Research Interests: Genetics, Molecular Biology, Biology, Medicine, Molecular, and 15 moreMutation, Escherichia coli, Nucleic acid hybridization, Bacteria, Proteins, Gene, Biological evolution, Genes, Molecular cloning, Gel electrophoresis, Amino Acid Sequence, Base Sequence, Biochemistry and cell biology, Molecular Sequence Data, and Nucleotide sequence
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Noonan syndrome (NS) is characterized by reduced growth, craniofacial abnormalities, congenital heart defects, and variable cognitive deficits. NS belongs to the RASopathies, genetic conditions linked to mutations in components and... more
Noonan syndrome (NS) is characterized by reduced growth, craniofacial abnormalities, congenital heart defects, and variable cognitive deficits. NS belongs to the RASopathies, genetic conditions linked to mutations in components and regulators of the Ras signaling pathway. Approximately 50% of NS cases are caused by mutations in PTPN11. However, the molecular mechanisms underlying cognitive impairments in NS patients are still poorly understood. Here, we report the generation and characterization of a new conditional mouse strain that expresses the overactive Ptpn11D61Y allele only in the forebrain. Unlike mice with a global expression of this mutation, this strain is viable and without severe systemic phenotype, but shows lower exploratory activity and reduced memory specificity, which is in line with a causal role of disturbed neuronal Ptpn11 signaling in the development of NS-linked cognitive deficits. To explore the underlying mechanisms we investigated the neuronal activity-regu...
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Research Interests: Neuroscience, Psychology, Animal Behavior, Fear, Long Term Potentiation, and 15 moreMedicine, Memory, Biological Sciences, Biological Psychiatry, Hippocampus, Mice, Animals, Amnesia, Fear conditioning, Associative learning, Retrograde Amnesia, Excitatory Postsynaptic Potentials, Avoidance Learning, Psychology and Cognitive Sciences, and Medical and Health Sciences
Research Interests: Endocrinology, Genetics, Long Term Potentiation, Biology, Medicine, and 15 moreSignal Transduction, Hippocampus, Internal Medicine, Mice, Animals, Dendrites, Phosphorylation, CREB, Neurons, SYNAPSES, Gonadotropin Releasing Hormone, PLoS Genetics, Knockout Mice, Hippocampal formation, and Brain-derived neurotrophic factor (BDNF)
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Onion bulb formation is a pathological feature observed in peripheral nerves of patients suffering from inherited peripheral neuropathies such as Charcot‐Marie‐Tooth and Déjérine‐Sottas diseases. An onion bulb consists of small... more
Onion bulb formation is a pathological feature observed in peripheral nerves of patients suffering from inherited peripheral neuropathies such as Charcot‐Marie‐Tooth and Déjérine‐Sottas diseases. An onion bulb consists of small circumferentially oriented (supernumerary) cells and their processes surrounding a large caliber axon. In the present study, we investigated the molecular phenotype of supernumerary cells at the light and electron microscopic levels. The major motor (quadriceps muscle) branch of the femoral nerve from 16‐ to 24‐month‐old mice with an inactivated allele of the myelin protein zero gene or deficient for myelin‐associated glycoprotein (MAG; PO‐ ‐ and MAG‐ ‐ mice, respectively), which have numerous onion bulbs, was teased to obtain single nerve fibers, which were then processed for immunocytochemistry. Corresponding nerves from wild‐type mice served as controls. In both PO‐ ‐ and MAG‐ ‐ mice, supernumerary cells expressed S‐100, the low‐affinity nerve growth factor receptor (p75, NGFr), the cell adhesion molecule L1, the neural cell adhesion molecule (N‐CAM), and glial fibrillary acidic protein (GFAP). At the electron microscopic level, the cell surface of supernumerary cells was NGFr immunoreactive and L1 and N‐CAM were expressed at points of contact between supernumerary cells. NGFr, L1, and N‐CAM were also present in the basal lamina surrounding myelinated axons associated with onion bulbs. Both S‐100 and GFAP immunoreactivities were seen in the cytoplasm of supernumerary cells. In contrast, in wild‐type mice myelinating Schwann cells only expressed S‐100 intracellularly and L1 and N‐CAM in their basal lamina, whereas non‐myelinating Schwann cells expressed all five molecules investigated. The present study indicates that supernumerary cells in onion bulbs have a molecular phenotype characteristic of immature, differentiated non‐myelinating, and denervated Schwann cells, thus excluding the possibility that supernumerary cells are perineurial cells. © 1996 Wiley‐Liss, Inc.
