Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P50583 (asymmetrical)
 12,197 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fast excitatory synaptic responses in basolateral amygdala (BLA) neurons are mainly mediated by ionotropic glutamate receptors of the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) subtype. AMPA receptors containing an edited GluR2 subunit are calcium impermeable, whereas those that lack this subunit are calcium permeable and also inwardly rectifying. Here, we sought to determine the extent to which synapses in the rat BLA have AMPA receptors with GluR2 subunits. We assessed GluR2 protein expression in the BLA by immunocytochemistry with a GluR2 subunit-specific antiserum at the light and electron microscopic level; for comparison, a parallel examination was carried out in the hippocampus. We also recorded from amygdala brain slices to examine the voltage-dependent properties of AMPA receptor- mediated evoked synaptic currents in BLA principal neurons. At the light microscopic level, GluR2 immunoreactivity was localized to the perikarya and proximal dendrites of BLA neurons; dense labeling was also present over the pyramidal cell layer of hippocampal subfields CA1 and CA3. In electron micrographs from the BLA, most of the synapses were asymmetrical with pronounced postsynaptic densities (PSD). They contained clear, spherical vesicles apposed to the PSD and were predominantly onto spines (86%), indicating that they are mainly with BLA principal neurons. Only 11% of morphological synapses in the BLA were onto postsynaptic elements that showed GluR2 immunoreactivity, in contrast to hippocampal subfields CA1 and CA3 in which 76% and 71% of postsynaptic elements were labeled (p < 0.001). Synaptic staining in the BLA and hippocampus, when it occurred, was exclusively postsynaptic, and particularly heavy over the PSD. In whole-cell voltage clamp recordings, 72% of BLA principal neurons exhibited AMPA receptor-mediated synaptic currents evoked by external capsule stimulation that were inwardly rectifying. Although BLA principal neurons express perikaryal and proximal dendritic GluR2 immunoreactivity, few synapses onto these neurons express GluR2, and a preponderance of principal neurons have inwardly rectifying AMPA-mediated synaptic currents, suggesting that targeting of GluR2 to synapses is restricted. Many BLA synaptic AMPA receptors are likely to be calcium permeable and could play roles in synaptic plasticity, epileptogenesis and excitoxicity.
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PMID:Evidence for low GluR2 AMPA receptor subunit expression at synapses in the rat basolateral amygdala. 1604 45

Input-dependent left-right asymmetry of NMDA receptor epsilon2 (NR2B) subunit allocation was discovered in hippocampal Schaffer collateral (Sch) and commissural fiber pyramidal cell synapses (Kawakami et al., 2003). To investigate whether this asymmetrical epsilon2 allocation is also related to the types of the postsynaptic cells, we compared postembedding immunogold labeling for epsilon2 in left and right Sch synapses on pyramidal cells and interneurons. To facilitate the detection of epsilon2 density difference, we used epsilon1 (NR2A) knock-out (KO) mice, which have a simplified NMDA receptor subunit composition. The labeling density for epsilon2 but not zeta1 (NR1) and subtype 2/3 glutamate receptor (GluR2/3) in Sch-CA1 pyramidal cell synapses was significantly different between the left and right hippocampus with opposite directions in strata oriens and radiatum; the left to right ratio of epsilon2 labeling density was 1:1.50 in stratum oriens and 1.44:1 in stratum radiatum. No significant difference, however, was detected in CA1 stratum radiatum between the left and right Sch-GluR4-positive (mostly parvalbumin-positive) and Sch-GluR4-negative interneuron synapses. Consistent with the anatomical asymmetry, the amplitude ratio of NMDA EPSCs to non-NMDA EPSCs in pyramidal cells was approximately two times larger in right than left stratum radiatum and vice versa in stratum oriens of epsilon1 KO mice. Moreover, the amplitude of long-term potentiation in the Sch-CA1 synapses of left stratum radiatum was significantly larger than that in the right corresponding synapses. These results indicate that the asymmetry of epsilon2 distribution is target cell specific, resulting in the left-right difference in NMDA receptor content and plasticity in Sch-CA1 pyramidal cell synapses in epsilon1 KO mice.
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PMID:Target-cell-specific left-right asymmetry of NMDA receptor content in schaffer collateral synapses in epsilon1/NR2A knock-out mice. 1620 81

