Neuroscience bulletin最新文献

Epilepsy is one of the most prevalent and severe neurological disorders, and it is inadequately controlled with currently available medications. While cinnabar (mercury(II) sulfide)-a traditional Chinese medicine-has historical application in epilepsy treatment, its therapeutic efficacy and underlying mechanisms are unclear. In this study, we find that cinnabar exerts model-dependent antiseizure efficacy in mice. Specifically, it significantly attenuates acute seizures, enhances the termination of diazepam-resistant status epilepticus, and reduces spontaneous seizures in the kainic acid (KA)-induced seizure model. Conversely, no therapeutic effect was found in the maximal electroshock-, pentylenetetrazole-, or kindling-induced seizure model. Fiber photometry revealed that cinnabar normalizes KA-induced hippocampal neurotransmission imbalances by simultaneously decreasing glutamate hyperactivity and γ-aminobutyric acid hypoactivity. Furthermore, cinnabar has neuroprotective effects and alleviates comorbid anxiety-like behaviors, while showing no alterations in motor function. Our findings suggest cinnabar's potential as a therapeutic agent for seizure management, via a mechanism associated with the reversal of the hippocampal excitatory/inhibitory imbalance.

GABA_A receptors containing α5-subunits (GABA_AR-α5) cluster at both extrasynaptic and synaptic locations, interacting with the scaffold proteins radixin and gephyrin, respectively, and the re-localization of GABA_AR-α5 influences GABAergic transmission. Here, we found that when early spatial memory deficits occurred in aged mice at 24 h after sevoflurane anesthesia, there was a re-localization of GABA_AR-α5 that enhanced tonic inhibition and reduced the decay kinetics of miniature inhibitory postsynaptic currents in the hippocampal CA1 region. Mechanistically, increased phosphorylation of radixin at threonine 564 (Thr564) mediates the re-localization of GABA_AR-α5. Acute treatment with the selective extrasynaptic GABA_AR-α5 antagonist S44819 restored the GABA_AR-α5-mediated inhibitory currents by reversing radixin phosphorylation-dependent GABA_AR-α5 re-localization, then improved the sevoflurane-induced spatial memory impairment in aged mice. Our results suggest that the localization of GABA_AR-α5 altered by sevoflurane is linked to unbalanced GABAergic transmission, which induces early memory impairment in aged mice. Modulating the GABA_AR-α5 localization might be a novel strategy to improve memory after sevoflurane exposure.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by neurotoxic amyloid beta (Aβ) deposition in the brain. Neurons can internalize and exocytose Aβ; however, the molecular pathways governing Aβ release remain poorly understood. To identify key regulators of Aβ42 transport, we applied formaldehyde cross-linking of protein complexes combined with co-immunoprecipitation and mass spectrometry analysis to identify TMED10 as a novel Aβ42-interacting protein. In cultured neurons, TMED10 knockdown (KD) increased intracellular Aβ42 levels by preventing Aβ42 exocytosis. TMED10 expression was significantly reduced in the cortex of AD patients. Overexpression of TMED10 in primary neurons mitigated the toxic effects of exogenous Aβ42. In 5 × FAD mice, overexpression of TMED10 via tail vein injection of a brain-penetrable adeno-associated virus improved cognitive function and reduced Aβ42 plaque accumulation. Together, these findings position TMED10 as a potential regulator of Aβ42 exocytosis and underscore the need for further studies to evaluate its therapeutic potential in AD.

Temporomandibular disorders (TMDs) comprise a spectrum of conditions affecting the temporomandibular joint, masticatory musculature, dental occlusion, and even multiple systemic structures. Epidemiological data indicate that approximately 40% of patients with TMDs experience comorbid affective disorders, creating complex diagnostic and therapeutic challenges, further resulting in suboptimal management. This review summarizes the comorbidity spectrum of TMDs, especially focusing on the bidirectional relationship between TMD-related pain and affective disorders, with the aims of (1) elucidating shared neurobiological mechanisms involving central sensitization, maladaptive neuroplasticity, and neuro-endocrine-immune dysregulation in TMDs; (2) analyzing the role of psychosocial factors in perpetuating this comorbidity; and (3) evaluating evidence-based treatment strategies that address both somatic and psychological symptoms. This review concludes by highlighting emerging new technologies with the potential for improved risk assessment and advocates for personalized treatment paradigms in this complex patient population. Future research directions should prioritize longitudinal studies examining the trajectories of comorbidity as well as testing emerging intervention approaches.

