Is -Associated Hearing Loss (DFNB93) a Gene Therapy Target? Preclinical Progress and Patient Registry.

modulates presynaptic Ca1.3 Ca channel function in inner hair cells (IHCs) and is required for indefatigable synaptic sound encoding. Biallelic variants in are associated with non-syndromic hearing loss (DFNB93).

Local activity alterations in individuals with autism correlate with neurotransmitter properties and ketamine-induced brain changes.

Autism is a neurodevelopmental condition associated with altered resting-state brain function. An increased excitation-inhibition ratio is discussed as a pathomechanism but in-vivo evidence of disturbed neurotransmission underlying functional alterations remains scarce. We compare local resting-state brain activity and neurotransmitter co-localizations between autism (N = 405, N = 395) and neurotypical controls (N = 473, N = 474) in two independent cohorts and correlate them with excitation-inhibition changes induced by glutamatergic (ketamine) and GABAergic (midazolam) medication.

Mechanisms of intrinsic osmolality and sodium detection by magnocellular neurosecretory neurons.

The maintenance of extracellular fluid (ECF) osmolality and sodium concentration ([Na]) near optimal "set point" values sustains physiological functions and prevents pathological states such as hypo- and hypernatremia. The peptide hormones vasopressin (antidiuretic hormone) and oxytocin (a natriuretic hormone in rats) play key roles in this process. These hormones are synthesized by hypothalamic magnocellular neurosecretory cells (MNCs) that project to the neurohypophysis and are released into the systemic circulation in response to rises in ECF osmolality or [Na].

Distinct Neural Mechanisms of Visual and Sound Adaptation in the Cat Visual Cortex.

Sensory areas exhibit modular selectivity to stimuli, but they can also respond to features outside of their basic modality. Several studies have shown cross-modal plastic modifications between visual and auditory cortices; however, the exact mechanisms of these modifications are yet not completely known. To this aim, we investigated the effect of 12 min of visual versus sound adaptation (referring to forceful application of an optimal/nonoptimal stimulus to a neuron[s] under observation) on the infragranular and supragranular primary visual neurons (V1) of the cat (Felis catus).

Presenilin loss impairs synaptic transmission and causes axonal degeneration through ryanodine receptor dysfunction, independent of γ-secretase activity.

Presenilin mutations are the most common cause of familial Alzheimer's disease (FAD), but the mechanisms by which they disrupt neuronal function remain unresolved, particularly in relation to γ-secretase activity. Using , we show that the presenilin ortholog SEL-12 supports synaptic transmission and axonal integrity through a pathway involving the ryanodine receptor RYR-1. Loss-of-function mutations in either or reduce neurotransmitter release and cause neuronal structural defects, with no additional impairment in double mutants, suggesting a shared pathway.

Sex-specific behavioral impairments and neuronal alterations in Wistar rats following repeated sevoflurane exposure during developmental stages.

Objectives: This study aimed to investigate the effects of repeated exposure to sevoflurane as an anesthetic agent during various developmental stages, namely neonatal, preadolescent, and adult, on behavioral, synaptic, and neuronal plasticity in male and female Wistar rats.

Methods: Rats were exposed to sevoflurane during three developmental stages: neonatal (PN7), pre-adolescence (PN28), and adulthood (PN90). Behavioral performance was evaluated with the Morris Water Maze.

Chronic treatment with fluoxetine regulates mitochondrial features and plasticity-associated transcriptomic pathways in parvalbumin-positive interneurons of prefrontal cortex.

Chronic treatment with fluoxetine, a widely prescribed selective serotonin reuptake inhibitor (SSRI), is known to promote neural plasticity. The role of fluoxetine in plasticity has been particularly tied to parvalbumin-positive interneurons, a key population of GABAergic neurons that regulate inhibitory tone and network stability. While our previous studies have highlighted fluoxetine-induced plasticity in the visual cortex and hippocampus, its cell-type-specific effects in the prefrontal cortex (PFC) remain unclear.

PI(3)P coordinates SNX17- and SNX27-dependent protein recycling for long-term synaptic plasticity.