Research Interests: Biology, Medicine, Immunocytochemistry, Axon, Onion, and 4 moreMyelin, Glia, Schwann Cell, and Neurosciences
In humans, loss or alteration of the CHL1/CALL gene may contribute to mental impairment associated with the 3p-syndrome, caused by distal deletions of the short (p) arm of chromosome 3, and schizophrenia. Mice deficient for the Close... more
In humans, loss or alteration of the CHL1/CALL gene may contribute to mental impairment associated with the 3p-syndrome, caused by distal deletions of the short (p) arm of chromosome 3, and schizophrenia. Mice deficient for the Close Homologue of L1 (CHL1) show aberrant connectivity of hippocampal mossy fibers and olfactory sensory axons, suggesting participation of CHL1 in the establishment of neuronal networks. Furthermore, behavioral studies showed that CHL1-deficient mice react differently towards novel experimental environments. These data raise the hypothesis that processing of information, possibly novel versus familiar, may be altered in the absence of CHL1. To test this hypothesis, brain activities were investigated after presentation of a novel, familiar, or neutral gustatory stimulus using metabolic mapping with ((14)C)-2-deoxyglucose (2-DG) and analysis of mRNA expression of the immediate early genes (IEGs) c-fos and arg 3.1/arc by in situ hybridization. 2-DG labeling revealed only small differences between CHL1-deficient and wild-type littermate mice. In contrast, while the specific novelty-induced increase in c-fos expression was maintained in most of the brain areas analyzed, c-fos mRNA expression was similar after the novel and familiar taste in several brain areas of the CHL1-deficient mice. Furthermore, in these mutants, arg 3.1/arc expression was slightly reduced after the novel taste and increased after the familiar taste, leading to a similar arg 3.1/arc mRNA expression after both stimuli. Our results indicate that, in contrast to controls, CHL1-deficient mice might process novel and familiar information similarly and suggest that the altered neuronal connectivity in these mutants disturbs information processing at the molecular level.
Research Interests: Neuroscience, Cognitive Science, Biology, Neurobiology, Medicine, and 14 moreInformation Processing, In Situ Hybridization, Brain Mapping, Brain, Mice, Animals, Mental processes, Proteins, Medical Physiology, Olfactory Bulb, Neurosciences, Gene Expression Regulation, Cell Adhesion Molecules, and Hippocampal formation
Abstract: In this study, we have investigated the ability of galectin-3, a β-galactoside-binding animal lectin, to interact in vitro with different neural tissue-derived glycoproteins involved in cell-cell and cell-substrate adhesion.... more
Abstract: In this study, we have investigated the ability of galectin-3, a β-galactoside-binding animal lectin, to interact in vitro with different neural tissue-derived glycoproteins involved in cell-cell and cell-substrate adhesion. Galectin-3 interacted to varying degrees with the cell ...