Clinical investigations have suggested a potential link between cataracts and Alzheimer's disease (AD). However, whether cataract has an impact on the progression of AD remains unclear. The objective of this research was to determine the relationship between cataracts and AD. A cataract model was established in APP/PS1 [mutant amyloid precursor protein (APP) and a mutant presenilin-1 (PS1) gene] mice via lens puncture. Behavioural assays were used to evaluate cognitive function. Immunohistochemistry, immunofluorescence, and enzyme-linked immunosorbent assays (ELISA) were applied to detect AD-related pathology. Visual signals were markedly obstructed following surgery to induce cataracts, and these mice presented an increased cerebral amyloid-beta (Aβ) load, while no significant alterations in the levels of enzymes associated with Aβ metabolism were detected. In addition, compared with control mice, cataract model mice presented increased astrogliosis and microgliosis, along with elevated levels of proinflammatory factors. Moreover, cataract model mice presented more pronounced cognitive impairments than did control mice. Our study offers experimental confirmation that cataract considerably contributes to the pathogenesis of AD, thereby emphasizing the importance of visual signals in maintaining cognitive well-being.

The mammalian cochlea relies on outer and inner hair cells (OHCs/IHCs) for sound amplification and signal transmission. Rab3-interacting molecular binding protein 2 (RIMBP2), expressed in receptor cells and neurons at synaptic active zones, remains poorly characterized in hearing. We therefore generated a Rimbp2 knockout (KO) mouse model (Rimbp2^-/-), which exhibited severe hearing loss with elevated thresholds, prolonged latencies, and reduced amplitudes in auditory brainstem response Wave I. OHC loss via apoptosis was correlated with threshold elevation. In IHCs, patch-clamp recordings revealed reduced exocytosis, including a diminished readily-releasable pool, impaired sustained release, and blocked fast endocytosis. Immunostaining showed unchanged ribbon synapse numbers but positional shifts in the basal pole of KO IHCs. These findings demonstrated RIMBP2's essential role in OHC survival and its broader regulatory functions in IHC synaptic transmission than previously recognized.

Maintaining a stable body temperature is essential for survival. Multiple brain regions contribute to thermoregulation, but their specific characteristics and underlying neural mechanisms in the coordination of thermoregulation are not fully clarified. Here, we reveal the distinct roles of two preoptic subregions in warm defense in mice: the anterior ventromedial preoptic area (VMPO) and the ventral part of the lateral preoptic nucleus (vLPO). VMPO vesicular glutamate transporter 2​​ (Vglut2) neurons exhibited dramatic responses to rising temperatures, producing a marked decrease in core temperature by warm defense responses. In contrast, excitatory and inhibitory vLPO neurons responded gently to warm stimuli, exerting moderate effects on warm defense. Further postsynaptic tracing and caspase ablation identified distinct cell type-specific downstream targets in the dorsomedial hypothalamus (DMH) mediating these different warm defense responses. Taken together, our findings reveal distinct yet complementary pathways in the preoptic DMH network that enable both rapid and fine-tuned regulation of body temperature under elevated thermal conditions.

Vestibular hair cells (HCs) in the inner ear, crucial for balance and spatial orientation, are classified into type I and type II subtypes, but the mechanisms regulating their differentiation remain unclear. In this study, we examined the role of Pou4f3, an important transcription factor, in vestibular HC differentiation using Pou4f3^DTR/DTR (deficient) and Pou4f3^CreER/CreER (knockout) mouse models. In Pou4f3-deficient mice, the HC number decreased, and immature HCs failed to develop type I characteristics, indicating a developmental arrest. While type II HCs differentiated normally, Pou4f3 deficiency disrupted HC bundle formation and cell polarity. Findings from knockout models further confirmed the essential role of Pou4f3 in vestibular HC subtype specification. This study underscores the critical role of Pou4f3 in determining vestibular HC subtypes and offers insights into potential strategies for restoring vestibular function through HC regeneration.