Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Amyloid-beta peptide is elevated in the brains of patients with Alzheimer disease and is believed to be causative in the disease process. Amyloid-beta reduces glutamatergic transmission and inhibits synaptic plasticity, although the underlying mechanisms are unknown. We found that application of amyloid-beta promoted endocytosis of NMDA receptors in cortical neurons. In addition, neurons from a genetic mouse model of Alzheimer disease expressed reduced amounts of surface NMDA receptors. Reducing amyloid-beta by treating neurons with a gamma-secretase inhibitor restored surface expression of NMDA receptors. Consistent with these data, amyloid-beta application produced a rapid and persistent depression of NMDA-evoked currents in cortical neurons. Amyloid-beta-dependent endocytosis of NMDA receptors required the alpha-7 nicotinic receptor, protein phosphatase 2B (PP2B) and the tyrosine phosphatase STEP. Dephosphorylation of the NMDA receptor subunit NR2B at Tyr1472 correlated with receptor endocytosis. These data indicate a new mechanism by which amyloid-beta can cause synaptic dysfunction and contribute to Alzheimer disease pathology.
 ...
PMID:Regulation of NMDA receptor trafficking by amyloid-beta. 1604 22

NMDA receptor (NMDAR) 2A (NR2A)- and NR2B-type NMDARs coexist in synapses of CA1 pyramidal cells. Recent studies using pharmacological blockade of NMDAR subtypes proposed that the NR2A type is responsible for inducing long-term potentiation (LTP), whereas the NR2B type induces long-term depression (LTD). This contrasts with the finding in genetically modified mice that NR2B-type NMDARs induce LTP when NR2A signaling is absent or impaired, although compensatory mechanisms might have contributed to this result. We therefore assessed the contribution of the two NMDAR subtypes to LTP in mouse hippocampal slices by different induction protocols and in the presence of NMDAR antagonists, including the NR2A-type blocker NVP-AAM077, for which an optimal concentration for subtype selectivity was determined on recombinant and native NMDARs. Partial blockade of NMDA EPSCs by 40%, either by preferentially antagonizing NR2A- or NR2B-type NMDARs or by the nonselective antagonist D-AP-5, did not impair LTP, demonstrating that hippocampal LTP induction can be generated by either NMDAR subtype.
 ...
PMID:Lack of NMDA receptor subtype selectivity for hippocampal long-term potentiation. 1603

The anterior cingulate cortex (ACC) is thought to be important for the establishment, consolidation and retrieval of permanent memory. In many brain regions, including the hippocampus, it is suggested that long-term potentiation (LTP) and long-term depression (LTD), the cellular mechanisms for learning and memory, require the activation of glutamate N-methyl-D-aspartate receptors (NMDARs). In the hippocampus, the NR2A subunit is believed to be involved in the induction of LTP, whereas the NR2B subunit contributes to the formation of LTD. However, LTD has been less well studied in the ACC as compared with the hippocampus and little is known about the role of NMDA subtype receptors in cingulate LTD. Here we show that LTD can be induced by the combination of presynaptic stimulation with postsynaptic depolarization ('pairing training') in adult mouse ACC neurons. This form of LTD is an NMDAR- and voltage-dependent mechanism and a postsynaptic Ca2+ increase is required for the induction of LTD. Furthermore, our studies provide direct physiological evidence that both NR2A and NR2B subunits are involved in the induction of LTD in the ACC.
 ...
PMID:Roles of NMDA receptor NR2A and NR2B subtypes for long-term depression in the anterior cingulate cortex. 1604 1

Rett syndrome is an X-linked neurodevelopmental disorder caused by mutations in the gene encoding the transcriptional repressor methyl-CpG-binding protein 2 (MeCP2). Here we demonstrate that the Mecp2-null mouse model of Rett syndrome shows an age-dependent impairment in hippocampal CA1 long-term potentiation induced by tetanic or theta-burst stimulation. Long-term depression induced by repetitive low-frequency stimulation is also absent in behaviorally symptomatic Mecp2-null mice. Immunoblot analyses from behaviorally symptomatic Mecp2-null mice reveal altered expression of N-methyl-d-aspartate receptor subunits NR2A and NR2B. Presynaptic function is also affected, as demonstrated by a significant reduction in paired-pulse facilitation. Interestingly, the properties of basal neurotransmission are normal in the Mecp2-null mice, consistent with our observations that the levels of expression of synaptic and cytoskeletal proteins, including glutamate receptor subunits GluR1 and GluR2, PSD95, synaptophysin-1, synaptobrevin-2, synaptotagmin-1, MAP2, betaIII-tubulin and NF200, are not significantly altered. Together, these data provide the first evidence that the loss of Mecp2 expression is accompanied by age-dependent alterations in excitatory synaptic plasticity that are likely to contribute to the cognitive and functional deficits underlying Rett syndrome.
 ...
PMID:Hippocampal synaptic plasticity is impaired in the Mecp2-null mouse model of Rett syndrome. 1608 43

