Circadian rhythms orchestrate the mechanisms of numerous illnesses, including those affecting the central nervous system. Depression, autism, and stroke, among other brain disorders, are fundamentally influenced by the intricacies of circadian cycles. Comparative studies on rodent models of ischemic stroke reveal a tendency towards smaller cerebral infarct volumes during the active phase of the night, contrasted with the inactive daytime phase, as previously established. However, the internal mechanisms of this system remain shrouded in mystery. Conclusive evidence highlights the substantial influence of glutamate systems and autophagy mechanisms in the pathology of stroke. Our findings indicate a decline in GluA1 expression and a concurrent surge in autophagic activity in active-phase male mouse stroke models, in comparison to their inactive-phase counterparts. Autophagy's activation, within the active-phase model, resulted in decreased infarct volume; conversely, autophagy's suppression expanded infarct volume. Autophagy's activation was accompanied by a decrease in GluA1 expression, and a subsequent increase in the expression was observed when autophagy was inhibited. We employed Tat-GluA1 to sever the link between p62, an autophagic adapter protein, and GluA1. This resulted in preventing GluA1's degradation, a consequence comparable to the effect of inhibiting autophagy in the active-phase model. Our results indicated that the deletion of the circadian rhythm gene Per1 completely suppressed the circadian rhythm of infarction volume, and simultaneously abolished GluA1 expression and autophagic activity in wild-type mice. Our findings propose a fundamental mechanism through which the circadian cycle interacts with autophagy to regulate GluA1 expression, thereby affecting infarct volume in stroke. Earlier investigations suggested that circadian oscillations may influence the size of infarcts resulting from stroke, yet the precise mechanisms underlying this effect are still largely unknown. We demonstrate a relationship between a smaller infarct volume after middle cerebral artery occlusion/reperfusion (MCAO/R), during the active phase, and reduced GluA1 expression coupled with autophagy activation. GluA1 expression diminishes during the active phase due to the p62-GluA1 interaction, culminating in autophagic degradation. In essence, autophagic degradation of GluA1 is a prominent process, largely following MCAO/R events within the active stage but not the inactive.
The excitatory circuit's long-term potentiation (LTP) is enabled by the presence of cholecystokinin (CCK). Our investigation focused on how this substance influences the augmentation of inhibitory synaptic function. The neocortical responses of both male and female mice to a forthcoming auditory stimulus were dampened by the activation of GABAergic neurons. The suppression of GABAergic neurons was enhanced by the application of high-frequency laser stimulation. Cholecystokinin (CCK) interneurons exhibiting HFLS properties can induce a long-term strengthening of their inhibitory influences on pyramidal cells. Potentiation was nullified in CCK knockout mice, but was still observed in mice with knockouts in CCK1R and CCK2R receptors, for both sexes. In the subsequent step, we leveraged bioinformatics analysis, multiple unbiased cellular assays, and histology to characterize a novel CCK receptor, GPR173. Our proposition is that GPR173 is the CCK3 receptor, mediating the link between cortical CCK interneuron signaling and inhibitory long-term potentiation in mice of either sex. Consequently, targeting GPR173 could prove beneficial in treating neurological disorders resulting from an imbalance between neuronal excitation and inhibition in the brain cortex. check details Numerous studies indicate a potential involvement of CCK in modifying GABA signaling, a crucial inhibitory neurotransmitter, throughout various brain regions. Undoubtedly, the contribution of CCK-GABA neurons to the micro-structure of the cortex is presently unclear. A novel CCK receptor, GPR173, located in CCK-GABA synapses, was shown to amplify the inhibitory effects of GABA. This finding may indicate a promising therapeutic target for brain disorders stemming from a mismatch in excitatory and inhibitory processes within the cortex.
