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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.

Over the past 3 decades, the prevalence of autism spectrum disorder (ASD) has increased globally from 20 to 28 million cases making ASD the fastest-growing developmental disability in the world. Neurexins are a family of presynaptic cell adhesion molecules that have been increasingly implicated in ASD, as evidenced by genetic mutations in the clinical population. Neurexins function as context-dependent specifiers of synapse properties and critical modulators in maintaining the balance between excitatory and inhibitory transmission (E/I balance). Disrupted E/I balance has long been established as a hallmark of ASD making neurexins excellent starting points for understanding the etiology of ASD. Herein we review neurexin mutations that have been discovered in ASD patients. Further, we discuss distinct synaptic mechanisms underlying the aberrant neurotransmission and behavioral deficits observed in different neurexin mouse models, with focus on recent discoveries from the previously overlooked neurexin-2 gene (Nrxn2 in mice and NRXN2 in humans). Hence, the aim of this review is to provide a summary of new synaptic insights into the molecular underpinnings of ASD.

The postsynaptic density (PSD) is a massive protein complex, critical for synaptic strength and plasticity in excitatory neurons. Here, the scaffolding protein PSD‐95 plays a crucial role as it organizes key PSD components essential for synaptic signaling, development, and survival. Re-cently, variants in DLG4 encoding PSD‐95 were found to cause a neurodevelopmental disorder with a variety of clinical features including intellectual disability, developmental delay, and epilepsy. Genetic variants in several of the interaction partners of PSD‐95 are associated with similar pheno-types, suggesting that deficient PSD‐95 may affect the interaction partners, explaining the overlap-ping symptoms. Here, we review the transmembrane interaction partners of PSD‐95 and their association with neurodevelopmental disorders. We assess how the structural changes induced by DLG4 missense variants may disrupt or alter such protein–protein interactions, and we argue that the pathological effect of DLG4 variants is, at least partly, exerted indirectly through interaction partners of PSD‐95. This review presents a direction for functional studies to elucidate the pathogenic mechanism of deficient PSD‐95, providing clues for therapeutic strategies.

The postsynaptic density (PSD) is a massive protein complex, critical for synaptic strength and plasticity in excitatory neurons. Here, the scaffolding protein PSD‐95 plays a crucial role as it organizes key PSD components essential for synaptic signaling, development, and survival. Re-cently, variants in DLG4 encoding PSD‐95 were found to cause a neurodevelopmental disorder with a variety of clinical features including intellectual disability, developmental delay, and epilepsy. Genetic variants in several of the interaction partners of PSD‐95 are associated with similar pheno-types, suggesting that deficient PSD‐95 may affect the interaction partners, explaining the overlap-ping symptoms. Here, we review the transmembrane interaction partners of PSD‐95 and their association with neurodevelopmental disorders. We assess how the structural changes induced by DLG4 missense variants may disrupt or alter such protein–protein interactions, and we argue that the pathological effect of DLG4 variants is, at least partly, exerted indirectly through interaction partners of PSD‐95. This review presents a direction for functional studies to elucidate the pathogenic mechanism of deficient PSD‐95, providing clues for therapeutic strategies.

The current Research Topic tries to highlight some of the most relevant recent advances regarding sensorineural hearing loss (SNHL). The etiology of SNHL primarily involves hereditary factors, ototoxic drugs, noise, and aging, all of which trigger two main mechanisms: damage to the organ of Corti, namely mechanosensory hair cells (HCs) and non-sensory supporting cells (SCs), and/or loss of spiral ganglion neurons (SGNs) that subsequently form the auditory nerve and hence connect the inner ear to the brain.

[Introduction]: Excessive exposure to noise is a common occurrence that contributes to approximately 50% of the non-genetic hearing loss cases. Researchers need to develop standardized preclinical models and identify molecular targets to effectively develop prevention and curative therapies., [Areas covered]: In this review, the authors discuss the many facets of human noise-induced pathology, and the primary experimental models for studying the basic mechanisms of noise-induced damage, making connections and inferences among basic science studies, preclinical proofs of concept and clinical trials., [Expert opinion]: Whilst experimental research in animal models has helped to unravel the mechanisms of noise-induced hearing loss, there are often methodological variations and conflicting results between animal and human studies which make it difficult to integrate data and translate basic outcomes to clinical practice. Standardization of exposure paradigms and application of -omic technologies will contribute to improving the effectiveness of transferring newly gained knowledge to clinical practice.

