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At least 703 records · Page 39Linked to original sources
PubMed1993

Serotonin-containing terminals synapse on septohippocampal neurons in the rat.

Serotonin [5-hydroxytryptamine (5-HT)] is thought to be involved in mnemonic functions and dysfunctions possibly by directly contacting neurons in the medial septal and diagonal band nuclei (i.e., the septal complex) that project to the hippocampal formation. However, there is no cellular substrate for this modulation. Thus, we examined the ultrastructure and synaptic associations of 5-HT-containing terminals in relation to septohippocampal neurons in the septal complex of the rat brain. Projection neurons were identified by retrograde transport of wheat germ agglutinated apo-horseradish peroxidase conjugated to colloidal gold particles (WAHG) following an injection into the ventral hippocampal formation of anesthetized adult rats. After a 1 day survival, sections through the septal complex were labeled with antibodies to 5-HT. By light microscopy, numerous processes with 5-HT immunoreactivity (5-HT-I) were observed in close proximity to neurons containing retrogradely transported WAHG. By electron microscopy, 5-HT-I was found exclusively in axons and axon terminals. Axons were primarily unmyelinated. Terminals with 5-HT-I were 0.35-1.2 microns in diameter and contained numerous small, clear vesicles and 0-4 large, dense-core vesicles. The 5-HT-labeled terminals: 1) contacted perikarya and dendrites (220 of 349); 2) were closely apposed to other terminals (25 of 349); or 3) had no neuronal contacts in the plane of section analyzed (104 of 349). The 5-HT-labeled terminals formed exclusively symmetric synapses on perikarya; some of these perikarya as well as some large dendrites similarly contacted by the 5-HT-labeled terminals also contained WAHG affiliated with lysosomes and multivesicular and "sequestration" bodies in the cytoplasm. However, the majority of terminals with 5-HT-I formed contacts on the shafts of small unlabeled dendrites (69% of 220); most of these were characterized as either asymmetric synapses or appositions not separated by astrocytes in the plane of section analyzed. We conclude that 5-HT-containing terminals in the rat septal complex: 1) directly modulate septohippocampal and other neurons through symmetric (potentially inhibitory) synapses on soma and proximal dendrites; and 2) form primarily asymmetric (potentially excitatory) synapses with distal (small) dendrites from neurons of unidentified origin. These findings suggest that serotonin may affect learning and memory through modulation of septal efferents to the hippocampal formation and may have direct relevance to the neuropathological basis for Alzheimer's disease.

Animals↗
PubMed1986

Lithium mechanisms in bipolar illness and altered intracellular calcium functions.

Calcium functions as an intracellular second messenger, transducing a variety of hormonal, electrical, and mechanical stimuli by activating a wide range of enzymes. There is evidence, ranging from definitive to strongly presumptive in quality, that lithium can alter many calcium-dependent processes. The list of enzyme systems dependent on calcium and altered by lithium includes adenylate cyclase, glycogen synthase, inositol-1-phosphatase, and calcium adenosine triphosphatase (ATPase). Lithium also interferes with calcium regulation of receptor sensitivity, parathyroid hormone release, microtubule structure, and other systems. All of the neural mechanisms that are hypothesized to explain various psychopharmacological treatments of bipolar illness involve functions that are critically controlled by calcium. Moreover, in every instance, a known action of lithium on calcium function could account for lithium's therapeutic or prophylactic results. From these considerations the dual hypotheses emerge that bipolar illnesses arise from disorders in calcium-regulated functions and that lithium acts by reversing or counterbalancing the effects of these calcium dysfunctions.

Adenylyl Cyclases↗
PubMed2005

Come together, right...now: synchronization of rhythms in a mammalian circadian clock.

In mammals, the suprachiasmatic nuclei (SCN) of the hypothalamus act as a dominant circadian pacemaker, coordinating rhythms throughout the body and regulating daily and seasonal changes in physiology and behavior. This review focuses on the mechanisms that mediate synchronization of circadian rhythms between SCN neurons. Understanding how these neurons communicate as a network of circadian oscillators has begun to shed light on the adaptability and dysfunction of the brain's master clock.

