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Mutations in the SLC1A4 transporter lead to neurodevelopmental impairments, spastic tetraplegia, thin corpus callosum and microcephaly in children. SLC1A4 catalyses obligatory amino acid exchange between neutral amino acids, but the physiopathology of SLC1A4 disease mutations and progressive microcephaly remain unclear. Here, we examined the phenotype and metabolic profile of three Slc1a4 mouse models: a constitutive Slc1a4-knockout mouse; a knock-in mouse with the major human Slc1a4 mutation (Slc1a4-K256E); and a selective knockout of Slc1a4 in brain endothelial cells (Slc1a4tie2-cre). We show that Slc1a4 is a bona fide L- serine transporter at the blood–brain barrier (BBB) and that acute inhibition or deletion of Slc1a4 leads to a decrease in serine influx into the brain. This results in microcephaly associated with decreased L- serine content in the brain, accumulation of atypical and cytotoxic 1-deoxysphingolipids, neurodegeneration, synaptic and mitochondrial abnormalities and behavioural impairments. Prenatal and early postnatal oral administration of L- serine at levels that replenish the serine pool in the brain rescued the observed biochemical and behavioural changes. Administration of L- serine until the second postnatal week also normalized brain weight in Slc1a4-E256K mice. Our observations suggest that the transport of 'non-essential' amino acids from the blood through the BBB is at least as important as that of essential amino acids for brain metabolism and development. We propose that SLC1A4 mutations cause a BBB aminoacidopathy with deficits in serine import across the BBB, required for optimal brain growth, leading to a metabolic microcephaly, which may be amenable to treatment with L- serine. [ABSTRACT FROM AUTHOR]

Background: Noise-induced cochlear synaptopathy has recently emerged as a focus in hearing research. Purpose: This study aimed to examine the impact of repeated noise exposure on the quantification and mRNA expression levels of cochlear synapses. Methods: Measurements were conducted at baseline, 1 day, and 14 days post-exposure to 88 or 97 dB SPL noise (2 h/day for 7 days, frequency range 2-20 kHz). Auditory brainstem responses (ABRs), immunofluorescence and quantitative real-time PCR (qRT-PCR) were used to examine the results. Results: 1. Exposure to 88 dB SPL caused minimal changes in ABRs, ribbon morphology and medial olivocochlear (MOC) efferent synapses; elevation of synaptophysin(SYP) and α9α10 nAchR mRNA levels were observed. 2. Exposure to 97 dB SPL caused threshold shift and synaptopathy of ribbon and MOC; downregulation of α10nAchR, SYP and ctbp2 mRNA levels were observed. Conclusion: Noise-induced cochlear synaptic degeneration involves both afferent and efferent synaptopathy. [ABSTRACT FROM AUTHOR]

Frontotemporal dementia and amyotrophic lateral sclerosis are common forms of neurodegenerative disease that share overlapping genetics and pathologies. Crucially, no significantly disease-modifying treatments are available for either disease. Identifying the earliest changes that initiate neuronal dysfunction is important for designing effective intervention therapeutics. The genes mutated in genetic forms of frontotemporal dementia and amyotrophic lateral sclerosis have diverse cellular functions, and multiple disease mechanisms have been proposed for both. Identification of a convergent disease mechanism in frontotemporal dementia and amyotrophic lateral sclerosis would focus research for a targetable pathway, which could potentially effectively treat all forms of frontotemporal dementia and amyotrophic lateral sclerosis (both familial and sporadic). Synaptopathies are diseases resulting from physiological dysfunction of synapses, and define the earliest stages in multiple neuronal diseases, with synapse loss a key feature in dementia. At the presynapse, the process of synaptic vesicle recruitment, fusion and recycling is necessary for activity-dependent neurotransmitter release. The unique distal location of the presynaptic terminal means the tight spatio-temporal control of presynaptic homeostasis is dependent on efficient local protein translation and degradation. Recently, numerous publications have shown that mutations associated with frontotemporal dementia and amyotrophic lateral sclerosis present with synaptopathy characterized by presynaptic dysfunction. This review will describe the complex local signalling and membrane trafficking events that occur at the presynapse to facilitate neurotransmission and will summarize recent publications linking frontotemporal dementia/amyotrophic lateral sclerosis genetic mutations to presynaptic function. This evidence indicates that presynaptic synaptopathy is an early and convergent event in frontotemporal dementia and amyotrophic lateral sclerosis and illustrates the need for further research in this area, to identify potential therapeutic targets with the ability to impact this convergent pathomechanism. [ABSTRACT FROM AUTHOR]

Abstract Background Multiple sclerosis (MS) is a progressive neurodegenerative disease of the central nervous system characterized by inflammation-driven synaptic abnormalities. Interleukin-9 (IL-9) is emerging as a pleiotropic cytokine involved in MS pathophysiology. Methods Through biochemical, immunohistochemical, and electrophysiological experiments, we investigated the effects of both peripheral and central administration of IL-9 on C57/BL6 female mice with experimental autoimmune encephalomyelitis (EAE), a model of MS. Results We demonstrated that both systemic and local administration of IL-9 significantly improved clinical disability, reduced neuroinflammation, and mitigated synaptic damage in EAE. The results unveil an unrecognized central effect of IL-9 against microglia- and TNF-mediated neuronal excitotoxicity. Two main mechanisms emerged: first, IL-9 modulated microglial inflammatory activity by enhancing the expression of the triggering receptor expressed on myeloid cells-2 (TREM2) and reducing TNF release. Second, IL-9 suppressed neuronal TNF signaling, thereby blocking its synaptotoxic effects. Conclusions The data presented in this work highlight IL-9 as a critical neuroprotective molecule capable of interfering with inflammatory synaptopathy in EAE. These findings open new avenues for treatments targeting the neurodegenerative damage associated with MS, as well as other inflammatory and neurodegenerative disorders of the central nervous system.