Tauopathies are a class of neurodegenerative diseases associated with the microtubuleassociated protein tau, with Alzheimer’s disease (AD) being the most prevalent related disorder. Neurofibrillary tangles (NFTs) are one of the neuropathological hallmarks present in the brains of AD patients. Because NFTs are aberrant intracellular inclusions formed by hyperphosphorylated tau, it was initially proposed that phosphorylated and/or aggregated intracellular tau protein was causative of neuronal death. However, recent studies suggest a toxic role for non-phosphorylated and non-aggregated tau when it is located in the brain extracellular space. In this work, we will discuss the neurotoxic role of extracellular tau as well its involvement in the spreading of tau pathologies., Unión Europea. Horizonte 2020, Ministerio de Ciencia y Educación, Universidad Complutense de Madrid/Banco de Santander, Sección Deptal. de Bioquímica y Biología Molecular (Veterinaria), Fac. de Veterinaria, TRUE, pub

Movement is a prerequisite for normal fetal development and growth. Intrauterine movement restrictions cause a broad spectrum of disorders in which the unifying feature is a reduction or lack of fetal movement, giving rise to the term fetal akinesia deformations sequence (FADS [OMIM 208150]). FADS corresponds to a clinically and genetically heterogeneous constellation of properties and is characterized by multiple joint contractures, facial abnormalities, and lung hypoplasia as a result of the decreased in utero movement of the fetuses. Affected babies are often prematurely and stillborn, and those born alive typically die within minutes or hours after birth. The genetic causes for this fatal disorder are ill-defined as a genetic diagnosis is rarely executed, but mutations in three genes, namely RAPSN, DOK7, and MUSK, as well as in the subunits of the muscular nicotinic acetylcholine receptor (AChR) have been described. These mutations are thought to affect neuromuscular junctions, although this has not been proven experimentally.The nucleoporin NUP88 is a constituent of the nuclear pore complex (NPC), the gate for all trafficking between the nucleus and the cytoplasm. NUP88 resides on both the cytoplasmic and the nuclear side of NPCs, and it is found in two distinct subcomplexes. It associates with NUP214 and NUP62 on the cytoplasmic face, while on the nuclear side NUP88 binds NUP98 and the intermediate filament protein lamin A. The NUP88-NUP214-NUP62 complex plays an essential role in the nuclear export of a subset of proteins and pre-ribosomes, which is mediated by the nuclear export receptor CRM1. NUP88 in particular somewhat participates in the nuclear export of NF-κB proteins in a CRM1-dependent manner. Moreover, NUP88 is frequently overexpressed in a variety of human cancers, and its role in cancer appears linked to the deregulation of the anaphase-promoting complex. Here, we report the first Mendelian disorders caused by mutations in NUP88 and with that the, Doctorat en Sciences, info:eu-repo/semantics/nonPublished

Reactive astrogliosis, a complex process characterized by cell hypertrophy and upregulation ofcomponents of intermediate filaments, is a common feature in brains of Alzheimer’s patients. Reac-tive astrocytes are found in close association with neuritic plaques; however, the precise role ofthese glial cells in disease pathogenesis is unknown. In this study, using immunohistochemical tech-niques and light and electron microscopy, we report that plaque-associated reactive astrocytesenwrap, engulf and may digest presynaptic dystrophies in the hippocampus of amyloid precursorprotein/presenilin-1 (APP/PS1) mice. Microglia, the brain phagocytic population, was apparentlynot engaged in this clearance. Phagocytic reactive astrocytes were present in 35% and 67% ofamyloid plaques at 6 and 12 months of age, respectively. The proportion of engulfed dystrophicneurites was low, around 7% of total dystrophies around plaques at both ages. This fact, alongwith the accumulation of dystrophic neurites during disease course, suggests that the efficiency ofthe astrocyte phagocytic process might be limited or impaired. Reactive astrocytes surroundingand engulfing dystrophic neurites were also detected in the hippocampus of Alzheimer’spatientsby confocal and ultrastructural analysis. We posit that the phagocytic activity of reactive astrocytesmight contribute to clear dysfunctional synapses or synaptic debris, thereby restoring impairedneural circuits and reducing the inflammatory impact of damaged neuronal parts and/or limitingthe amyloid pathology. Therefore, potentiation of the phagocytic properties of reactive astrocytesmay represent a potential therapy in Alzheimer s disease.