We report a sporadic tauopathy of 6-year duration in a 76-year-old woman. Her initial symptoms were asymmetrical parkinsonism and muscle weakness, with apraxia appearing 2 years later. The brain showed frontal and temporal cerebral atrophy; severe neuronal loss and gliosis were observed in the precentral cortex (loss of Betz cells was also evident) and premotor area, and in the medial temporal lobe, including the temporal tip, amygdala, and hippocampal CA1-subiculum border zone. The substantia nigra showed moderate neuronal loss and gliosis. In the spinal cord, loss of the anterior horn cells and degeneration of the corticospinal tracts were a characteristic feature. In addition, in the affected regions, the remaining neurons were often found to contain intracytoplasmic inclusions resembling neurofibrillary tangles. Tau immunostaining revealed widespread glial-predominant lesions in the cerebral gray and white matter. In contrast, predominance of neuronal lesions (pretangles/tangles) was a feature in the subcortical gray matter, including the spinal cord. The remaining upper and lower motor neurons were also affected by tau pathology. Accumulated tau in these glial cells and neurons was clearly recognized by a specific antibody against four-repeat (4R) tau. The ultrastructural presence of tau-positive tubular structures was confirmed in the glial cells and neurons (tangles). Immunoblotting of a frozen frontal lobe sample revealed accumulation of 4R-predominant tau isoforms. No mutations were found in the tau gene. These findings indicate that a sporadic 4R tauopathy can cause frontotemporal degeneration, parkinsonism, and motor neuron disease. The present case could represent a new clinicopathological phenotype of non-familial tauopathy.
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PMID:Sporadic four-repeat tauopathy with frontotemporal degeneration, parkinsonism and motor neuron disease. 1632 30

Transmembrane alpha-amino-3-hydroxyl-5-isoxazolepropionate (AMPA) receptor regulatory proteins (TARPs) play pivotal roles in AMPA receptor trafficking and gating. Here we examined cellular and subcellular distribution of TARP gamma-8 in the mouse brain. Immunoblot and immunofluorescence revealed the highest concentration of gamma-8 in the hippocampus. Immunogold electron microscopy demonstrated dense distribution of gamma-8 on the synaptic and extrasynaptic surface of hippocampal neurons with very low intracellular labeling. Of the neuronal surface, gamma-8 was distributed at the highest level on asymmetrical synapses of pyramidal cells and interneurons, whereas their symmetrical synapses selectively lacked immunogold labeling. Then, the role of gamma-8 in AMPA receptor expression was pursued in the hippocampus using mutant mice defective in the gamma-8 gene. In the mutant cornu ammonis (CA)1 region, synaptic and extrasynaptic AMPA receptors on dendrites and spines were severely reduced to 35-37% of control levels, whereas reduction was mild for extrasynaptic receptors on somata (74%) and no significant decrease was seen for intracellular receptors within spines. In the mutant CA3 region, synaptic AMPA receptors were reduced mildly at asymmetrical synapses in the stratum radiatum (67% of control level), and showed no significant decrease at mossy fiber-CA3 synapses. Therefore, gamma-8 is abundantly distributed on hippocampal excitatory synapses and extrasynaptic membranes, and plays an important role in increasing the number of synaptic and extrasynaptic AMPA receptors on dendrites and spines, particularly, in the CA1 region. Variable degrees of reduction further suggest that other TARPs may also mediate this function at different potencies depending on hippocampal subregions, input sources and neuronal compartments.
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PMID:Abundant distribution of TARP gamma-8 in synaptic and extrasynaptic surface of hippocampal neurons and its major role in AMPA receptor expression on spines and dendrites. 1707 43

Eph receptors and their ephrin ligands assume various roles during central nervous system development. Several of these proteins are also expressed in the mature brain, and notably in the hippocampus, where EphA4 and ephrins have been shown to influence dendritic spine morphology and long-term potentiation (LTP). To examine the cellular and subcellular localization of EphA4 in adult rat ventral hippocampus, we used light and electron microscopic immunocytochemistry with a specific polyclonal antibody against EphA4. After immunoperoxidase labeling, EphA4 immunoreactivity was found to be enriched in the neuropil layers of CA1, CA3, and dentate gyrus. In all examined layers of these regions, myelinated axons, small astrocytic leaflets, unmyelinated axons, dendritic spines, and axon terminals were immunolabeled in increasing order of frequency. Neuronal cell bodies and dendritic branches were immunonegative. EphA4-labeled dendritic spines and axon terminals corresponded to 9-19% and 25-40% of the total number of spines and axon terminals, respectively. Most labeled spines were innervated by unlabeled terminals, but synaptic contacts between two labeled elements were seen. The vast majority of synaptic junctions made by labeled elements was asymmetrical and displayed features of excitatory synapses. Immunogold labeling of EphA4 was located mostly on the plasma membrane of axons, dendritic spines, and axon terminals, supporting its availability for surface interactions with ephrins. The dual preferential labeling of EphA4 on pre- or postsynaptic specializations of excitatory synapses in adult rat hippocampus is consistent with roles for this receptor in synaptic plasticity and LTP.
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PMID:Localization of EphA4 in axon terminals and dendritic spines of adult rat hippocampus. 1729 51