Abstract Background Syntaxin 1A is a member of a membrane-integrated nervous system-specific protein superfamily involved in the neuromediator release from synaptic vesicles and one of the proteins included in axonal integrity. Studies that discussed the role of Syntaxin 1A in multiple sclerosis are few and limited. Gene studying sometimes shows unexpected results in different populations. The aim of this work was to investigate Syntaxin 1A genetic polymorphism (rs1569061) in a sample of Egyptian patients with MS and the relation between Syntaxin 1A gene polymorphism and disease course and disability. A case–control study included 150 subjects; 75 Egyptian MS patients of different clinical courses and 75 age and sex matched healthy controls. Patients were subjected to clinical evaluation, assessment of disability, and cognition. Both patient and control groups were subjected to Syntaxin 1A genotyping. Results There was no significant difference between different genotypes distribution for Syntaxin 1A (rs 1569061) between MS patients and controls. No significant difference was found between genotypes and allele distribution for Syntaxin 1A (rs 1569061) among cases of MS regarding EDSS or results of BICAMS). There was no statistically significant difference between syntaxin genotypes among cases of MS regarding demographic or clinical characteristics of the disease. Conclusion Here we show no statistically significant difference between MS patients and control regarding Syntaxin 1A genotypes and different alleles. Syntaxin 1A genotypes have no impact on clinical characteristics of the disease, disability, or cognition. These negative findings open the floor for the study of other MS related genes in Egypt.

MiR-142-3p has recently emerged as key factor in tailoring personalized treatments for multiple sclerosis (MS), a chronic autoimmune demyelinating disease of the central nervous system (CNS) with heterogeneous pathophysiology and an unpredictable course. With its involvement in a detrimental regulatory axis with interleukin-1beta (IL1β), miR-142-3p orchestrates excitotoxic synaptic alterations that significantly impact both MS progression and therapeutic outcomes. In this study, we investigated for the first time the influence of individual genetic variability on the miR-142-3p excitotoxic effect in MS. We specifically focused on the single-nucleotide polymorphism Val66Met (rs6265) of the brain-derived neurotrophic factor (BDNF) gene, known for its crucial role in CNS functioning. We assessed the levels of miR-142-3p and IL1β in cerebrospinal fluid (CSF) obtained from a cohort of 114 patients with MS upon diagnosis. By stratifying patients according to their genetic background, statistical correlations with clinical parameters were performed. Notably, in Met-carrier patients, we observed a decoupling of miR-142-3p levels from IL1β levels in the CSF, as well as from of disease severity (Expanded Disability Status Score, EDSS; Multiple Sclerosis Severity Score, MSSS; Age-Related Multiple Sclerosis Severity Score, ARMSS) and progression (Progression Index, PI). Our discovery of the interference between BDNF Val66Met polymorphism and the synaptotoxic IL1β-miR-142-3p axis, therefore hampering miR-142-3p action on MS course, provides valuable insights for further development of personalized medicine in the field. [ABSTRACT FROM AUTHOR]

Background: Multiple sclerosis (MS) is a progressive neurodegenerative disease of the central nervous system characterized by inflammation-driven synaptic abnormalities. Interleukin-9 (IL-9) is emerging as a pleiotropic cytokine involved in MS pathophysiology. Methods: Through biochemical, immunohistochemical, and electrophysiological experiments, we investigated the effects of both peripheral and central administration of IL-9 on C57/BL6 female mice with experimental autoimmune encephalomyelitis (EAE), a model of MS. Results: We demonstrated that both systemic and local administration of IL-9 significantly improved clinical disability, reduced neuroinflammation, and mitigated synaptic damage in EAE. The results unveil an unrecognized central effect of IL-9 against microglia- and TNF-mediated neuronal excitotoxicity. Two main mechanisms emerged: first, IL-9 modulated microglial inflammatory activity by enhancing the expression of the triggering receptor expressed on myeloid cells-2 (TREM2) and reducing TNF release. Second, IL-9 suppressed neuronal TNF signaling, thereby blocking its synaptotoxic effects. Conclusions: The data presented in this work highlight IL-9 as a critical neuroprotective molecule capable of interfering with inflammatory synaptopathy in EAE. These findings open new avenues for treatments targeting the neurodegenerative damage associated with MS, as well as other inflammatory and neurodegenerative disorders of the central nervous system. [ABSTRACT FROM AUTHOR]