Reactive astrogliosis, a complex process characterized by cell hypertrophy and upregulation ofcomponents of intermediate filaments, is a common feature in brains of Alzheimer’s patients. Reac-tive astrocytes are found in close association with neuritic plaques; however, the precise role ofthese glial cells in disease pathogenesis is unknown. In this study, using immunohistochemical tech-niques and light and electron microscopy, we report that plaque-associated reactive astrocytesenwrap, engulf and may digest presynaptic dystrophies in the hippocampus of amyloid precursorprotein/presenilin-1 (APP/PS1) mice. Microglia, the brain phagocytic population, was apparentlynot engaged in this clearance. Phagocytic reactive astrocytes were present in 35% and 67% ofamyloid plaques at 6 and 12 months of age, respectively. The proportion of engulfed dystrophicneurites was low, around 7% of total dystrophies around plaques at both ages. This fact, alongwith the accumulation of dystrophic neurites during disease course, suggests that the efficiency ofthe astrocyte phagocytic process might be limited or impaired. Reactive astrocytes surroundingand engulfing dystrophic neurites were also detected in the hippocampus of Alzheimer’spatientsby confocal and ultrastructural analysis. We posit that the phagocytic activity of reactive astrocytesmight contribute to clear dysfunctional synapses or synaptic debris, thereby restoring impairedneural circuits and reducing the inflammatory impact of damaged neuronal parts and/or limitingthe amyloid pathology. Therefore, potentiation of the phagocytic properties of reactive astrocytesmay represent a potential therapy in Alzheimer s disease.

Reactive astrogliosis, a complex process characterized by cell hypertrophy and upregulation ofcomponents of intermediate filaments, is a common feature in brains of Alzheimer’s patients. Reac-tive astrocytes are found in close association with neuritic plaques; however, the precise role ofthese glial cells in disease pathogenesis is unknown. In this study, using immunohistochemical tech-niques and light and electron microscopy, we report that plaque-associated reactive astrocytesenwrap, engulf and may digest presynaptic dystrophies in the hippocampus of amyloid precursorprotein/presenilin-1 (APP/PS1) mice. Microglia, the brain phagocytic population, was apparentlynot engaged in this clearance. Phagocytic reactive astrocytes were present in 35% and 67% ofamyloid plaques at 6 and 12 months of age, respectively. The proportion of engulfed dystrophicneurites was low, around 7% of total dystrophies around plaques at both ages. This fact, alongwith the accumulation of dystrophic neurites during disease course, suggests that the efficiency ofthe astrocyte phagocytic process might be limited or impaired. Reactive astrocytes surroundingand engulfing dystrophic neurites were also detected in the hippocampus of Alzheimer’spatientsby confocal and ultrastructural analysis. We posit that the phagocytic activity of reactive astrocytesmight contribute to clear dysfunctional synapses or synaptic debris, thereby restoring impairedneural circuits and reducing the inflammatory impact of damaged neuronal parts and/or limitingthe amyloid pathology. Therefore, potentiation of the phagocytic properties of reactive astrocytesmay represent a potential therapy in Alzheimer s disease.

Reactive astrogliosis, a complex process characterized by cell hypertrophy and upregulation ofcomponents of intermediate filaments, is a common feature in brains of Alzheimer’s patients. Reac-tive astrocytes are found in close association with neuritic plaques; however, the precise role ofthese glial cells in disease pathogenesis is unknown. In this study, using immunohistochemical tech-niques and light and electron microscopy, we report that plaque-associated reactive astrocytesenwrap, engulf and may digest presynaptic dystrophies in the hippocampus of amyloid precursorprotein/presenilin-1 (APP/PS1) mice. Microglia, the brain phagocytic population, was apparentlynot engaged in this clearance. Phagocytic reactive astrocytes were present in 35% and 67% ofamyloid plaques at 6 and 12 months of age, respectively. The proportion of engulfed dystrophicneurites was low, around 7% of total dystrophies around plaques at both ages. This fact, alongwith the accumulation of dystrophic neurites during disease course, suggests that the efficiency ofthe astrocyte phagocytic process might be limited or impaired. Reactive astrocytes surroundingand engulfing dystrophic neurites were also detected in the hippocampus of Alzheimer’spatientsby confocal and ultrastructural analysis. We posit that the phagocytic activity of reactive astrocytesmight contribute to clear dysfunctional synapses or synaptic debris, thereby restoring impairedneural circuits and reducing the inflammatory impact of damaged neuronal parts and/or limitingthe amyloid pathology. Therefore, potentiation of the phagocytic properties of reactive astrocytesmay represent a potential therapy in Alzheimer s disease.