Animals↗
PubMed2005

Modulation of dendritic spines in epilepsy: cellular mechanisms and functional implications.

Epilepsy patients often suffer from significant neurological deficits, including memory impairment, behavioral problems, and psychiatric disorders. While the causes of neuropsychological dysfunction in epilepsy are multifactorial, accumulating evidence indicates that seizures themselves may directly cause brain injury. Although seizures sometimes result in neuronal death, they may also cause more subtle pathological changes in neuronal structure and function, including abnormalities in synaptic transmission. Dendritic spines receive a majority of the excitatory synaptic inputs to cortical neurons and are critically involved in synaptic plasticity and learning. Studies of human epilepsy and experimental animal models demonstrate that seizures may directly affect the morphological and functional properties of dendritic spines, suggesting that seizure-related changes in spines may represent a mechanistic basis for cognitive deficits in epilepsy. Novel therapeutic strategies directed at modulation of spine motility may prevent the detrimental effects of seizures on cognitive function in epilepsy.

Animals↗
PubMedDate not supplied

Age-dependent alterations in hippocampal synaptic plasticity: relation to memory disorders.

In this paper, we review the evidence indicating that the common disturbance in recent memory associated with aging is a consequence of functional and structural impairment in the hippocampal formation. In the Fischer 344 rat, an experimental model of the human age-related memory disorder was developed. The majority of aged rats of this strain show impaired performance in the 8-arm radial maze in a manner typical of young rats with bilateral hippocampal lesions. Aged animals also exhibit rapid decay of LTP and slower kindling of the perforant path-dentate synapse. Furthermore, quantitative morphometric analysis of the hippocampal synaptic architecture revealed that aged, memory-impaired rats had a specific loss of perforated axospinous synapses in the middle third of the dentate gyrus molecular layer; the extent of loss was directly related to the degree of memory dysfunction. Most important was the fact that the electrophysiological and morphological abnormalities did not appear in equally old animals with good memory.

Aging↗
PubMed2005

[Current aspects of psychosomatic and endocrine stress research].

This review covers basic principles of (neural-)endocrine and psychosomatic aspects and its relationship to stress science. The term stress is rather imprecise, recent reviews defined stress in biological systems as any condition that seriously perturbs the physiological and psychological homeostasis of concerning organism. The review summarizes current knowledge of regulation of the HPA axis and other neural-endocrine-systems. The neurobiological data obtained suggest that inappropriate stress control involve dysfunction of hypothalamo-pituitary-adrenocortical (HPA) axis, limbic system and other brain regions. Stress induced different functional (increase of catecholamines and glucocorticoids) and structural changes in brain regions such as the hippocampus, with suppression of adult neurogenesis and synaptic plasticity. These stress associated changes can potentially influence among other things learning and memory processes. The plasticity of brain allows to conceptualize a neurobiological perspective on psychotherapy that reflects the dynamic nature of the interaction between genes and the environment, respectively the consequences of stress. These developments point the way towards a new era of psychotherapy research and practice.

Humans↗
PubMed1996

Profound disturbances of pre- and postsynaptic GABAB-receptor-mediated processes in region CA1 in a chronic model of temporal lobe epilepsy.