Introduction: Cochlear afferent synapses connecting inner hair cells to spiral ganglion neurons are susceptible to excitotoxic trauma on exposure to loud sound, resulting in a noise-induced cochlear synaptopathy (NICS). Here we assessed the ability of cyclic AMP-dependent protein kinase (PKA) signaling to promote cochlear synapse regeneration, inferred from its ability to promote axon regeneration in axotomized CNS neurons, another system refractory to regeneration. Methods: We mimicked NICS in vitro by applying a glutamate receptor agonist, kainic acid (KA) to organotypic cochlear explant cultures and experimentally manipulated cAMP signaling to determine whether PKA could promote synapse regeneration. We then delivered the cAMP phosphodiesterase inhibitor rolipram via implanted subcutaneous minipumps in noise-exposed CBA/CaJ mice to test the hypothesis that cAMP signaling could promote cochlear synapse regeneration in vivo. Results: We showed that the application of the cell membrane-permeable cAMP agonist 8-cpt-cAMP or the cAMP phosphodiesterase inhibitor rolipram promotes significant regeneration of synapses in vitro within twelve hours after their destruction by KA. This is independent of neurotrophin-3, which also promotes synapse regeneration. Moreover, of the two independent signaling effectors activated by cAMP - the cAMP Exchange Protein Activated by cAMP and the cAMP-dependent protein kinase - it is the latter that mediates synapse regeneration. Finally, we showed that systemic delivery of rolipram promotes synapse regeneration in vivo following NICS. Discussion: In vitro experiments show that cAMP signaling promotes synapse regeneration after excitotoxic destruction of cochlear synapses and does so via PKA signaling. The cAMP phosphodiesterase inhibitor rolipram promotes synapse regeneration in vivo in noise-exposed mice. Systemic administration of rolipram or similar compounds appears to provide a minimally invasive therapeutic approach to reversing synaptopathy post-noise. [ABSTRACT FROM AUTHOR]

Pure-tone audiograms often poorly predict elderly humans' ability to communicate in everyday complex acoustic scenes. Binaural processing is crucial for discriminating sound sources in such complex acoustic scenes. The compromised perception of communication signals presented above hearing threshold has been linked to both peripheral and central age-related changes in the auditory system. Investigating young and old Mongolian gerbils of both sexes, an established model for human hearing, we demonstrate age-related supra-threshold deficits in binaural hearing using behavioral, electrophysiological, anatomical, and imaging methods. Binaural processing ability was measured as the binaural masking level difference (BMLD), an established measure in human psychophysics. We tested gerbils behaviorally with "virtual headphones," recorded single-unit responses in the auditory midbrain and evaluated gross midbrain and cortical responses using positron emission tomography (PET) imaging. Furthermore, we obtained additional measures of auditory function based on auditory brainstem responses, auditory-nerve synapse counts, and evidence for central inhibitory processing revealed by PET. BMLD deteriorates already in middle-aged animals having normal audiometric thresholds and is even worse in old animals with hearing loss. The magnitude of auditory brainstem response measures related to auditory-nerve function and binaural processing in the auditory brainstem also deteriorate. Furthermore, central GABAergic inhibition is affected by age. Because the number of synapses in the apical turn of the inner ear was not reduced in middle-aged animals, we conclude that peripheral synaptopathy contributes little to binaural processing deficits. Exploratory analyses suggest increased hearing thresholds, altered binaural processing in the brainstem and changed central GABAergic inhibition as potential contributors. [ABSTRACT FROM AUTHOR]

Although sudden sensorineural hearing loss (SSNHL) is a serious condition, there are currently no approved drugs for its treatment. Nevertheless, there is a growing understanding that the cochlear pathologies that underlie SSNHL include apoptotic death of sensory outer hair cells (OHCs) as well as loss of ribbon synapses connecting sensory inner hair cells (IHCs) and neurites of the auditory nerve, designated synaptopathy. Noise-induced hearing loss (NIHL) is a common subtype of SSNHL and is widely used to model hearing loss preclinically. Here, we demonstrate that a single interventive application of a small pyridoindole molecule (AC102) into the middle ear restored auditory function almost to prenoise levels in a guinea pig model of NIHL. AC102 prevented noise-triggered loss of OHCs and reduced IHC synaptopathy suggesting a role of AC102 in reconnecting auditory neurons to their sensory target cells. Notably, AC102 exerted its therapeutic properties over a wide frequency range. Such strong improvements in hearing have not previously been demonstrated for other therapeutic agents. In vitro experiments of a neuronal damage model revealed that AC102 protected cells from apoptosis and promoted neurite growth. These effects may be explained by increased production of adenosine triphosphate, indicating improved mitochondrial function, and reduced levels of reactive-oxygen species which prevents the apoptotic processes responsible for OHC death. This action profile of AC102 might be causal for the observed hearing recovery in in vivo models. [ABSTRACT FROM AUTHOR]

Efferent feedback to the mammalian cochlea includes cholinergic medial olivocochlear neurons (MOCs) that release ACh to hyperpolarize and shunt the voltage change that drives electromotility of outer hair cells (OHCs). Via brainstem connectivity, MOCs are activated by sound in a frequency- and intensity-dependent manner, thereby reducing the amplification of cochlear vibration provided by OHC electromotility. Among other roles, this efferent feedback protects the cochlea from acoustic trauma. Lesion studies, as well as a variety of genetic mouse models, support the hypothesis of efferent protection from acoustic trauma. Genetic knockout and gain-of-function knockin of the unique a9a10-containing nicotinic acetylcholine receptor (nAChR) in hair cells show that acoustic protection correlates with the efficacy of cholinergic inhibition of OHCs. This protective effect was replicated by viral transduction of the gain-of-function a9L9'T nAChR into a9-knockout mice. Continued progress with "efferent gene therapy" will require a reliable method for visualizing nAChR expression in cochlear hair cells. To that end, mice expressing HA-tagged a9 or a10 nAChRs were generated using CRISPR technology. This progress will facilitate continued study of the hair cell nAChR as a therapeutic target to prevent hearing loss and potentially to ameliorate associated pathologies such as hyperacusis. [ABSTRACT FROM AUTHOR]