Two major protein recycling pathways have emerged as key regulators of enduring forms of synaptic plasticity, such as long-term potentiation (LTP), yet how these pathways are recruited during plasticity is unknown. Phosphatidylinositol-3-phosphate (PI(3)P) is a key regulator of endosomal trafficking and alterations in this lipid have been linked to neurodegeneration. Here, using primary hippocampal neurons, we demonstrate dynamic PI(3)P synthesis during chemical induction of LTP (cLTP), which drives coordinate recruitment of the SNX17-Retriever and SNX27-Retromer pathways to endosomes and synaptic sites.

MicroRNAs and synaptic dysfunction in Parkinson's disease.

Parkinson's disease (PD) is a debilitating neurodegenerative condition. Synaptic dysfunctions are associated with the onset and progressive neurodegeneration exhibited in PD. Healthy, active synapses are a prerequisite for non-pathological neurotransmission.

Role of CPEBs in Learning and Memory.

Memory formation involves a complex interplay of molecular and cellular processes, including synaptic plasticity mechanisms such as long-term potentiation (LTP) and long-term depression (LTD). These processes rely on activity-dependent gene expression and local protein synthesis at synapses. A central unresolved question in neuroscience is how memories can be stably maintained over time, despite the transient nature of the proteins involved in their initial encoding.

Therapeutic potential of small peptides in Alzheimer's disease: Advances in memory restoration and targeted delivery systems.

Despite extensive research into Alzheimer's disease (AD), few therapeutic strategies have successfully addressed its core pathology at the synaptic level. Small peptides represent a promising class of therapeutic agents capable of modulating key molecular pathways involved in amyloid toxicity, tau hyperphosphorylation, and synaptic degeneration. Their unique ability to cross biological barriers, interact with intracellular targets, and be modified for enhanced stability positions them as viable candidates for next-generation treatments targeting cognitive decline in AD.

The emerging roles of long non-coding RNAs in the nervous system.

Tens, if not hundreds, of thousands of long non-coding RNAs (lncRNAs) are transcribed from mammalian genomes, especially in the brain, wherein most exhibit region-specific and/or cell-specific expression patterns. Many lncRNAs are nuclear-localized and appear to be the products of developmental enhancers, whereas others are found in the cytoplasm, including at the synapse. Here, we describe the lncRNAs that have been shown to have roles in various aspects of brain development, synaptic function, learning, behaviour and brain disorders.

POU6F1 promote lumbar motor circuit reorganization following spinal cord injury.

Spinal cord injury (SCI) causes irreversible motor deficits due to disrupted lumbar circuitry. However, transcriptional mechanisms in distal lumbar circuits are poorly understood. We identify POU6F1 as a critical transcriptional regulator in spinal lumbar segment (SLS, L3-L5) motor circuit regeneration.

It must have been network (percolation for the synaptic function).

How does synaptic wiring depend on receptor clustering, scaffold networks, and signaling cohorts? In a recent study in Molecular Cell, Jia et al. demonstrate that targeting the interaction strength between the scaffold proteins, rather than the total amount of each protein component, modulates the signal propagation across the protein network.

Compensatory roles of STT3A and ALG5 in glucose metabolism of aged macaque hippocampus.

The hippocampus (HC), a central hub for memory and cognition, exhibits unique metabolic resilience during aging despite widespread brain glucose hypometabolism. Here, we report that aged humans and macaques paradoxically display elevated HC glucose uptake (18F-FDG PET SUVR) alongside strengthened connectivity to sensory-motor and limbic networks-an adaptive rewiring revealed by graph-theoretical metabolic network analysis. Integrated multi-omics profiling identified STT3A (oligosaccharyltransferase) and ALG5 (dolichyl-phosphate β-glucosyltransferase) as key regulators of age-related HC adaptation, with their upregulation in aged macaque hippocampi driving N-glycosylation-dependent metabolic reprogramming.

Mitochondrial dysfunction reveals HS-mediated synaptic sulfhydration as a potential mechanism for autism-associated social defects.

Clinical studies have identified multiple mitochondrial disturbances in the peripheral tissues of patients with autism. However, how neuronal metabolism contributes to the autism-associated phenotype remains unclear. In this study, we focused on the anterior cingulate cortex (ACC) and reported hydrogen sulfide (HS) elevation as a common outcome to mitochondrial dysfunction in Shank3b and Fmr1 neurons.