1. This report examines alterations in presynaptic and postsynaptic processes mediated by gamma-aminobutyric acid-B (GABAB) receptors within hippocampal region CA1 in a model of chronic temporal lobe epilepsy (TLE). Intracellular recordings were obtained in pyramidal cells from combined hippocampal/parahippocampal control slices and slices obtained > or = 1 mo after a period of self-sustaining limbic status epilepticus (SSLSE) induced by continuous hippocampal stimulation. 2. Monosynaptic inhibitory postsynaptic potentials (IPSPs) were evoked by placement of the stimulating electrode in stratum pyramidale within 500 microns of the recording electrode in the presence of the ionotropic glutamate receptor antagonists 6-cyano-7-nitroquinoxaline-2,3-dione and D(-)-2-amino-5-phosphonovaleric acid. Control IPSPs exhibited early (GABAA-receptor-mediated) and late (GABAB-receptor-mediated) components. In contrast, post-SSLSE IPSPs displayed only a GABAA-receptor-mediated IPSP. Post-SSLSE IPSPs were completely eliminated by antagonists of the GABAA receptor (bicuculline methiodide and picrotoxin). In control tissue, GABAB receptor antagonists P-(3-aminopropyl)-P-diethoxymethyl-phosphinic acid (CGP 55845A), 3-N[1-(S)-(3,4-dichlorophenyl) ethyl]amino-2-(S)- hydroxypropyl-P-benzyl-phosphinic acid (CGP 35348), and 2-hydroxysaclofen eliminated the late component of the biphasic IPSP but had no discernible effect on IPSPs evoked in post-SSLSE CA1 pyramidal cells. 3. A paired pulse paradigm was employed to investigate the integrity of presynaptic GABAB-receptor-mediated inhibition of GABA release. To isolate pure GABAA-receptor-mediated responses, and thus facilitate comparison with post-SSLSE tissue, control neurons were penetrated with intracellular electrodes containing Cs2SO4/lidocaine, N-ethyl bromide (QX-314), and IPSPs were evoked employing the monosynaptic IPSP protocol. In controls, paired pulses [interpulse intervals (IPIs) of 70-1,500 ms] resulted in a diminution of the second early, GABAA-receptor-mediated chloride IPSP (IPSPA) relative to the first; maximum paired pulse depression (PPD) occurred at an IPI of 100 ms. GABAB receptor antagonists reduced PPD without affecting the amplitude of IPSPAs; the GABAB receptor agonist baclofen reduced the amplitude of both the first and second IPSPA and largely alleviated PPD. In contrast, no PPD was evident at any IPI in post-SSLSE neurons. Neither antagonists nor agonists of GABAB-receptor-mediated processes had an effect on either the degree of PPD or the amplitude of IPSPs. 4. To better approximate the pattern of CA1 pyramidal cell activation occurring during epileptiform activity. IPSPAs were evoked by trains of stimuli. In controls, mean monosynaptic IPSPA amplitude decreased by approximately 60% during a 3-Hz, 5-s train, with more than half the decline coming between the first and second IPSPs. In post-SSLSE, no significant IPSPA depression resulted from delivery of stimulus trains. Baclofen reduced the amplitude of control IPSPAs evoked during stimulus trains; both agonist and antagonists significantly lessened the degree of IPSP depression. These same agents altered neither IPSP amplitude nor the degree of use-dependent IPSP depression produced in post-SSLSE tissue during stimulus trains. 5. We conclude that a dysfunction of both presynaptic and postsynaptic GABAB-receptor-mediated processes occurs in hippocampal area CA1 in the post-SSLSE model of TLE. GABAB receptor agonists and antagonists had no effect on post-SSLSE CA1 pyramidal cell synaptic responses, whereas antagonists of the GABAA receptor completely eliminated IPSPs. Repetitive activation produced no use-dependent synaptic depression. The implications of these findings for the epileptogenic potential of post-SSLSE CA1 and the "dormant basket cell" hypothesis are discussed.

Animals↗
PubMed1993

In vivo cerebral metabolism and central benzodiazepine-receptor binding in temporal lobe epilepsy.