Melatonin attenuates the short-term consequences of brain ischemia in several animal models. However, there is scant information regarding its efficacy for improving the long-term outcome. To further address that issue, we subjected gerbils to 5-min bilateral carotid occlusion. Some gerbils received acute peri-surgical administration of melatonin while others received continuous melatonin in their water. The gerbils' brains were histologically assessed at 20 wk postsurgery. Chronic but not acute melatonin attenuated ischemia-induced hyperactivity at 3 days postsurgery. Twenty weeks postsurgery, the ischemic gerbils showed varying degrees of bilateral loss of hippocampal CA1 pyramidal cells and elevation of glial fibrillary acidic protein immunoreactivity there. Both the cell loss and the immunoreactivity were markedly asymmetrical for some gerbils. Neither acute nor chronic melatonin altered this pattern of CA1 cell loss and glial immunoreactivity increase. Ischemia increased the number of CA1 cells that were immunoreactive for doublecortin (DCX), a marker for newborn neurons. This increase in CA1 DCX expression was not affected by either melatonin treatment. However, both acute and chronic melatonin reduced the number of DCX immunoreactive neurons in the dentate gyrus. Thus, neither acute nor chronic melatonin altered the long-term neural outcome of forebrain ischemia, although chronic administration seemed to attenuate the short-term behavioral effect. It is suggested that persistently high brain levels of melatonin may be essential for long-term neuroprotection against ischemia. The possibility that melatonin may modulate hippocampal neurogenesis merits further exploration both in normal animals and in models of brain insult.
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PMID:Chronic and acute melatonin effects in gerbil global forebrain ischemia: long-term neural and behavioral outcome. 1828 66

Spike timing dependent plasticity (STDP) has been demonstrated in various neural systems of many animals. It has been shown that STDP depends on the target and the location of the synapse and is dynamically regulated by the activity of adjacent synapses, the presence of postsynaptic calcium, presynaptic GABA inhibition or the action of neuromodulators. Recent experimental evidence has reported that the profile of STDP in the CA1 pyramidal neuron can be classified into two types depending on its dendritic location: (1) A symmetric STDP profile in the proximal to the soma dendrites, and (2) an asymmetric one in the distal dendrites. Bicuculline application revealed that GABA(A) is responsible for the symmetry of the STDP curve. We investigate via computer simulations how GABA(A) shapes the STDP profile in the CA1 pyramidal neuron dendrites when it is driven by excitatory spike pairs (doublets). The model constructed uses calcium as the postsynaptic signaling agent for STDP and is shown to be consistent with classical long-term potentiation (LTP) and long-term depression (LTD) induced by several doublet stimulation paradigms in the absence of inhibition. Overall, simulation results provide computational evidence for the first time that the switch between the symmetrical and the asymmetrical STDP operational modes is indeed due to GABA inhibition. Furthermore, gamma frequency inhibition and not theta one is responsible for the transition from asymmetry-to-symmetry. The resulted symmetrical STDP profile is centered at +10 ms with two distinct LTD tails at -10 and +40 ms. Finally, the asymmetry-to-symmetry transition is strongly dependent on the strength (conductance) of inhibition and its relative onset with respect to pre- and postsynaptic spike stimulation.
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PMID:GABA inhibition modulates NMDA-R mediated spike timing dependent plasticity (STDP) in a biophysical model. 2083 91