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Research Interests: Genetics, Molecular Biology, Biology, Medicine, Molecular, and 15 moreMutation, Escherichia coli, Nucleic acid hybridization, Bacteria, Gene, Biological evolution, Genes, Molecular cloning, Gel electrophoresis, Amino Acid Sequence, Base Sequence, Biochemistry and cell biology, Molecular Sequence Data, Nucleotide sequence, and Membrane receptor
Research Interests: Cognitive Science, Biology, Cell Adhesion, Cell Biology, Medicine, and 15 moreExtracellular Matrix, Mice, Animals, Cell Polarity, Neurons, Epidermal Growth Factor, Fibronectin, Neurite, Glutathione Transferase, Neurosciences, Extracellular, Neural Cell Adhesion Molecules, Contactins, CHO cells, and Cricetinae
Research Interests: Neuroscience, Electron Microscopy, Biology, Medicine, Extracellular Matrix, and 15 moreOptic Nerve, Mice, Animals, Embryonic Stem Cell, Central Nervous System, Conduction Velocity, Chondroitin Sulfate, Knock out, Decorin, Axons, Immunostaining, Immunoglobulin, Extracellular Matrix Proteins, Psychology and Cognitive Sciences, and Medical and Health Sciences
Ultrastructural analysis of myelin from 8-month-old mice deficient in the myelin-associated glycoprotein revealed pronounced and characteristic alterations of the periaxonal oligodendrocyte processes, consisting of intracytoplasmic... more
Ultrastructural analysis of myelin from 8-month-old mice deficient in the myelin-associated glycoprotein revealed pronounced and characteristic alterations of the periaxonal oligodendrocyte processes, consisting of intracytoplasmic deposition of vesicular material, multivesicular bodies, mitochondria, and lipofuscin granules, as well as granular or paracrystalline inclusions. These alterations are similar to those described before as "dying-back oligodendrogliopathy" in diseases of toxic or immune-mediated demyelination including multiple sclerosis.
Research Interests: Electron Microscopy, Biology, Scanning Electron Microscopy, Transmission Electron Microscopy, Medicine, and 14 moreMutation, Mice, Animals, Cell Death, P-glycoprotein, Ultrastructure, Oligodendrocyte, Myelin, Glia, Neurosciences, Nervous System Diseases, Myelin Sheath, Lipofuscin, and myelin associated glycoprotein
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Fasciculation and defasciculation of axons are major morphogenetic events in the formation of neuronal pathways during development. We have identified the extracellular matrix glycoprotein tenascin-R (TN-R) and its neuronal receptor, the... more
Fasciculation and defasciculation of axons are major morphogenetic events in the formation of neuronal pathways during development. We have identified the extracellular matrix glycoprotein tenascin-R (TN-R) and its neuronal receptor, the immunoglobulin superfamily recognition molecule F3, as promoters of neurite defasciculation in cerebellar explant cultures. Perturbation of the interaction between these two molecules using both antibodies and an antisense oligonucleotide resulted in increased neurite fasciculation. The domains involved in defasciculation were identified as the N-terminal region of TN-R containing the cysteine-rich stretch and the 4.5 epidermal growth factor-like repeats and the immunoglobulin-like domains of F3. Fasciculation induced by antibodies and the antisense oligonucleotide could be reverted by a phorbol ester activator of protein kinase C, whereas the protein kinase inhibitor staurosporine increased fasciculation. Our observations indicate that defasciculated neurite outgrowth does not only depend on the reduction of the expression of fasciculation enhancing adhesion molecules, such as L1 and the neural cell adhesion molecule (NCAM), but also on recognition molecules that actively induce defasciculation by triggering second messenger systems.
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The extracellular matrix molecule tenascin-R (TN-R), predominantly expressed in the central nervous system, has been implied in a variety of functions, e.g. during myelination, cerebellar neurite fasciculation and hippocampal long-term... more
The extracellular matrix molecule tenascin-R (TN-R), predominantly expressed in the central nervous system, has been implied in a variety of functions, e.g. during myelination, cerebellar neurite fasciculation and hippocampal long-term potentiation. In this study, we investigated in detail the impact of TN-R deficiency on the living animal by analyzing the behavior of TN-R-deficient mice. The general state, gross sensory functions, reflexes and motoric capabilities appeared normal. In contrast, motor coordination on the rota-rod was compromised in these mice, indicating a deficit in cerebellar functions. In the open field and the hole board, the mutants interact differently with their environment, probably due to differences in their exploratory behavior. TN-R-deficient mice were able to learn a reference memory task in the Morris water maze. In contrast to wild-type mice, the mutants displayed an alternative strategy; swimming around the pool using a stereotypical circling pattern, crossing all possible platform positions after relocation of the escape platform (reversal). These results, confirmed by relocating the platform in the center of the pool, suggest that TN-R-deficient mice may be impaired in constructing a goal-independent representation of space. In addition, a two-way active avoidance test (shuttle box) revealed a severe deficit in associative learning in TN-R-deficient mice. Our results support important functions of TN-R in vivo in the central nervous system, in particular in the cerebellum and the hippocampus.