Positron emission tomography measured interictal cerebral glucose metabolism with [18F]fluorodeoxyglucose and central benzodiazepine-receptor binding with [11C]flumazenil in 10 mesial temporal lobe epilepsy (TLE) patients and in normal subjects. Eight TLE patients had mesial temporal, lateral temporal, and thalamic hypometabolism ipsilateral to EEG ictal onsets, with additional extratemporal hypometabolism in four. One had unilateral anterior mesial temporal hypometabolism only, and one had normal metabolism. Each patient had decreased benzodiazepine-receptor binding in the ipsilateral anterior mesial temporal region, without neocortical changes. Thus, interictal metabolic dysfunction is variable and usually extensive in TLE, whereas decreased central benzodiazepine-receptor density is more restricted to mesial temporal areas. Metabolic patterns in TLE may reflect diaschisis, while benzodiazepine-receptor changes may reflect localized neuronal and synaptic loss that is specific to the epileptogenic zone. [11C]Flumazenil imaging may be useful in presurgical evaluation of refractory complex partial seizures.

Adult↗
PubMed1997

Oxidative injury of synapse and alteration of antioxidative defense systems in rats, and its prevention by vitamin E.

In order to define whether active oxygen species actually induce oxidative damage to the nervous system, and how antioxidative defense systems are changed by oxidative stress, morphological and functional changes in the nervous system and antioxidant status were investigated. When rats were exposed to 100% oxygen in a chamber, many morphological changes, e.g. swollen astrocytes around vessels, deformed nuclei in nerve cells, pigmentation, swollen mitochondria, and abnormal accumulation of synaptic vesicles in swollen nerve terminals, were observed by electron microscopy. When synaptosomes isolated from oxygen-exposed rats were stimulated by KCl, acetylcholine release from the terminal was decreased more significantly than in synaptosomes from unexposed rats (P < 0.01). Synaptic plasma membrane fluidity decreased in response to oxygen exposure, and plasma membrane permeability to sucrose was increased significantly (P < 0.05). The cholesterol/phospholipid ratio of the plasma membranes was increased by oxidative stress and the content of unsaturated fatty acids, especially arachidonic acid and docosahexaenoic acid, decreased. The levels of thiobarbituric-acid-reactive substances in the plasma membranes of oxygen-exposed rats were significantly higher than in unexposed rats (P < 0.01). These results suggest that free radicals derived from oxygen may attack nerve terminals and peroxidize the plasma membrane. It was found that in response to the oxidative stress, the status of the defense system in synapse, i.e. the concentration of vitamin E, activities of superoxide dismutase and glutathione peroxidase changed, and that many of the changes observed were reduced remarkably by the intraperitoneal administration of vitamin E prior to stress. Data support the idea that vitamin E contributes to the protection against nerve dysfunction caused by oxidative stress.

Acetylcholine↗
PubMed2003

Nicotinic acetylcholine receptors: from structure to brain function.

Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels and can be divided into two groups: muscle receptors, which are found at the skeletal neuromuscular junction where they mediate neuromuscular transmission, and neuronal receptors, which are found throughout the peripheral and central nervous system where they are involved in fast synaptic transmission. nAChRs are pentameric structures that are made up of combinations of individual subunits. Twelve neuronal nAChR subunits have been described, alpha2-alpha10 and beta2-beta4; these are differentially expressed throughout the nervous system and combine to form nAChRs with a wide range of physiological and pharmacological profiles. The nAChR has been proposed as a model of an allosteric protein in which effects arising from the binding of a ligand to a site on the protein can lead to changes in another part of the molecule. A great deal is known about the structure of the pentameric receptor. The extracellular domain contains binding sites for numerous ligands, which alter receptor behavior through allosteric mechanisms. Functional studies have revealed that nAChRs contribute to the control of resting membrane potential, modulation of synaptic transmission and mediation of fast excitatory transmission. To date, ten genes have been identified in the human genome coding for the nAChRs. nAChRs have been demonstrated to be involved in cognitive processes such as learning and memory and control of movement in normal subjects. Recent data from knockout animals has extended the understanding of nAChR function. Dysfunction of nAChR has been linked to a number of human diseases such as schizophrenia, Alzheimer's and Parkinson's diseases. nAChRs also play a significant role in nicotine addiction, which is a major public health concern. A genetically transmissible epilepsy, ADNFLE, has been associated with specific mutations in the gene coding for the alpha4 or beta2 subunits, which leads to altered receptor properties.