Reactive astrogliosis, a complex process characterized by cell hypertrophy and upregulation ofcomponents of intermediate filaments, is a common feature in brains of Alzheimer’s patients. Reac-tive astrocytes are found in close association with neuritic plaques; however, the precise role ofthese glial cells in disease pathogenesis is unknown. In this study, using immunohistochemical tech-niques and light and electron microscopy, we report that plaque-associated reactive astrocytesenwrap, engulf and may digest presynaptic dystrophies in the hippocampus of amyloid precursorprotein/presenilin-1 (APP/PS1) mice. Microglia, the brain phagocytic population, was apparentlynot engaged in this clearance. Phagocytic reactive astrocytes were present in 35% and 67% ofamyloid plaques at 6 and 12 months of age, respectively. The proportion of engulfed dystrophicneurites was low, around 7% of total dystrophies around plaques at both ages. This fact, alongwith the accumulation of dystrophic neurites during disease course, suggests that the efficiency ofthe astrocyte phagocytic process might be limited or impaired. Reactive astrocytes surroundingand engulfing dystrophic neurites were also detected in the hippocampus of Alzheimer’spatientsby confocal and ultrastructural analysis. We posit that the phagocytic activity of reactive astrocytesmight contribute to clear dysfunctional synapses or synaptic debris, thereby restoring impairedneural circuits and reducing the inflammatory impact of damaged neuronal parts and/or limitingthe amyloid pathology. Therefore, potentiation of the phagocytic properties of reactive astrocytesmay represent a potential therapy in Alzheimer s disease.

Tauopathies are a class of neurodegenerative diseases associated with the microtubule-associated protein tau, with Alzheimer's disease (AD) being the most prevalent related disorder. Neurofibrillary tangles (NFTs) are one of the neuropathological hallmarks present in the brains of AD patients. Because NFTs are aberrant intracellular inclusions formed by hyperphosphorylated tau, it was initially proposed that phosphorylated and/or aggregated intracellular tau protein was causative of neuronal death. However, recent studies suggest a toxic role for non-phosphorylated and non-aggregated tau when it is located in the brain extracellular space. In this work, we will discuss the neurotoxic role of extracellular tau as well its involvement in the spreading of tau pathologies.

PURPOSE. Optic nerve hypoplasia (ONH) is the most common cause of childhood congenital blindness in developed nations, yet the fundamental pathobiology of ONH remains unknown. The objective of this study was to employ a ‘face validated’ murine model to determine the timing of onset and the pathologic characteristics of ONH. METHODS. Based on the robust linkage between X-linked CASK haploinsufficiency and clinically diagnosed ONH, we hypothesized that heterozygous deletion of CASK (CASK(⁺/⁻)) in rodents will produce an optic nerve pathology closely recapitulating ONH. We quantitatively analyzed the entire subcortical visual system in female CASK(⁺/⁻) mice using immunohistochemistry, anterograde axonal tracing, toluidine blue staining, transmission electron microscopy, and serial block-face scanning electron microscopy. RESULTS. CASK haploinsuffiency in mice phenocopies human ONH with complete penetrance, thus satisfying the ‘face validity’. We demonstrate that the optic nerve in CASK(⁺/⁻) mice is not only thin, but is comprised of atrophic retinal axons and displays reactive astrogliosis. Myelination of the optic nerve axons remains unchanged. Moreover, we demonstrate a significant decrease in retinal ganglion cell (RGC) numbers and perturbation in retinothalamic connectivity. Finally, we used this mouse model to define the onset and progression of ONH pathology, demonstrating for the first time that optic nerve defects arise at neonatally in CASK(⁺/⁻) mice. CONCLUSIONS. Optic nerve hypoplasia is a complex neuropathology of the subcortical visual system involving RGC loss, axonopathy, and synaptopathy and originates at a developmental stage in mice that corresponds to the late third trimester development in humans.

Background: Multiple sclerosis (MS) is an inflammatory demyelinating disease classically associated with axonal damage and loss; more recently, however, synaptic changes have been recognized as additional contributing factors. An anatomical area commonly affected in MS is the visual pathway; yet, changes other than those associated with inflammatory demyelination of the optic nerve, i.e., optic neuritis, have not been described in detail. Methods: Adult mice were subjected to a diet containing cuprizone to mimic certain aspects of inflammatory demyelination as seen in MS. Demyelination and inflammation were assessed by real-time polymerase chain reaction and immunohistochemistry. Synaptic changes associated with inflammatory demyelination in the dorsal lateral geniculate nucleus (dLGN) were determined by immunohistochemistry, Western blot analysis, and electrophysiological field potential recordings. Results: In the cuprizone model, demyelination was observed in retinorecipient regions of the subcortical visual system, in particular the dLGN, where it was found accompanied by microglia activation and astrogliosis. In contrast, anterior parts of the pathway, i.e., the optic nerve and tract, appeared largely unaffected. Under the inflammatory demyelinating conditions, as seen in the dLGN of cuprizone-treated mice, there was an overall decrease in excitatory synaptic inputs from retinal ganglion cells. At the same time, the number of synaptic complexes arising from gamma-aminobutyric acid (GABA)-generating inhibitory neurons was found increased, as were the synapses that contain the N-methyl-D-aspartate receptor (NMDAR) subunit GluN2B and converge onto inhibitory neurons. These synaptic changes were functionally found associated with a shift toward an overall increase in network inhibition. Conclusions: Using the cuprizone model of inflammatory demyelination, our data reveal a novel form of synaptic (mal)adaption in the CNS that is characterized by a shift of the excit