Research Interests: Neuroscience, Cognition, Long Term Potentiation, Medicine, Biological Sciences, and 15 moreHippocampus, Cerebellum, Mice, Animals, Motor Coordination, Central Nervous System, Genes, Exploratory Behavior, Maze Learning, Cell Adhesion Molecules, Hippocampal formation, Motor activity, Avoidance Learning, Medical and Health Sciences, and Hand strength
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Research Interests: Animal Behavior, Biology, Membrane Proteins, Cell Biology, Medicine, and 15 moreInformation Processing, In Situ Hybridization, Biological Sciences, Hippocampus, Humans, Mice, Female, Animals, Male, Axon Guidance, Central Nervous System, Elevated Plus Maze, Brain Chemistry, Cell Adhesion Molecules, and Medical and Health Sciences
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Research Interests: Biochemistry, Biology, GABAergic Neurotransmission, Cell Biology, Biological Chemistry, and 15 moreMedicine, Biological Sciences, GABA receptors, Animals, Dentate Gyrus, CHEMICAL SCIENCES, Glutamic Acid, Gene Expression Regulation, Cell Adhesion Molecules, Hippocampal formation, Excitatory Postsynaptic Potentials, Gabaergic, GABAA receptor, Cell count, and Medical and Health Sciences
The brain- and testis-specific Ig superfamily protein (BT-IgSF, also termed IgSF11) is a homotypic cell adhesion protein. In the nervous system, BT-IgSF regulates the stability of AMPA receptors in the membrane of cultured hippocampal... more
The brain- and testis-specific Ig superfamily protein (BT-IgSF, also termed IgSF11) is a homotypic cell adhesion protein. In the nervous system, BT-IgSF regulates the stability of AMPA receptors in the membrane of cultured hippocampal neurons, modulates the connectivity of chandelier cells and controls gap junction-mediated astrocyte-astrocyte communication. Here, we performed behavioral tests in BT-IgSF-deficient mice. BT-IgSF-deficient mice were similar to control littermates with respect to their reflexes, motor coordination and gating, and associative learning. However, BT-IgSF-deficient mice displayed an increased tendency to stay in the central illuminated areas in the open field and O-Maze paradigms suggesting reduced anxiety or increased scotophobia (fear of darkness). Although BT-IgSF-deficient mice initially found the platform in the water maze their behavior was compromised when the platform was moved, indicating reduced behavioral flexibility. This deficit was overcome b...
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The distal part of the long tail fiber of Escherichia coli bacteriophage T4 consists of a dimer of protein 37. Dimerization requires the catalytic action of protein 38, which is encoded by T4 and is not present in the virion. It had... more
The distal part of the long tail fiber of Escherichia coli bacteriophage T4 consists of a dimer of protein 37. Dimerization requires the catalytic action of protein 38, which is encoded by T4 and is not present in the virion. It had previously been shown that gene tfa of the otherwise entirely unrelated phage lambda can functionally replace gene 38. Open reading frame (ORF) 314, which encodes a protein that exhibits homology to a COOH-terminal area of protein 37, is located immediately upstream of tfa. The gene was cloned and expressed in E. coli. An antiserum against the corresponding polypeptide showed that it was present in phage lambda. The serum also reacted with the long tail fibers of phage T4 near their free ends. An area of the gene encoding a COOH-terminal region of ORF 314 was recombined, together with tfa, into the genome of T4, thus replacing gene 38 and a part of gene 37 that codes for a COOH-terminal part of protein 37. Such T4-lambda hybrids, unlike T4, required the ...
