, dampened PV neuronal function leads to a paradoxical decrease in overall excitability in cortical circuits. Our study demonstrates that, by modulating PV circuit plasticity and development, TrkB plays a critical role in shaping the evoked pattern of activity in a cortical network.

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.