Loss of COL20A1 in Schwann Cells Alters Regeneration of the Neuromuscular Junction and Locomotor Activity in Mice.

Collagen type XX alpha 1 (COL20A1) was recently found to be highly concentrated in perisynaptic Schwann cells (PSCs), the synaptic glia of the neuromuscular junction (NMJ), suggesting that COL20A1 plays important roles in PSCs and at the NMJ. To investigate this possibility, we generated mice lacking Col20a1 only in Schwann cells (Col20a1-SCKO) and globally (Col20a1-gKO). PSCs and NMJs were morphologically unchanged in adult Col20a1-SCKO mice despite these conditional mice exhibiting gait abnormalities.

Evolving insights on the role of microglia in neuroinflammation, plasticity, and regeneration of the injured spinal cord.

Microglia have emerged as central players in the pathophysiology of traumatic spinal cord injury (SCI). The purpose of this brief review is to highlight the evolution of knowledge on the role of microglia in SCI. We explore the initial discovery of macrophages and their role in SCI lesions, followed by how microglia were examined and distinguished from monocyte-derived macrophages.

Dissociable Neural Connectome Mapping of Reward and Punishment Responsiveness in Young Adults: Associations with Genetic Variability and Neurotransmitter Profiles.

While the hyper- and hypo- reward or punishment sensitivities (RS, PS) have received considerable attention as prominent transdiagnostic features of psychopathology, the lack of an overarching neurobiological characterization currently limits their early identification and neuromodulation. Here we combined microarray data from the Allen Human Brain Atlas with a multimodal fMRI approach to uncover the neurobiological signatures of RS and PS in a discovery-replication design (N=655 healthy participants, 442 Females). Both RS and PS were mapped separately in the brain, with the functional connectome in the fronto-striatal network encoding reward responsiveness, while the fronto-insular system was particularly engaged in punishment sensitivity.

Biomarker-related phospho-tau217 appears in synapses around Aβ plaques prior to tau tangle in cerebral cortex of preclinical Alzheimer's disease.

Phospho-tau protein p-tau181 is a cerebrospinal fluid biomarker for Alzheimer's disease (AD), while p-tau217 is the most sensitive plasma biomarker for cerebral amyloid β (Aβ) load prior to tau pathology in preclinical AD. Diagnostic and prognostic use of these p-tau biomarkers requires neuropathological interpretation. Here, we analyzed the cellular localization of biomarker p-tau species in postmortem human brains harboring different extents of Aβ plaque and tau pathology.

Neuroprotective effects of saikosaponin-A in ethanol-induced glia-mediated neuroinflammation, oxidative stress via RAGE/TLR4/NFkB signaling.

Chronic use of ethanol leads to psychological and physiological dependence followed by neurodegeneration via glia-mediated neuroinflammation, and oxidative stress. The current study is aimed at the neuroprotective effects of saikosaponin-A against ethanol-induced neurodegeneration. Here, saikosaponin-A 10 mg/kg i.

Cell membrane cholesterol affects serotonin transporter efflux due to altered transporter oligomerization.

The human monoamine transporters (MATs) for serotonin (SERT), dopamine (DAT), and norepinephrine (NET) play a key role in neurotransmission by transporting neurotransmitters from the synaptic cleft back into the neuron. MATs are embedded in the cell membrane's lipid bilayer, encompassing cholesterol, phospholipids, and sphingolipids as main components. Membrane cholesterol association has been shown for all MATs impacting transporter conformation, substrate affinity, transport velocity, and turnover rates.

Network Activity Shapes Inhibitory Synaptic Development in the Mouse Hippocampus.

The proper development of excitatory/inhibitory balance is critical for brain function, as any imbalance has been associated with myriad neuropsychiatric disorders. How this balance evolves during synaptic development remains unclear. To address this question, we examine how manipulations of SIRPα, a cell-adhesion molecule that organizes excitatory synaptic development in the hippocampus, affect inhibitory synaptogenesis to maintain excitatory/inhibitory balance, using mice of either sex.