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Retrograde amnesia is the inability to remember events or information. The successful acquisition and memory of information is required before retrograde amnesia may occur. Often, the trigger for retrograde amnesia is a traumatic event.... more
Retrograde amnesia is the inability to remember events or information. The successful acquisition and memory of information is required before retrograde amnesia may occur. Often, the trigger for retrograde amnesia is a traumatic event. Loss of memories may be caused in two ways: either by loss/erasure of the memory itself or by the inability to access the memory, which is still present. In general, memories and learning are associated with a positive connotation although the extinction of unpleasant experiences and memories of traumatic events may be highly welcome. In contrast to the many experimental models addressing learning deficits caused by anterograde amnesia, the incapability to acquire new information, retrograde amnesia could so far only be investigated sporadically in human patients and in a limited number of model systems. Apart from models and diseases in which neurodegeneration or dementia like Alzheimer’s disease result in loss of memory, retrograde amnesia can be e...
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Ex vivo Aβ42 uptake by cells from wildtype C57BL/6 mice. Ex vivo phagocytosis assay was performed with mononuclear cells isolated from C57BL/6 mouse brains. Populations were gated as described in Fig. 3a and Aβ42 uptake was quantified... more
Ex vivo Aβ42 uptake by cells from wildtype C57BL/6 mice. Ex vivo phagocytosis assay was performed with mononuclear cells isolated from C57BL/6 mouse brains. Populations were gated as described in Fig. 3a and Aβ42 uptake was quantified using imaging flow cytometry. Bars indicate the median fluorescence intensity (MFI) of each population and data are displayed as mean + SEM (n = 5). Significance levels (p values) determined by Fisher's LSD test are indicated. ns, not significant, *p ≤ 0.05, **p ≤ 0.01, ****p ≤ 0.0001. (TIF 144 kb)
Antigen presentation pathway according to IPAâ ˘. Symbols are explained in a table (part B). Filled symbols represent proteins found to be altered in synaptosomes according to MS data, green indicates reduced levels, and red notifies... more
Antigen presentation pathway according to IPAâ ˘. Symbols are explained in a table (part B). Filled symbols represent proteins found to be altered in synaptosomes according to MS data, green indicates reduced levels, and red notifies increased levels compared to controls. (PDF 1690 kb)
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Jacob, the protein encoded by the Nsmf gene, is involved in synapto-nuclear signaling and docks an N-Methyl-D-Aspartate receptor (NMDAR)-derived signalosome to nuclear target sites like the transcription factor... more
Jacob, the protein encoded by the Nsmf gene, is involved in synapto-nuclear signaling and docks an N-Methyl-D-Aspartate receptor (NMDAR)-derived signalosome to nuclear target sites like the transcription factor cAMP-response-element-binding protein (CREB). Several reports indicate that mutations in NSMF are related to Kallmann syndrome (KS), a neurodevelopmental disorder characterized by idiopathic hypogonadotropic hypogonadism (IHH) associated with anosmia or hyposmia. It has also been reported that a protein knockdown results in migration deficits of Gonadotropin-releasing hormone (GnRH) positive neurons from the olfactory bulb to the hypothalamus during early neuronal development. Here we show that mice that are constitutively deficient for the Nsmf gene do not present phenotypic characteristics related to KS. Instead, these mice exhibit hippocampal dysplasia with a reduced number of synapses and simplification of dendrites, reduced hippocampal long-term potentiation (LTP) at CA1...
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The recent identification of plasma membrane (Ca2+)-ATPase (PMCA)-Neuroplastin (Np) complexes has renewed attention on cell regulation of cytosolic calcium extrusion, which is of particular relevance in neurons. Here, we tested the... more
The recent identification of plasma membrane (Ca2+)-ATPase (PMCA)-Neuroplastin (Np) complexes has renewed attention on cell regulation of cytosolic calcium extrusion, which is of particular relevance in neurons. Here, we tested the hypothesis that PMCA-Neuroplastin complexes exist in specific ganglioside-containing rafts, which could affect calcium homeostasis. We analyzed the abundance of all four PMCA paralogs (PMCA1-4) and Neuroplastin isoforms (Np65 and Np55) in lipid rafts and bulk membrane fractions from GM2/GD2 synthase-deficient mouse brains. In these fractions, we found altered distribution of Np65/Np55 and selected PMCA isoforms, namely PMCA1 and 2. Cell surface staining and confocal microscopy identified GM1 as the main complex ganglioside co-localizing with Neuroplastin in cultured hippocampal neurons. Furthermore, blocking GM1 with a specific antibody resulted in delayed calcium restoration of electrically evoked calcium transients in the soma of hippocampal neurons. Th...