Background: Multiple sclerosis (MS) is an inflammatory demyelinating disease classically associated with axonal damage and loss; more recently, however, synaptic changes have been recognized as additional contributing factors. An anatomical area commonly affected in MS is the visual pathway; yet, changes other than those associated with inflammatory demyelination of the optic nerve, i.e., optic neuritis, have not been described in detail. Methods: Adult mice were subjected to a diet containing cuprizone to mimic certain aspects of inflammatory demyelination as seen in MS. Demyelination and inflammation were assessed by real-time polymerase chain reaction and immunohistochemistry. Synaptic changes associated with inflammatory demyelination in the dorsal lateral geniculate nucleus (dLGN) were determined by immunohistochemistry, Western blot analysis, and electrophysiological field potential recordings. Results: In the cuprizone model, demyelination was observed in retinorecipient regions of the subcortical visual system, in particular the dLGN, where it was found accompanied by microglia activation and astrogliosis. In contrast, anterior parts of the pathway, i.e., the optic nerve and tract, appeared largely unaffected. Under the inflammatory demyelinating conditions, as seen in the dLGN of cuprizone-treated mice, there was an overall decrease in excitatory synaptic inputs from retinal ganglion cells. At the same time, the number of synaptic complexes arising from gamma-aminobutyric acid (GABA)-generating inhibitory neurons was found increased, as were the synapses that contain the N-methyl-D-aspartate receptor (NMDAR) subunit GluN2B and converge onto inhibitory neurons. These synaptic changes were functionally found associated with a shift toward an overall increase in network inhibition. Conclusions: Using the cuprizone model of inflammatory demyelination, our data reveal a novel form of synaptic (mal)adaption in the CNS that is characterized by a shift of the excit

PURPOSE. Optic nerve hypoplasia (ONH) is the most common cause of childhood congenital blindness in developed nations, yet the fundamental pathobiology of ONH remains unknown. The objective of this study was to employ a ‘face validated’ murine model to determine the timing of onset and the pathologic characteristics of ONH. METHODS. Based on the robust linkage between X-linked CASK haploinsufficiency and clinically diagnosed ONH, we hypothesized that heterozygous deletion of CASK (CASK(⁺/⁻)) in rodents will produce an optic nerve pathology closely recapitulating ONH. We quantitatively analyzed the entire subcortical visual system in female CASK(⁺/⁻) mice using immunohistochemistry, anterograde axonal tracing, toluidine blue staining, transmission electron microscopy, and serial block-face scanning electron microscopy. RESULTS. CASK haploinsuffiency in mice phenocopies human ONH with complete penetrance, thus satisfying the ‘face validity’. We demonstrate that the optic nerve in CASK(⁺/⁻) mice is not only thin, but is comprised of atrophic retinal axons and displays reactive astrogliosis. Myelination of the optic nerve axons remains unchanged. Moreover, we demonstrate a significant decrease in retinal ganglion cell (RGC) numbers and perturbation in retinothalamic connectivity. Finally, we used this mouse model to define the onset and progression of ONH pathology, demonstrating for the first time that optic nerve defects arise at neonatally in CASK(⁺/⁻) mice. CONCLUSIONS. Optic nerve hypoplasia is a complex neuropathology of the subcortical visual system involving RGC loss, axonopathy, and synaptopathy and originates at a developmental stage in mice that corresponds to the late third trimester development in humans.

Background: Multiple sclerosis (MS) is an inflammatory demyelinating disease classically associated with axonal damage and loss; more recently, however, synaptic changes have been recognized as additional contributing factors. An anatomical area commonly affected in MS is the visual pathway; yet, changes other than those associated with inflammatory demyelination of the optic nerve, i.e., optic neuritis, have not been described in detail. Methods: Adult mice were subjected to a diet containing cuprizone to mimic certain aspects of inflammatory demyelination as seen in MS. Demyelination and inflammation were assessed by real-time polymerase chain reaction and immunohistochemistry. Synaptic changes associated with inflammatory demyelination in the dorsal lateral geniculate nucleus (dLGN) were determined by immunohistochemistry, Western blot analysis, and electrophysiological field potential recordings. Results: In the cuprizone model, demyelination was observed in retinorecipient regions of the subcortical visual system, in particular the dLGN, where it was found accompanied by microglia activation and astrogliosis. In contrast, anterior parts of the pathway, i.e., the optic nerve and tract, appeared largely unaffected. Under the inflammatory demyelinating conditions, as seen in the dLGN of cuprizone-treated mice, there was an overall decrease in excitatory synaptic inputs from retinal ganglion cells. At the same time, the number of synaptic complexes arising from gamma-aminobutyric acid (GABA)-generating inhibitory neurons was found increased, as were the synapses that contain the N-methyl-D-aspartate receptor (NMDAR) subunit GluN2B and converge onto inhibitory neurons. These synaptic changes were functionally found associated with a shift toward an overall increase in network inhibition. Conclusions: Using the cuprizone model of inflammatory demyelination, our data reveal a novel form of synaptic (mal)adaption in the CNS that is characterized by a shift of the excit