Background: Syntaxin 1A is a member of a membrane-integrated nervous system-specific protein superfamily involved in the neuromediator release from synaptic vesicles and one of the proteins included in axonal integrity. Studies that discussed the role of Syntaxin 1A in multiple sclerosis are few and limited. Gene studying sometimes shows unexpected results in different populations. The aim of this work was to investigate Syntaxin 1A genetic polymorphism (rs1569061) in a sample of Egyptian patients with MS and the relation between Syntaxin 1A gene polymorphism and disease course and disability. A case–control study included 150 subjects; 75 Egyptian MS patients of different clinical courses and 75 age and sex matched healthy controls. Patients were subjected to clinical evaluation, assessment of disability, and cognition. Both patient and control groups were subjected to Syntaxin 1A genotyping. Results: There was no significant difference between different genotypes distribution for Syntaxin 1A (rs 1569061) between MS patients and controls. No significant difference was found between genotypes and allele distribution for Syntaxin 1A (rs 1569061) among cases of MS regarding EDSS or results of BICAMS). There was no statistically significant difference between syntaxin genotypes among cases of MS regarding demographic or clinical characteristics of the disease. Conclusion: Here we show no statistically significant difference between MS patients and control regarding Syntaxin 1A genotypes and different alleles. Syntaxin 1A genotypes have no impact on clinical characteristics of the disease, disability, or cognition. These negative findings open the floor for the study of other MS related genes in Egypt. [ABSTRACT FROM AUTHOR]

In mammalian hearing, type-I afferent auditory nerve fibers comprise the basis of the afferent auditory pathway. They are connected to inner hair cells of the cochlea via specialized ribbon synapses. Auditory nerve fibers of different physiological types differ subtly in their synaptic location and morphology. Low-spontaneous-rate auditory nerve fibers typically connect on the modiolar side of the inner hair cell, while high-spontaneous-rate fibers are typically found on the pillar side. In aging and noise-damaged ears, this fine-tuned balance between auditory nerve fiber populations can be disrupted and the functional consequences are currently unclear. Here, using immunofluorescent labeling of presynaptic ribbons and postsynaptic glutamate receptor patches, we investigated changes in synaptic morphology at three different tonotopic locations along the cochlea of aging gerbils compared to those of young adults. Quiet-aged gerbils showed about 20% loss of afferent ribbon synapses. While the loss was random at apical, low-frequency cochlear locations, at the basal, high-frequency location it almost exclusively affected the modiolar-located synapses. The subtle differences in volumes of pre- and postsynaptic elements located on the inner hair cell's modiolar versus pillar side were unaffected by age. This is consistent with known physiology and suggests a predominant, age-related loss in the low-spontaneous-rate auditory nerve population in the cochlear base, but not the apex. [ABSTRACT FROM AUTHOR]

In multiple sclerosis, only immunomodulatory and immunosuppressive drugs are recognized as disease-modifying therapies. However, in recent years, several data from pre-clinical and clinical studies suggested a possible role of physical exercise as disease-modifying therapy in multiple sclerosis. Current evidence is sparse and often conflicting, and the mechanisms underlying the neuroprotective and antinflammatory role of exercise in multiple sclerosis have not been fully elucidated. Data, mainly derived from pre-clinical studies, suggest that exercise could enhance long-term potentiation and thus neuroplasticity, could reduce neuroinflammation and synaptopathy, and dampen astrogliosis and microgliosis. In humans, most trials focused on direct clinical and MRI outcomes, as investigating synaptic, neuroinflammatory, and pathological changes is not straightforward compared to animal models. The present review analyzed current evidence and limitations in research concerning the potential disease-modifying therapy effects of exercise in multiple sclerosis in animal models and human studies.

Autism spectrum disorders represent a diverse etiological spectrum that converge on a syndrome characterized by discrepant deficits in developmental domains often highlighted by concerns in socialization, sensory integration, and autonomic functioning. Importantly, the incidence and prevalence of autism spectrum disorders have seen sharp increases since the syndrome was first described in the 1940s. The wide etiological spectrum and rising number of individuals being diagnosed with the condition lend urgency to capturing a more nuanced understanding of the pathogenic mechanisms underlying the autism spectrum disorders. The current review seeks to understand how the disruption of AMPA receptor (AMPAr)-mediated neurotransmission in the cerebrocerebellar circuit, particularly in genetic autism related to SHANK3 or SYNGAP1 protein dysfunction function and autism associated with in utero exposure to the anti-seizure medications valproic acid and topiramate, may contribute to the disease presentation. Initially, a discussion contextualizing AMPAr signaling in the cerebro-cerebellar circuitry and microstructural circuit considerations is offered. Subsequently, a detailed review of the literature implicating mutations or deletions of SHANK3 and SYNGAP1 in disrupted AMPAr signaling reveals how bidirectional pathogenic modulation of this key circuit may contribute to autism. Finally, how pharmacological exposure may interact with this pathway, via increased risk of autism diagnosis with valproic acid and topiramate exposure and potential treatment of autism using AMPAr modulator perampanel, is discussed. Through the lens of the review, we will offer speculation on how neuromodulation may be used as a rational adjunct to therapy. Together, the present review seeks to synthesize the disparate considerations of circuit understanding, genetic etiology, and pharmacological modulation to understand the mechanistic interaction of this important and complex disorder. [ABSTRACT FROM AUTHOR]