Left-right asymmetry of human brain function has been known for a century, although much of molecular and cellular basis of brain laterality remains to be elusive. Recent studies suggest that hippocampal CA3-CA1 excitatory synapses are asymmetrically arranged, however, the functional implication of the asymmetrical circuitry has not been studied at the behavioral level. In order to address the left-right asymmetry of hippocampal function in behaving mice, we analyzed the performance of "split-brain" mice in the Barnes maze. The "split-brain" mice received ventral hippocampal commissure and corpus callosum transection in addition to deprivation of visual input from one eye. In such mice, the hippocampus in the side of visual deprivation receives sensory-driven input. Better spatial task performance was achieved by the mice which were forced to use the right hippocampus than those which were forced to use the left hippocampus. In two-choice spatial maze, forced usage of left hippocampus resulted in a comparable performance to the right counterpart, suggesting that both hippocampal hemispheres are capable of conducting spatial learning. Therefore, the results obtained from the Barnes maze suggest that the usage of the right hippocampus improves the accuracy of spatial memory. Performance of non-spatial yet hippocampus-dependent tasks (e.g. fear conditioning) was not influenced by the laterality of the hippocampus.
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PMID:Right-hemispheric dominance of spatial memory in split-brain mice. 2106 82

Calmodulin (CaM) and neurogranin (Ng) are two abundant neuronal proteins in the forebrain whose interactions are implicated in the enhancement of synaptic plasticity. To gain further insight into the actions of these two proteins we investigated whether they co-localize in principle neurons and whether they respond to high frequency stimulation in a coordinated fashion. Immunohistochemical staining of CaM and Ng in mouse hippocampal slices revealed that CaM was highly concentrated in the nucleus of CA1 pyramidal neurons, whereas Ng was more broadly localized throughout the soma and dendrites. The asymmetrical localization of CaM in the nucleus of pyramidal neurons was in sharp contrast to the distribution observed in pyramidal cells of the neighboring subiculum, where CaM was uniformly localized throughout the soma and dendrites. The somatic concentrations of CaM and Ng in CA1 pyramidal neurons were approximately 10- and two-fold greater than observed in the dendrites, respectively. High frequency stimulation (HFS) of hippocampal slices promoted mobilization of CaM and Ng from soma to dendrites. These responses were spatially restricted to the area close to the site of stimulation and were inhibited by the N-methyl-D-asparate receptor antagonist 2-amino-5-phosphonopentanoic acid. Furthermore, HFS failed to promote translocation of CaM from soma to dendrites of slices from Ng knockout mice, which also exhibited deficits in HFS-induced long-term potentiation. Translocated CaM and Ng exhibited distinct puncta decorating the apical dendrites of pyramidal neurons and appeared to be concentrated in dendritic spines. These findings suggest that mobilization of CaM and Ng to stimulated dendritic spines may enhance synaptic efficacy by increasing and prolonging the Ca2+ transients and activation of Ca2+/CaM-dependent enzymes.
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PMID:Stimulation-mediated translocation of calmodulin and neurogranin from soma to dendrites of mouse hippocampal CA1 pyramidal neurons. 2125 30

Alzheimer's disease (AD) is a neurodegenerative pathology that deteriorates mnesic functions and associated brain regions including the hippocampus. Serotonin (5-HT) has an important role in cognition. We recently demonstrated an increase in 5-HT transporter (SERT) fibre density in the hippocampal CA1 in an AD triple transgenic mouse model (3xTg-AD). Here, we analyse the ultrastructural localisation, distribution and numerical density (N(v)) of hippocampal SERT axons (SERT-Ax) and terminals (SERT-Te) and their relationship with SERT fibre sprouting and altered synaptic N(v) in 3xTg-AD compared with non-transgenic control mice. 3xTg-AD animals showed a significant increase in SERT-Te N(v) in CA1 at both, 3 (95%) and 18 months of age (144%), being restricted to the CA1 stratum moleculare (S. Mol; 227% at 3 and 180% at 18 months). 3xTg-AD animals also exhibit reduced N(v) of perforated axospinous synapses (PS) in CA1 S. Mol (56% at 3 and 52% at 18 months). No changes were observed in the N(v) of symmetric and asymmetrical synapses or SERT-Ax. Our results suggest that concomitant SERT-Te N(v) increase and PS reduction in 3xTg-AD mice may act as a compensatory mechanism maintaining synaptic efficacy as a response to the AD cognitive impairment.
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PMID:Increased hippocampal CA1 density of serotonergic terminals in a triple transgenic mouse model of Alzheimer's disease: an ultrastructural study. 2191 44


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