PURPOSE. Optic nerve hypoplasia (ONH) is the most common cause of childhood congenital blindness in developed nations, yet the fundamental pathobiology of ONH remains unknown. The objective of this study was to employ a ‘face validated’ murine model to determine the timing of onset and the pathologic characteristics of ONH. METHODS. Based on the robust linkage between X-linked CASK haploinsufficiency and clinically diagnosed ONH, we hypothesized that heterozygous deletion of CASK (CASK(⁺/⁻)) in rodents will produce an optic nerve pathology closely recapitulating ONH. We quantitatively analyzed the entire subcortical visual system in female CASK(⁺/⁻) mice using immunohistochemistry, anterograde axonal tracing, toluidine blue staining, transmission electron microscopy, and serial block-face scanning electron microscopy. RESULTS. CASK haploinsuffiency in mice phenocopies human ONH with complete penetrance, thus satisfying the ‘face validity’. We demonstrate that the optic nerve in CASK(⁺/⁻) mice is not only thin, but is comprised of atrophic retinal axons and displays reactive astrogliosis. Myelination of the optic nerve axons remains unchanged. Moreover, we demonstrate a significant decrease in retinal ganglion cell (RGC) numbers and perturbation in retinothalamic connectivity. Finally, we used this mouse model to define the onset and progression of ONH pathology, demonstrating for the first time that optic nerve defects arise at neonatally in CASK(⁺/⁻) mice. CONCLUSIONS. Optic nerve hypoplasia is a complex neuropathology of the subcortical visual system involving RGC loss, axonopathy, and synaptopathy and originates at a developmental stage in mice that corresponds to the late third trimester development in humans.

Background: Multiple sclerosis (MS) is an inflammatory demyelinating disease classically associated with axonal damage and loss; more recently, however, synaptic changes have been recognized as additional contributing factors. An anatomical area commonly affected in MS is the visual pathway; yet, changes other than those associated with inflammatory demyelination of the optic nerve, i.e., optic neuritis, have not been described in detail. Methods: Adult mice were subjected to a diet containing cuprizone to mimic certain aspects of inflammatory demyelination as seen in MS. Demyelination and inflammation were assessed by real-time polymerase chain reaction and immunohistochemistry. Synaptic changes associated with inflammatory demyelination in the dorsal lateral geniculate nucleus (dLGN) were determined by immunohistochemistry, Western blot analysis, and electrophysiological field potential recordings. Results: In the cuprizone model, demyelination was observed in retinorecipient regions of the subcortical visual system, in particular the dLGN, where it was found accompanied by microglia activation and astrogliosis. In contrast, anterior parts of the pathway, i.e., the optic nerve and tract, appeared largely unaffected. Under the inflammatory demyelinating conditions, as seen in the dLGN of cuprizone-treated mice, there was an overall decrease in excitatory synaptic inputs from retinal ganglion cells. At the same time, the number of synaptic complexes arising from gamma-aminobutyric acid (GABA)-generating inhibitory neurons was found increased, as were the synapses that contain the N-methyl-D-aspartate receptor (NMDAR) subunit GluN2B and converge onto inhibitory neurons. These synaptic changes were functionally found associated with a shift toward an overall increase in network inhibition. Conclusions: Using the cuprizone model of inflammatory demyelination, our data reveal a novel form of synaptic (mal)adaption in the CNS that is characterized by a shift of the excit

PURPOSE. Optic nerve hypoplasia (ONH) is the most common cause of childhood congenital blindness in developed nations, yet the fundamental pathobiology of ONH remains unknown. The objective of this study was to employ a ‘face validated’ murine model to determine the timing of onset and the pathologic characteristics of ONH. METHODS. Based on the robust linkage between X-linked CASK haploinsufficiency and clinically diagnosed ONH, we hypothesized that heterozygous deletion of CASK (CASK(⁺/⁻)) in rodents will produce an optic nerve pathology closely recapitulating ONH. We quantitatively analyzed the entire subcortical visual system in female CASK(⁺/⁻) mice using immunohistochemistry, anterograde axonal tracing, toluidine blue staining, transmission electron microscopy, and serial block-face scanning electron microscopy. RESULTS. CASK haploinsuffiency in mice phenocopies human ONH with complete penetrance, thus satisfying the ‘face validity’. We demonstrate that the optic nerve in CASK(⁺/⁻) mice is not only thin, but is comprised of atrophic retinal axons and displays reactive astrogliosis. Myelination of the optic nerve axons remains unchanged. Moreover, we demonstrate a significant decrease in retinal ganglion cell (RGC) numbers and perturbation in retinothalamic connectivity. Finally, we used this mouse model to define the onset and progression of ONH pathology, demonstrating for the first time that optic nerve defects arise at neonatally in CASK(⁺/⁻) mice. CONCLUSIONS. Optic nerve hypoplasia is a complex neuropathology of the subcortical visual system involving RGC loss, axonopathy, and synaptopathy and originates at a developmental stage in mice that corresponds to the late third trimester development in humans.