The disruption of the synaptic connection between the sensory inner hair cells (IHCs) and the auditory nerve fiber terminals of the type I spiral ganglion neurons (SGN) has been observed early in several auditory pathologies (e.g., noise-induced or ototoxic drug-induced or age-related hearing loss). It has been suggested that glutamate excitotoxicity may be an inciting element in the degenerative cascade observed in these pathological cochlear conditions. Moreover, oxidative damage induced by free hydroxyl radicals and nitric oxide may dramatically enhance cochlear damage induced by glutamate excitotoxicity. To investigate the underlying molecular mechanisms involved in cochlear excitotoxicity, we examined the molecular basis responsible for kainic acid (KA, a full agonist of AMPA/KA-preferring glutamate receptors)-induced IHC synapse loss and degeneration of the terminals of the type I spiral ganglion afferent neurons using a cochlear explant culture from P3 mouse pups. Our results demonstrated that disruption of the synaptic connection between IHCs and SGNs induced increased levels of oxidative stress, as well as altered both mitochondrial function and neurotrophin signaling pathways. Additionally, the application of exogenous antioxidants and neurotrophins (NT3, BDNF, and small molecule TrkB agonists) clearly increases synaptogenesis. These results suggest that understanding the molecular pathways involved in cochlear excitotoxicity is of crucial importance for the future clinical trials of drug interventions for auditory synaptopathies. [ABSTRACT FROM AUTHOR]

Introduction: Exposure to occupational or recreational loud noise activates multiple biological regulatory circuits and damages the cochlea, causing permanent changes in hearing sensitivity. Currently, no effective clinical therapy is available for the treatment or mitigation of noise-induced hearing loss (NIHL). Here, we describe an application of localized and non-invasive therapeutic hypothermia and targeted temperature management of the inner ear to prevent NIHL. Methods: We developed a custom-designed cooling neck collar to reduce the temperature of the inner ear by 3-4°C post-injury to deliver mild therapeutic hypothermia. Results: This localized and non-invasive therapeutic hypothermia successfully mitigated NIHL in rats. Our results show that mild hypothermia can be applied quickly and safely to the inner ear following noise exposure. We show that localized hypothermia after NIHL preserves residual hearing and rescues noiseinduced synaptopathy over a period of months. Discussion: This study establishes a minimally-invasive therapeutic paradigm with a high potential for rapid translation to the clinic for long-term preservation of hearing health. [ABSTRACT FROM AUTHOR]

The central nervous system (CNS) is finely protected by the blood–brain barrier (BBB). Immune soluble factors such as cytokines (CKs) are normally produced in the CNS, contributing to physiological immunosurveillance and homeostatic synaptic scaling. CKs are peptide, pleiotropic molecules involved in a broad range of cellular functions, with a pivotal role in resolving the inflammation and promoting tissue healing. However, pro-inflammatory CKs can exert a detrimental effect in pathological conditions, spreading the damage. In the inflamed CNS, CKs recruit immune cells, stimulate the local production of other inflammatory mediators, and promote synaptic dysfunction. Our understanding of neuroinflammation in humans owes much to the study of multiple sclerosis (MS), the most common autoimmune and demyelinating disease, in which autoreactive T cells migrate from the periphery to the CNS after the encounter with a still unknown antigen. CNS-infiltrating T cells produce pro-inflammatory CKs that aggravate local demyelination and neurodegeneration. This review aims to recapitulate the state of the art about CKs role in the healthy and inflamed CNS, with focus on recent advances bridging the study of adaptive immune system and neurophysiology. [ABSTRACT FROM AUTHOR]

This study aimed to assess the validity of a high-frequency audiometry tool based on Bayesian learning to provide a reliable, repeatable, automatic, and fast test to clinics. The study involved 85 people (138 ears) who had their high-frequency thresholds measured with three tests: standard audiometry (SA), alternative forced choice (AFC)-based algorithm, and Bayesian active (BA) learning-based algorithm. The results showed median differences within ±5 dB up to 10 kHz when comparing the BA with the other two tests, and median differences within ±10 dB at higher frequencies. The variability increased from lower to higher frequencies. The BA showed lower thresholds compared to the SA at the majority of the frequencies. The results of the different tests were consistent across groups (age, hearing loss, and tinnitus). The data for the BA showed high test–retest reliability (>90%). The time required for the BA was shorter than for the AFC (4 min vs. 13 min). The data suggest that the BA test for high-frequency audiometry could be a good candidate for clinical screening. It would add reliable and significant information without adding too much time to the visit. [ABSTRACT FROM AUTHOR]