Animals↗
PubMed2002

Deficit in hippocampal long-term potentiation in monosodium glutamate-treated rats.

Rats subjected to monosodium glutamate (MSG) administration during the neonatal period present chronic neuroendocrine dysfunction associated with marked cognitive deficits. Long-term potentiation (LTP) in the hippocampus provides a model suited for the study of mammalian brain plasticity and memory formation. In the present work, we used the LTP protocol to investigate the synaptic plasticity in the hippocampal CA1 area of adult rats subjected to MSG treatment during the first 10 days of life. Synaptic transmission in CA1 area was analyzed using extracellular field recordings in response to Schaffer's collateral fiber stimulation in hippocampal slices. Animals injected with MSG exhibited a dramatic decrement of LTP field excitatory postsynaptic potentials (fEPSPs) compared to control group. Analysis of percent enhancement of fEPSP slope at 2 min after high frequency stimulation (HFS) increased by 189.3 +/- 33.2% in slices from control rats and 129.45 +/- 18.5% (p < 0.01) in slices from MSG-treated rats. Additionally, MSG-treated animals failed to maintain or consolidate LTP as revealed by a significant reduction in fEPSP slope enhancement over time after HFS. The mean fEPSP slope, 60 min after HFS, was 154.28 +/- 21% of the average baseline slope in control slices versus only 124.4 +/- 15% in MSG-treated rats (p < 0.01). At 90 min after HFS, slices from controls reached a potentiation of 44.5 +/- 2.9%, whereas the MSG group displayed an overall response enhancement of 17.65 +/- 2.7% of basal levels (p < 0.01). These findings indicate that MSG-treated rats display a chronic impairment of CA1 synaptic plasticity.

Aging↗
PubMed2006

Zinc neurotoxicity is dependent on intracellular NAD levels and the sirtuin pathway.

Zinc neurotoxicity has been demonstrated in ischemic, seizure, hypoglycemic, and trauma-induced neuronal death where Zn(2+) is thought to be synaptically released and taken up in neighbouring neurons, reaching toxic concentrations. We previously demonstrated that toxicity of extracellular Zn(2+) depended on entry, elevation in intracellular free Zn(2+) ([Zn(2+)](i)), a reduction in NAD(+) and ATP levels, and dysfunction of glycolysis and cellular metabolism. We suggested that PARP-1 activation alone can not explain this loss of neuronal NAD(+). NAD(+) was recently demonstrated to permeate neurons and glia, and we have now shown that exogenous NAD(+) can reduce Zn(2+) neurotoxicity, and 3-acetylpyridine, which generates inactive NAD(+), potentiated Zn(2+) neurotoxicity. Sirtinol and 2-hydroxynaphthaldehyde, inhibitors of the sirtuin pathway (SIRT proteins are NAD(+)-catabolic protein deacetylases), attenuated both acute and chronic Zn(2+) neurotoxicity. Resveratrol and fisetin (sirtuin activators) potentiated NAD(+) loss and Zn(2+) neurotoxicities. Furthermore, neuronal cultures derived from the Wld(s) mouse, which overexpress the NAD(+) synthetic enzyme nicotinamide mononucleotide adenyl transferase (NMNAT-1), had reduced sensitivity to Zn(2+) neurotoxicity. Finally, nicotinamide was demonstrated to attenuate CA1 neuronal death after 10 min of global ischemia in rat even if administered 1 h after the insult. Together with previous data, these results further implicate NAD(+) levels in Zn(2+) neurotoxicity.

Aldehydes↗
PubMed2005

Functional, structural, and metabolic abnormalities of the hippocampal formation in Williams syndrome.