Ca2+-binding protein 2 (CaBP2) inhibits the inactivation of heterologously expressed voltage-gated Ca2+ channels of type 1.3 (CaV1.3) and is defective in human autosomal-recessive deafness 93 (DFNB93). Here, we report a newly identified mutation in CABP2 that causes a moderate hearing impairment likely via nonsense-mediated decay of CABP2-mRNA. To study the mechanism of hearing impairment resulting from CABP2 loss of function, we disrupted Cabp2 in mice (Cabp2LacZ/LacZ). CaBP2 was expressed by cochlear hair cells, preferentially in inner hair cells (IHCs), and was lacking from the postsynaptic spiral ganglion neurons (SGNs). Cabp2LacZ/LacZ mice displayed intact cochlear amplification but impaired auditory brainstem responses. Patch-clamp recordings from Cabp2LacZ/LacZ IHCs revealed enhanced Ca2+-channel inactivation. The voltage dependence of activation and the number of Ca2+ channels appeared normal in Cabp2LacZ/LacZ mice, as were ribbon synapse counts. Recordings from single SGNs showed reduced spontaneous and sound-evoked firing rates. We propose that CaBP2 inhibits CaV1.3 Ca2+-channel inactivation, and thus sustains the availability of CaV1.3 Ca2+ channels for synaptic sound encoding. Therefore, we conclude that human deafness DFNB93 is an auditory synaptopathy.

The appearance of motor manifestations in Parkinson's disease (PD) is invariably linked to degeneration of nigral dopaminergic neurons of the substantia nigra pars compacta. Traditional views on PD neuropathology have been grounded in the assumption that the prime event of neurodegeneration involves neuronal cell bodies with the accumulation of metabolic products. However, this view has recently been challenged by both clinical and experimental evidence. Neuropathological studies in human brain samples and both in vivo and in vitro models support the hypothesis that nigrostriatal synapses may indeed be affected at the earliest stages of the neurodegenerative process. The mechanisms leading to either structural or functional synaptic dysfunction are starting to be elucidated and include dysregulation of axonal transport, impairment of the exocytosis and endocytosis machinery, altered intracellular trafficking, and loss of corticostriatal synaptic plasticity. The aim of this review is to try to integrate different lines of evidence from both pathogenic and genetic animal models that, to different extents, suggest that early synaptic impairment may represent the key event in PD pathogenesis. Understanding the molecular and cellular events underlying such synaptopathy is a fundamental step toward developing specific biomarkers of early dopaminergic dysfunction and, more importantly, designing novel therapies targeting the synaptic apparatus of selective, vulnerable synapses. (C) 2016 International Parkinson and Movement Disorder Society

Many neurologic diseases cause discrete episodic impairment in contrast with progressive deterioration. The symptoms of these episodic disorders exhibit striking variety. Herein we review what is known of the phenotypes, genetics, and pathophysiology of episodic neurologic disorders. Of these, most are genetically complex, with unknown or polygenic inheritance. In contrast, a fascinating panoply of episodic disorders exhibit Mendelian inheritance. We classify episodic Mendelian disorders according to the primary neuroanatomical location affected: skeletal muscle, cardiac muscle, neuromuscular junction, peripheral nerve, or central nervous system (CNS). Most known Mendelian mutations alter genes that encode membrane-bound ion channels. These mutations cause ion channel dysfunction, which ultimately leads to altered membrane excitability as manifested by episodic disease. Other Mendelian disease genes encode proteins essential for ion channel trafficking or stability. These observations have cemented the channelopathy paradigm, in which episodic disorders are conceptualized as disorders of ion channels. However, we expand on this paradigm to propose that dysfunction at the synaptic and neuronal circuit levels may underlie some episodic neurologic entities.