Efferent feedback to the mammalian cochlea includes cholinergic medial olivocochlear neurons (MOCs) that release ACh to hyperpolarize and shunt the voltage change that drives electromotility of outer hair cells (OHCs). Via brainstem connectivity, MOCs are activated by sound in a frequency- and intensity-dependent manner, thereby reducing the amplification of cochlear vibration provided by OHC electromotility. Among other roles, this efferent feedback protects the cochlea from acoustic trauma. Lesion studies, as well as a variety of genetic mouse models, support the hypothesis of efferent protection from acoustic trauma. Genetic knockout and gain-of-function knockin of the unique α9α10-containing nicotinic acetylcholine receptor (nAChR) in hair cells show that acoustic protection correlates with the efficacy of cholinergic inhibition of OHCs. This protective effect was replicated by viral transduction of the gain-of-function α9L9’T nAChR into α9-knockout mice. Continued progress with “efferent gene therapy” will require a reliable method for visualizing nAChR expression in cochlear hair cells. To that end, mice expressing HA-tagged α9 or α10 nAChRs were generated using CRISPR technology. This progress will facilitate continued study of the hair cell nAChR as a therapeutic target to prevent hearing loss and potentially to ameliorate associated pathologies such as hyperacusis.

IntroductionExposure to occupational or recreational loud noise activates multiple biological regulatory circuits and damages the cochlea, causing permanent changes in hearing sensitivity. Currently, no effective clinical therapy is available for the treatment or mitigation of noise-induced hearing loss (NIHL). Here, we describe an application of localized and non-invasive therapeutic hypothermia and targeted temperature management of the inner ear to prevent NIHL.MethodsWe developed a custom-designed cooling neck collar to reduce the temperature of the inner ear by 3–4°C post-injury to deliver mild therapeutic hypothermia.ResultsThis localized and non-invasive therapeutic hypothermia successfully mitigated NIHL in rats. Our results show that mild hypothermia can be applied quickly and safely to the inner ear following noise exposure. We show that localized hypothermia after NIHL preserves residual hearing and rescues noise-induced synaptopathy over a period of months.DiscussionThis study establishes a minimally-invasive therapeutic paradigm with a high potential for rapid translation to the clinic for long-term preservation of hearing health.

MiR-142-3p has recently emerged as key factor in tailoring personalized treatments for multiple sclerosis (MS), a chronic autoimmune demyelinating disease of the central nervous system (CNS) with heterogeneous pathophysiology and an unpredictable course. With its involvement in a detrimental regulatory axis with interleukin-1beta (IL1β), miR-142-3p orchestrates excitotoxic synaptic alterations that significantly impact both MS progression and therapeutic outcomes. In this study, we investigated for the first time the influence of individual genetic variability on the miR-142-3p excitotoxic effect in MS. We specifically focused on the single-nucleotide polymorphism Val66Met (rs6265) of the brain-derived neurotrophic factor (BDNF) gene, known for its crucial role in CNS functioning. We assessed the levels of miR-142-3p and IL1β in cerebrospinal fluid (CSF) obtained from a cohort of 114 patients with MS upon diagnosis. By stratifying patients according to their genetic background, statistical correlations with clinical parameters were performed. Notably, in Met-carrier patients, we observed a decoupling of miR-142-3p levels from IL1β levels in the CSF, as well as from of disease severity (Expanded Disability Status Score, EDSS; Multiple Sclerosis Severity Score, MSSS; Age-Related Multiple Sclerosis Severity Score, ARMSS) and progression (Progression Index, PI). Our discovery of the interference between BDNF Val66Met polymorphism and the synaptotoxic IL1β-miR-142-3p axis, therefore hampering miR-142-3p action on MS course, provides valuable insights for further development of personalized medicine in the field.

In mammalian hearing, type-I afferent auditory nerve fibers comprise the basis of the afferent auditory pathway. They are connected to inner hair cells of the cochlea via specialized ribbon synapses. Auditory nerve fibers of different physiological types differ subtly in their synaptic location and morphology. Low-spontaneous-rate auditory nerve fibers typically connect on the modiolar side of the inner hair cell, while high-spontaneous-rate fibers are typically found on the pillar side. In aging and noise-damaged ears, this fine-tuned balance between auditory nerve fiber populations can be disrupted and the functional consequences are currently unclear. Here, using immunofluorescent labeling of presynaptic ribbons and postsynaptic glutamate receptor patches, we investigated changes in synaptic morphology at three different tonotopic locations along the cochlea of aging gerbils compared to those of young adults. Quiet-aged gerbils showed about 20% loss of afferent ribbon synapses. While the loss was random at apical, low-frequency cochlear locations, at the basal, high-frequency location it almost exclusively affected the modiolar-located synapses. The subtle differences in volumes of pre- and postsynaptic elements located on the inner hair cell’s modiolar versus pillar side were unaffected by age. This is consistent with known physiology and suggests a predominant, age-related loss in the low-spontaneous-rate auditory nerve population in the cochlear base, but not the apex.