Williams syndrome (WS), caused by microdeletion of some 21 genes on chromosome 7q11.23, is characterized by dysmorphic features, mental retardation or learning difficulties, elastin arteriopathy, and striking neurocognitive and social-behavioral abnormalities. Recent studies of murine knockouts of key genes in the microdeleted region, LIM kinase 1 (LIMK1) and cytoplasmatic linker protein 2 (CYLN2), demonstrated significant functional and metabolic abnormalities, but grossly normal structure, in the hippocampal formation (HF). Furthermore, deficits in spatial navigation and long-term memory, major cognitive domains dependent on hippocampal function, have been described in WS. We used multimodal neuroimaging to characterize hippocampal structure, function, and metabolic integrity in 12 participants with WS and 12 age-, sex-, and IQ-matched healthy controls. PET and functional MRI studies showed profound reduction in resting blood flow and absent differential response to visual stimuli in the anterior HF in WS. Spectroscopic measures of N-acetyl aspartate, considered a marker of synaptic activity, were reduced. Hippocampal size was preserved, but subtle alterations in shape were present. These data demonstrate abnormalities in HF in WS in agreement with murine models, implicate LIMK1 and CYLN2 in human hippocampal function, and suggest that hippocampal dysfunction may contribute to neurocognitive abnormalities in WS.

Adult↗
PubMed2006

Synaptic alterations at inner hair cells precede spiral ganglion cell loss in aging C57BL/6J mice.

Hearing deficits have often been associated with loss of or damage to receptor hair cells and/or degeneration of spiral ganglion cells. There are, however, some physiological abnormalities that are not reliably attributed to loss of these cells. The afferent synapse between radial fibers of spiral ganglion neurons and inner hair cells (IHCs) emerges as another site that could be involved in transmission abnormalities. We tested the hypothesis that the structure of these afferent terminals would differ between young animals and older animals with significant hearing loss. Afferent endings and their synapses were examined by transmission electron microscopy at approximately 45% distance from the basal end of the cochlea in 2-3 month-old and 8-12 month-old C57BL/6J mice. The number of terminals in older animals was reduced by half compared to younger animals. In contrast, there was no difference in the density of SGCs between the age groups. Older animals featured enlarged terminals and mitochondria and enlarged postsynaptic densities and presynaptic bodies. These morphological changes may be a combination of pathologic, adaptive and compensatory responses to sensory dysfunction. Improved knowledge of these processes is necessary to understand the role of afferent connectivity in dysfunction of the aging cochlea.

Aging↗
PubMed1991

Ammonia-induced alterations in glutamate and muscimol binding to cerebellar synaptic membranes.

Binding of glutamate and muscimol (an agonist for GABAA receptors) to their respective receptors has been studied in the cerebellum of normal and hyperammonemic rats. There was a decrease in both high- and low-affinity binding of glutamate in the cerebellum during hyperammonemia. Kinetic studies revealed that the decrease is due to a reduction in the number of binding sites, but not due to changes in the binding affinities. Further studies also revealed that the decrease was only in the N-methyl-D-aspartate (NMDA)-specific binding sites without any alterations in the binding to non-NMDA sites represented by kianic acid (KA)- and quisqualic acid (QQ)-sensitive receptor sites. These effects were also mimicked when the membrane preparations from the cerebellum of normal animals were incubated with ammonium acetate. Enhancement of muscimol binding was observed in animals injected with ammonium acetate. It is concluded that hyperammonemic states, even in the presence of a functional liver, are capable of altering amino acid neurotransmission and this might play an important role in cerebral dysfunction under these conditions.

Ammonia↗
PubMed1997

Energetic dysfunction in quinolinic acid-lesioned rat striatum.