ObjectiveTo review new insights into the pathophysiology of sensorineural hearing impairment. Specifically, we address defects of the ribbon synapses between inner hair cells and spiral ganglion neurons that cause auditory synaptopathy.Data sources and study selectionHere, we review original publications on the genetics, animal models, and molecular mechanisms of hair cell ribbon synapses and their dysfunction.ConclusionHair cell ribbon synapses are highly specialized to enable indefatigable sound encoding with utmost temporal precision. Their dysfunctions, which we term auditory synaptopathies, impair audibility of sounds to varying degrees but commonly affect neural encoding of acoustic temporal cues essential for speech comprehension. Clinical features of auditory synaptopathies are similar to those accompanying auditory neuropathy, a group of genetic and acquired disorders of spiral ganglion neurons. Genetic auditory synaptopathies include alterations of glutamate loading of synaptic vesicles, synaptic Ca influx or synaptic vesicle turnover. Acquired synaptopathies include noise-induced hearing loss because of excitotoxic synaptic damage and subsequent gradual neural degeneration. Alterations of ribbon synapses likely also contribute to age-related hearing loss.

Many neurologic diseases cause discrete episodic impairment in contrast with progressive deterioration. The symptoms of these episodic disorders exhibit striking variety. Herein we review what is known of the phenotypes, genetics, and pathophysiology of episodic neurologic disorders. Of these, most are genetically complex, with unknown or polygenic inheritance. In contrast, a fascinating panoply of episodic disorders exhibit Mendelian inheritance. We classify episodic Mendelian disorders according to the primary neuroanatomical location affected: skeletal muscle, cardiac muscle, neuromuscular junction, peripheral nerve, or central nervous system (CNS). Most known Mendelian mutations alter genes that encode membrane-bound ion channels. These mutations cause ion channel dysfunction, which ultimately leads to altered membrane excitability as manifested by episodic disease. Other Mendelian disease genes encode proteins essential for ion channel trafficking or stability. These observations have cemented the channelopathy paradigm, in which episodic disorders are conceptualized as disorders of ion channels. However, we expand on this paradigm to propose that dysfunction at the synaptic and neuronal circuit levels may underlie some episodic neurologic entities.

ObjectiveTo review new insights into the pathophysiology of sensorineural hearing impairment. Specifically, we address defects of the ribbon synapses between inner hair cells and spiral ganglion neurons that cause auditory synaptopathy.Data sources and study selectionHere, we review original publications on the genetics, animal models, and molecular mechanisms of hair cell ribbon synapses and their dysfunction.ConclusionHair cell ribbon synapses are highly specialized to enable indefatigable sound encoding with utmost temporal precision. Their dysfunctions, which we term auditory synaptopathies, impair audibility of sounds to varying degrees but commonly affect neural encoding of acoustic temporal cues essential for speech comprehension. Clinical features of auditory synaptopathies are similar to those accompanying auditory neuropathy, a group of genetic and acquired disorders of spiral ganglion neurons. Genetic auditory synaptopathies include alterations of glutamate loading of synaptic vesicles, synaptic Ca influx or synaptic vesicle turnover. Acquired synaptopathies include noise-induced hearing loss because of excitotoxic synaptic damage and subsequent gradual neural degeneration. Alterations of ribbon synapses likely also contribute to age-related hearing loss.

Hearing loss is usually diagnosed through pure-tone threshold audiometry. However, some listeners who have normal hearing thresholds complain about difficulty communicating in environments where there are competing sounds and noise. Animal research has shown that this problem may arise from a loss of synapses between inner hair cells and auditory nerve fibres. This is known as synaptopathy and is thought to mainly affect medium to high-threshold auditory nerve fibres, which are responsible for encoding moderate to loud sounds, but do not respond to quiet sounds. If true, this would explain why hearing thresholds are not affected. This ‘hidden’ hearing loss may explain some of the difficulties that some listeners experience whilst having clinically normal audiograms. Synaptopathy has been studied in humans using the auditory brainstem response (ABR), but so far, the results have been varied. One possible reason could be that auditory brainstem responses contain a high degree of inter-individual variability resulting from unrelated factors such as gender, head size, or cochlear length. These confounds may be alleviated by using relative rather than absolute ABR measures. This thesis investigated two ABR methodologies, based on relative measures, aimed at optimizing the response for detection of hidden hearing loss. The first is the wave I to V ratio, which is well established in the literature. It compares the amplitude of early (wave I) and late (wave V) components of the ABR. If synaptopathy has occurred, wave I is expected to be decreased but wave V is expected to be unchanged, due to compensatory changes in neuronal gain (hyperexcitability). This should, leading to a decrease in the wave I/V ratio. However, wave I is reportedly mainly elicited from high frequency regions of the cochlea, while wave V is thought to originate from a broader range of cochlear frequencies. This means the wave I/V ratio may be frequency-dependent, and so, using it in order to measure sy