The disruption of the synaptic connection between the sensory inner hair cells (IHCs) and the auditory nerve fiber terminals of the type I spiral ganglion neurons (SGN) has been observed early in several auditory pathologies (e.g., noise-induced or ototoxic drug-induced or age-related hearing loss). It has been suggested that glutamate excitotoxicity may be an inciting element in the degenerative cascade observed in these pathological cochlear conditions. Moreover, oxidative damage induced by free hydroxyl radicals and nitric oxide may dramatically enhance cochlear damage induced by glutamate excitotoxicity. To investigate the underlying molecular mechanisms involved in cochlear excitotoxicity, we examined the molecular basis responsible for kainic acid (KA, a full agonist of AMPA/KA-preferring glutamate receptors)-induced IHC synapse loss and degeneration of the terminals of the type I spiral ganglion afferent neurons using a cochlear explant culture from P3 mouse pups. Our results demonstrated that disruption of the synaptic connection between IHCs and SGNs induced increased levels of oxidative stress, as well as altered both mitochondrial function and neurotrophin signaling pathways. Additionally, the application of exogenous antioxidants and neurotrophins (NT3, BDNF, and small molecule TrkB agonists) clearly increases synaptogenesis. These results suggest that understanding the molecular pathways involved in cochlear excitotoxicity is of crucial importance for the future clinical trials of drug interventions for auditory synaptopathies.

Introduction: In the aging brain, cognitive abilities emerge from the coordination of complex pathways arising from a balance between protective lifestyle and environmental factors and accumulation of neuropathologies., Methods: As part of the Rush Memory and Aging Project (n = 440), we measured accelerometer-based actigraphy, cognitive performance, and after brain autopsy, selected reaction monitoring mass spectrometry. Multilevel network analysis was used to examine the relationships among the molecular machinery of vesicular neurotransmission, Alzheimer's disease (AD) neuropathology, cognition, and late-life physical activity., Results: Synaptic peptides involved in neuronal secretory function were the most influential contributors to the multilayer network, reflecting the complex interdependencies among AD pathology, synaptic processes, and late-life cognition. Older adults with lower physical activity evidenced stronger adverse relationships among phosphorylated tau peptides, markers of synaptic integrity, and tangle pathology., Discussion: Network-based approaches simultaneously model interdependent biological processes and advance understanding of the role of physical activity in age-associated cognitive impairment., Highlights: Network-based approaches simultaneously model interdependent biological processes. Secretory synaptic peptides were influential contributors to the multilayer network. Older adults with lower physical activity had adverse relationships among pathology. There was interdependence among phosphorylated tau, synaptic integrity, and tangles. Network methods elucidate the role of physical activity in cognitive impairment., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Syntaxin-binding protein 1 related disorder (STXBP1-RD) is a rare neurologic disorder associated with global neurodevelopmental delay, intellectual disability, early-onset epilepsy, motor abnormalities, and autism. The underlying pathophysiology stems from a de novo mutation in the STXBP1 gene, which codes for the STXBP1 protein. The STXBP1 protein is involved in synaptic vesicle fusion and neurotransmitter release. Pathogenic variants in the STXBP1 gene generally result in haploinsufficiency, an impairment in neurotransmitter release, and subsequent dysfunction in neuronal communication. The STXBP1 Foundation was founded in 2017 to support families of children with STXBP1-RD and accelerate the development of effective therapies and, ultimately, a cure for the disorder. The Foundation initially supported research aimed at better understanding the complex phenotypic presentation of the disease as well as the development of animal and cellular models usable by the research community to more fully characterize STXBP1 function and disease pathogenicity. In 2023, the Foundation embarked on its STXBP1 Fast Forward Strategic Plan, which includes a prospective natural history study and substantive biomarker work to drive forward the development of new precision therapies for STXBP1-RD., Competing Interests: The authors declare that there is no conflict of interest., (© The Author(s), 2024.)

• Recovery from noise-induced synaptopathy is more robust in C57Bl/6J than CBA/CaJ mice. • Most recovery is from reversible reduction in immunostaining for post-synaptic GluA2. • Immunostaining for ribbon markers is transiently increased by synaptopathic noise. • Synaptopathic noise causes transient neurite extension in C57Bl/6J not CBA/CaJ. • Interstrain differences may arise from noise-induced upregulation of neurotrophins. Acute noise-induced loss of synapses between inner hair cells (IHCs) and auditory nerve fibers (ANFs) has been documented in several strains of mice, but the extent of post-exposure recovery reportedly varies dramatically. If such inter-strain heterogeneity is real, it could be exploited to probe molecular pathways mediating neural remodeling in the adult cochlea. Here, we compared synaptopathy repair in CBA/CaJ vs. C57BL/6J, which are at opposite ends of the reported recovery spectrum. We evaluated C57BL/6J mice 0 h, 24 h, 2 wks or 8 wks after exposure for 2 h to octave-band noise (8–16 kHz) at either 90, 94 or 98 dB SPL, to compare with analogous post-exposure results in CBA/CaJ at 98 or 101 dB. We counted pre- and post-synaptic puncta in immunostained cochleas, using machine learning to classify paired (GluA2 and CtBP2) vs. orphan (CtBP2 only) puncta, and batch-processing to quantify immunostaining intensity. At 98 dB, both strains show ongoing loss of ribbons and synapses between 0 and 24 h, followed by partial recovery, however the extent and degree of these changes were greater in C57BL/6J. Much of the synaptic recovery is due to transient reduction in GluA2 intensity in synaptopathic regions. In contrast, CtBP2 intensity showed only transient increases (at 2 wks). Neurofilament staining revealed transient extension of ANF terminals in C57BL/6J, but not in CBA/CaJ, peaking at 24 h and reverting by 2 wks. Thus, although interstrain differences in synapse recovery are dominated by reversible changes in GluA2 receptor levels, the neurite extension seen in C57BL/6J suggests a qualitative difference in regenerative capacity. [ABSTRACT FROM AUTHOR]