Impairment of mitochondrial energy metabolism may contribute to the selective neuronal degeneration observed in Huntington's disease and other neurodegenerative disorders. Intrastriatal injection of the excitotoxin, quinolinic acid, produces a pattern of neuronal death similar to that seen in Huntington's disease. However, little is known about the effects of quinolinic acid on striatal energetics. In the present work, time-dependent changes in energy metabolism caused by injection of quinolinic acid into rat striatum were examined. Oxygen consumption by free and synaptic mitochondria was quantified and correlated with the concentrations of nucleotides and amino acids at different times after injection. Compared with saline-treated controls, a decrease in ADP-stimulated (state 3) to basal (state 4) oxygen consumption (respiratory control ratio) by free mitochondria was apparent in quinolinic acid-injected striata as early as 6 h after treatment. No significant changes were seen in nucleotide concentrations at this time. By 12 h after injection, the decline in the respiratory control ratio was more pronounced (45%), and reductions in ATP, NAD, aspartate, and glutamate (30-60%) were also observed. These results show that injection of quinolinic acid in vivo produces progressive mitochondrial dysfunction, which may be a common and critical event in the cell death cascade initiated in Huntington's disease and in animal models of this neurodegenerative disorder. The indicators of mitochondrial function examined in this study, therefore, may be useful in evaluating the efficacy of neuroprotective agents.

Amino Acids↗
PubMed2006

Molecular basis of human Usher syndrome: deciphering the meshes of the Usher protein network provides insights into the pathomechanisms of the Usher disease.

Usher syndrome (USH) is the most frequent cause of combined deaf-blindness in man. It is clinically and genetically heterogeneous and at least 12 chromosomal loci are assigned to three clinical USH types, namely USH1A-G, USH2A-C, USH3A (Davenport, S.L.H., Omenn, G.S., 1977. The heterogeneity of Usher syndrome. Vth Int. Conf. Birth Defects, Montreal; Petit, C., 2001. Usher syndrome: from genetics to pathogenesis. Annu. Rev. Genomics Hum. Genet. 2, 271-297). Mutations in USH type 1 genes cause the most severe form of USH. In USH1 patients, congenital deafness is combined with a pre-pubertal onset of retinitis pigmentosa (RP) and severe vestibular dysfunctions. Those with USH2 have moderate to severe congenital hearing loss, non-vestibular dysfunction and a later onset of RP. USH3 is characterized by variable RP and vestibular dysfunction combined with progressive hearing loss. The gene products of eight identified USH genes belong to different protein classes and families. There are five known USH1 molecules: the molecular motor myosin VIIa (USH1B); the two cell-cell adhesion cadherin proteins, cadherin 23 (USH1D) and protocadherin 15, (USH1F) and the scaffold proteins, harmonin (USH1C) and SANS (USH1G). In addition, two USH2 genes and one USH3A gene have been identified. The two USH2 genes code for the transmembrane protein USH2A, also termed USH2A ("usherin") and the G-protein-coupled 7-transmembrane receptor VLGR1b (USH2C), respectively, whereas the USH3A gene encodes clarin-1, a member of the clarin family which exhibits 4-transmembrane domains. Molecular analysis of USH1 protein function revealed that all five USH1 proteins are integrated into a protein network via binding to PDZ domains in the USH1C protein harmonin. Furthermore, this scaffold function of harmonin is supported by the USH1G protein SANS. Recently, we have shown that the USH2 proteins USH2A and VLGR1b as well as the candidate for USH2B, the sodium bicarbonate co-transporter NBC3, are also integrated into this USH protein network. In the inner ear, these interactions are essential for the differentiation of hair cell stereocilia but may also participate in the mechano-electrical signal transduction and the synaptic function of maturated hair cells. In the retina, the co-expression of all USH1 and USH2 proteins at the synapse of photoreceptor cells indicates that they are organized in an USH protein network there. The identification of the USH protein network indicates a common pathophysiological pathway in USH. Dysfunction or absence of any of the molecules in the mutual "interactome" related to the USH disease may lead to disruption of the network causing senso-neuronal degeneration in the inner ear and the retina, the clinical symptoms of USH.

Adaptor Proteins, Signal Transducing↗