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Research Interests: Biochemistry, Molecular Biology, Biology, GABAergic Neurotransmission, Cell Biology, and 15 moreBiological Chemistry, Medicine, Biological Sciences, Mice, GABA receptors, Animals, Neurons, Dentate Gyrus, CHEMICAL SCIENCES, Glutamic Acid, Gene Expression Regulation, Cell Adhesion Molecules, Excitatory Postsynaptic Potentials, Cell count, and Medical and Health Sciences
The recent identification of plasma membrane (Ca2+)-ATPase (PMCA)-Neuroplastin (Np) complexes has renewed attention on cell regulation of cytosolic calcium extrusion, which is of particular relevance in neurons. Here, we tested the... more
The recent identification of plasma membrane (Ca2+)-ATPase (PMCA)-Neuroplastin (Np) complexes has renewed attention on cell regulation of cytosolic calcium extrusion, which is of particular relevance in neurons. Here, we tested the hypothesis that PMCA-Neuroplastin complexes exist in specific ganglioside-containing rafts, which could affect calcium homeostasis. We analyzed the abundance of all four PMCA paralogs (PMCA1-4) and Neuroplastin isoforms (Np65 and Np55) in lipid rafts and bulk membrane fractions from GM2/GD2 synthase-deficient mouse brains. In these fractions, we found altered distribution of Np65/Np55 and selected PMCA isoforms, namely PMCA1 and 2. Cell surface staining and confocal microscopy identified GM1 as the main complex ganglioside co-localizing with Neuroplastin in cultured hippocampal neurons. Furthermore, blocking GM1 with a specific antibody resulted in delayed calcium restoration of electrically evoked calcium transients in the soma of hippocampal neurons. Th...
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Molecular mechanisms underlying neuropsychiatric and neurodegenerative diseases are insufficiently elucidated. A detailed understanding of these mechanisms may help to further improve medical intervention. Recently, intellectual... more
Molecular mechanisms underlying neuropsychiatric and neurodegenerative diseases are insufficiently elucidated. A detailed understanding of these mechanisms may help to further improve medical intervention. Recently, intellectual abilities, creativity, and amnesia have been associated with neuroplastin, a cell recognition glycoprotein of the immunoglobulin superfamily that participates in synapse formation and function and calcium signaling. Data from animal models suggest a role for neuroplastin in pathways affected in neuropsychiatric and neurodegenerative diseases. Neuroplastin loss or disruption of molecular pathways related to neuronal processes has been linked to various neurological diseases, including dementia, schizophrenia, and Alzheimer’s disease. Here, we review the molecular features of the cell recognition molecule neuroplastin, and its binding partners, which are related to neurological processes and involved in learning and memory. The emerging functions of neuroplast...
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Hearing deficits impact on the communication with the external world and severely compromise perception of the surrounding. Deafness can be caused by particular mutations in the neuroplastin (Nptn) gene, which encodes a transmembrane... more
Hearing deficits impact on the communication with the external world and severely compromise perception of the surrounding. Deafness can be caused by particular mutations in the neuroplastin (Nptn) gene, which encodes a transmembrane recognition molecule of the immunoglobulin (Ig) superfamily and plasma membrane Calcium ATPase (PMCA) accessory subunit. This study investigates whether the complete absence of neuroplastin or the loss of neuroplastin in the adult after normal development lead to hearing impairment in mice analyzed by behavioral, electrophysiological, and in vivo imaging measurements. Auditory brainstem recordings from adult neuroplastin-deficient mice (Nptn−/−) show that these mice are deaf. With age, hair cells and spiral ganglion cells degenerate in Nptn−/− mice. Adult Nptn−/− mice fail to behaviorally respond to white noise and show reduced baseline blood flow in the auditory cortex (AC) as revealed by single-photon emission computed tomography (SPECT). In adult Npt...