Autism spectrum disorder (ASD) is a developmental disorder with a rising prevalence and unknown etiology presenting with deficits in cognition and abnormal behavior. We hypothesized that the investigation of the synaptic component of prefrontal cortex may provide proteomic signatures that may identify the biological underpinnings of cognitive deficits in childhood ASD. Subcellular fractions of synaptosomes from prefrontal cortices of age-, brain area-, and postmortem-interval-matched samples from children and adults with idiopathic ASD vs. controls were subjected to HPLC-tandem mass spectrometry. Analysis of data revealed the enrichment of ASD risk genes that participate in slow maturation of the postsynaptic density (PSD) structure and function during early brain development. Proteomic analysis revealed down regulation of PSD-related proteins including AMPA and NMDA receptors, GRM3, DLG4, olfactomedins, Shank1-3, Homer1, CaMK2α, NRXN1, NLGN2, Drebrin1, ARHGAP32, and Dock9 in children with autism (FDR-adjusted P < 0.05). In contrast, PSD-related alterations were less severe or unchanged in adult individuals with ASD. Network analyses revealed glutamate receptor abnormalities. Overall, the proteomic data support the concept that idiopathic autism is a synaptopathy involving PSD-related ASD risk genes. Interruption in evolutionarily conserved slow maturation of the PSD complex in prefrontal cortex may lead to the development of ASD in a susceptible individual., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

• Different subtypes of AN synapses converge onto individual CN neurons. • Non-type Ia synapses preferentially degenerate during aging. • Bushy neurons also differentially degenerate during ARHL with compromised output. • Reduced input to d -stellate neurons contributes to weakened inhibition in the CN. Sound information is transduced from mechanical vibration to electrical signals in the cochlea, conveyed to and further processed in the brain to form auditory perception. During the process, spiral ganglion neurons (SGNs) are the key cells that connect the peripheral and central auditory systems by receiving information from hair cells in the cochlea and transmitting it to neurons of the cochlear nucleus (CN). Decades of research in the cochlea greatly improved our understanding of SGN function under normal and pathological conditions, especially about the roles of different subtypes of SGNs and their peripheral synapses. However, it remains less clear how SGN central terminals or auditory nerve (AN) synapses connect to CN neurons, and ultimately how peripheral pathology links to structural alterations and functional deficits in the central auditory nervous system. This review discusses recent progress about the morphological and physiological properties of different subtypes of AN synapses and associated postsynaptic CN neurons, their changes during aging, and the potential mechanisms underlying age-related hearing loss. [ABSTRACT FROM AUTHOR]

Paroxysmal movement disorders include two groups of intermittent neurologic disorders: paroxysmal dyskinesia, in which episodes of involuntary hyperkinetic movements (mainly chorea and/or dystonia) occur with preserved consciousness, and episodic ataxias, which are characterized by discrete attacks of cerebellar dysfunction, sometimes associated with progressive ataxia. Since episodic ataxias are individually discussed in Chapter 8 of this volume, we herein provide a deep overview of phenotypic, genetic, pathophysiologic, diagnostic, and treatment aspects of paroxysmal dyskinesia, following the trigger-based nomenclature which distinguishes paroxysmal kinesigenic dyskinesia, paroxysmal nonkinesigenic dyskinesia, and paroxysmal exercise-induced dyskinesia. Emerging paroxysmal dyskinesia not fulfilling the criteria for the above-mentioned subtypes will also be discussed. Phenotypic and genotypic overlap among paroxysmal movement disorders, epilepsy, and migraine have progressively emerged, thus shedding light on a shared pathophysiologic framework. Advances in our understanding of the pathomechanisms underlying paroxysmal movement disorders, which involve dysfunctions of ion channels, proteins associated with the vesical synaptic cycle machinery, and proteins involved in neuronal energy metabolism, point toward a discrete number of converging pathophysiologic pathways and may lay foundations for developing target-specific therapies., (Copyright © 2024 Elsevier B.V. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Neuronal synapse dysfunction is a key characteristic of several neurodegenerative disorders, such as Alzheimer's disease, spinocerebellar ataxias, and Huntington's disease. Modeling these disorders to study synaptic dysfunction requires a robust and reproducible method for assaying the subtle changes associated with synaptopathies in terms of structure and function of the synapses. Drosophila melanogaster neuromuscular junctions (NMJs) serve as good models to study such alterations. Further, modifications in the microenvironment of synapses can sometimes reflect in the behavior of the animal, which can also be assayed in a high-throughput manner. The methods outlined in this chapter highlight assays to study the behavioral changes associated with synaptic dysfunction in a spinocerebellar ataxia type 3 (SCA3) model. Further, molecular assessment of alterations in NMJ structure and function is also summarized, followed by effects of autophagy pathway upregulation in providing neuroprotection. These methods can be further extended and modified to study the therapeutic effects of drugs or small molecules in providing neuroprotection for any synaptopathy models., (© 2024. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)