Epilepsy syndromes, including developmental and epileptic encephalopathy, are associated with pathogenic variations in the HCN1 gene. The de novo, repeatedly occurring, pathogenic HCN1 variant (M305L) creates a cation leak, thus allowing the movement of excitatory ions when wild-type channels are in their inactive configuration. The Hcn1M294L mouse accurately mimics the seizure and behavioral characteristics seen in patients with the condition. Mutations in HCN1 channels, which are highly concentrated in the inner segments of rod and cone photoreceptors, are anticipated to influence visual function, as these channels play a critical role in shaping the visual response to light. Hcn1M294L mice, both male and female, exhibited a substantial reduction in photoreceptor sensitivity to light, as evidenced by their electroretinogram (ERG) recordings, and this reduction also affected bipolar cell (P2) and retinal ganglion cell responsiveness. Flickering light-induced ERG responses were also diminished in Hcn1M294L mice. The ERG's abnormalities align with the response pattern observed in a solitary female human subject. The variant's presence did not impact the retinal Hcn1 protein's structure or expression pattern. In silico photoreceptor simulations indicated that the mutated HCN1 channel significantly diminished light-induced hyperpolarization, resulting in a higher calcium ion flux in comparison to the wild-type situation. Our theory is that the light-mediated glutamate release from photoreceptors will diminish during a stimulus, substantially decreasing the dynamic range of this response. Our research data demonstrate HCN1 channels' critical role in retinal function, suggesting patients harboring pathogenic HCN1 variants may experience severely diminished light sensitivity and impaired temporal information processing. SIGNIFICANCE STATEMENT: Pathogenic mutations in HCN1 are increasingly implicated as a causative factor in the development of intractable epilepsy. human‐mediated hybridization Throughout the entire body, including the retina, HCN1 channels are present everywhere. Electroretinogram recordings from a mouse model exhibiting HCN1 genetic epilepsy indicated a substantial decrease in photoreceptor responsiveness to light stimuli, along with a reduced capacity for responding to high-frequency light flicker. transplant medicine There were no discernible morphological flaws. Computational modeling suggests that the mutated HCN1 channel reduces the extent of light-stimulated hyperpolarization, which in turn restricts the dynamic spectrum of the response. Our research offers crucial insight into how HCN1 channels influence retinal health, and stresses the significance of scrutinizing retinal dysfunction in diseases attributable to HCN1 variations. Due to the distinctive changes displayed within the electroretinogram, it is feasible to utilize it as a biomarker for this HCN1 epilepsy variant, facilitating the development of targeted treatments.
The sensory cortices' compensatory plasticity is triggered by damage to the sensory organs. The remarkable recovery of perceptual detection thresholds to sensory stimuli is a consequence of plasticity mechanisms restoring cortical responses, despite the reduction in peripheral input. Although peripheral damage frequently results in diminished cortical GABAergic inhibition, less is known regarding modifications in intrinsic properties and the corresponding biophysical mechanisms. This study of these mechanisms used a model of noise-induced peripheral damage, affecting both male and female mice. A marked, cell-type-specific diminishment in the intrinsic excitability of parvalbumin-expressing neurons (PVs) in layer 2/3 of the auditory cortex was uncovered. No alterations were detected in the inherent excitability of either L2/3 somatostatin-expressing neurons or L2/3 principal neurons. At 1 day post-noise exposure, a decrease in the L2/3 PV neuronal excitability was observed; this effect was absent at 7 days. Specifically, this involved a hyperpolarization of the resting membrane potential, a depolarization shift in the action potential threshold, and a reduced firing frequency in response to a depolarizing current. To analyze the underlying biophysical mechanisms, potassium currents were systematically measured. Within one day of noise exposure, a rise in KCNQ potassium channel activity was detected in the L2/3 pyramidal neurons of the auditory cortex, concomitant with a hyperpolarizing shift in the activation potential's minimum voltage for the KCNQ channels. A surge in activation levels is directly linked to a decrease in the inherent excitability of the PVs. Following noise-induced hearing loss, our research underscores the presence of cell- and channel-specific plasticity, which further elucidates the pathologic processes involved in hearing loss and related disorders such as tinnitus and hyperacusis. The complete picture of the mechanisms responsible for this plasticity is still lacking. Plasticity within the auditory cortex is a plausible mechanism for the recovery of sound-evoked responses and perceptual hearing thresholds. Significantly, recovery is not possible for other auditory functions, and the damage to the periphery can consequently result in detrimental plasticity-related ailments, including tinnitus and hyperacusis. Peripheral damage stemming from noise is accompanied by a rapid, transient, and specific decrease in the excitability of parvalbumin-expressing neurons within layer 2/3, potentially influenced by increased activity of KCNQ potassium channels. Investigations into these areas might uncover novel strategies for improving perceptual recovery from hearing loss, while simultaneously alleviating hyperacusis and tinnitus.
Modulation of single/dual-metal atoms supported on a carbon matrix can be achieved through adjustments to the coordination structure and neighboring active sites. Precisely engineering the geometric and electronic architectures of single/dual-metal atoms and deciphering the underlying structure-property correlations represent considerable hurdles.