Activation of NMDA receptors (NMDARs) within the CNS represents a major signal for persistent alterations in glutamatergic signaling, such as long-term potentiation (LTP) and long-term depression. NMDARs are composed of a combination of NR1 and NR2 subunits, with distinct NR2 subunits imparting distinct characteristics on the receptor. One particular NR2 subunit, NR2A (NRepsilon1), has been proposed to play an integral role in LTP induction in the hippocampus and cortex. Here, we report studies investigating the role of NR2A in LTP induction in the dorsolateral bed nucleus of the stria terminalis (dlBNST). The putative NR2A-specific inhibitor NVP-AAM077 (AAM077) has been used previously to demonstrate the dependence of cortical and hippocampal LTP on NMDARs containing NR2A subunits. We report here the same sensitivity of LTP to pretreatment with AAM077 (0.4 microm) in the dlBNST. However, inconsistent with the conclusion that LTP in the dlBNST is NR2A dependent, we see intact LTP in the dlBNST of NR2A knock-out mice. Because we also see blockade of this dlBNST LTP in NR2A knock-out mice after pretreatment with AAM077, we conclude that the antagonist is targeting non-NR2A subunit-containing receptors. Using a variety of cultured cell types, we find that AAM077 (0.4 microm) can attenuate transmission of NR2B subunit-containing NMDARs when preapplied rather than coapplied with an agonist. Therefore, we conclude that NR2A is not obligatory for the induction of LTP in the dlBNST. Furthermore, our data demonstrate that care must be exercised in the interpretation of data generated with AAM077 when the compound is applied before an agonist.
 ...
PMID:Activation of NR2A-containing NMDA receptors is not obligatory for NMDA receptor-dependent long-term potentiation. 1616 20

N-methyl-D-aspartate receptors (NMDARs) act as molecular coincidence detectors and allow for association or dissociation between pre- and postsynaptic neurons. NMDA receptors are central to remodeling of synaptic connections during postnatal development and associative learning abilities in adults. The ability to remodel neural networks is altered during postnatal development, possibly due to a change in the composition of NMDARs. That is, as forebrain systems (and cerebellum) develop, synaptic NR2B-containing NMDARs (NR2B-NMDARs) are replaced by NR2A-containing NMDARs (NR2A-NMDARs) and NR2B-NMDARs move to extrasynaptic sites. During the initial phase of the switch, synapses contain both NR2A- and NR2B-NMDARs and both long-term potentiation and long-term depression are enhanced. As NMDAR subunit expression decreases and NR2A-NMDARs come to predominate in the synapse, channel function and synaptic plasticity are reduced, and remodeling ability dissipates. The end result is a balance of plasticity and stability that is optimal for information processing and storage. Associative learning abilities involving different sensory modalities emerge sequentially, in accordance with synaptic maturation in related cortical and underlying brain structures. Thus, developmental alterations in NMDAR composition that occur at different ages in various brain structures may explain the protracted nature of the maturation of various associative learning abilities.
 ...
PMID:Developmental regulation of cognitive abilities: modified composition of a molecular switch turns on associative learning. 1618 26

To determine potential mechanisms contributing to ethanol-induced cognitive impairment, we examined acute effects of ethanol on hippocampal N-methyl-d-aspartate receptors and forms of synaptic plasticity thought to underlie memory processing. In the CA1 region of rat hippocampal slices, ethanol partially inhibited N-methyl-d-aspartate receptor-mediated synaptic responses at concentrations up to 180 mM. The block of synaptic N-methyl-d-aspartate receptors by 60mM ethanol occluded the effects of 10 microM ifenprodil, an agent that has relative selectivity for N-methyl-D-aspartate receptors expressing NR1 and NR2B subunits. Ethanol did not occlude the effects of a low concentration of 2-amino-5-phosphonovalerate, an antagonist with less N-methyl-d-aspartate receptor subtype selectivity. Recent studies indicate that ifenprodil and other NR2B-selective antagonists inhibit N-methyl-D-aspartate receptor-dependent long-term depression but not long-term potentiation. We found that ethanol reversibly inhibited long-term depression in a manner consistent with its effects on synaptic N-methyl-D-aspartate receptors. Ethanol also inhibited the induction of N-methyl-D-aspartate receptor-dependent long-term potentiation, but the actions on long-term potentiation were complex and largely irreversible over the time course of our experiments. Furthermore, ethanol inhibited a form of long-term potentiation induced by very high frequency stimulation that does not depend on N-methyl-D-aspartate receptor activation. The effects of ethanol on both forms of long-term potentiation, but not on long-term depression, were at least partially reversed by block of GABA type A receptors with picrotoxin. These results indicate that pharmacologically relevant concentrations of ethanol exert preferential effects on a subtype of synaptic N-methyl-D-aspartate receptors in the CA1 hippocampal region. Inhibition of synaptic N-methyl-D-aspartate receptors appears to contribute strongly to ethanol-mediated long-term depression inhibition, but effects on long-term potentiation are complex, involving, at least partially, changes in GABAergic transmission.
 ...
PMID:Acute effects of ethanol on hippocampal long-term potentiation and long-term depression are mediated by different mechanisms. 1621 26

In the auditory cortex, the properties of NMDA receptors depend primarily on the ratio of NR2A and NR2B subunits. NR2B subunit expression is high at the beginning of critical period and lower in adulthood. Because NMDA receptors are crucial in triggering long-term potentiation (LTP) and long-term depression, developmental or experience-dependent modification of NMDAR subunit composition is likely to influence synaptic plasticity. To examine how NMDA subunit change during postnatal development affect the adult synaptic plasticity, we employed chronic ifenprodil blockade of NR2B subunits and analyzed evoked field potentials in adult C57BL/6 mice auditory cortex (AC). We found that chronic loss of NR2B activity led to a decline in LTP magnitude in the AC of adult mice. Adding NMDA to the artificial cerebrospinal fluid (ACSF) in blocked mice had the opposite effect, producing LTP magnitudes at or exceeding those found in treated or untreated animals. These results suggest that, even in adulthood when NR2B expression is downregulated, these receptor subunits play an important role in experience-dependent plasticity of mouse auditory cortex. Blockade from P60 did not result in any decrease of LTP amplitude, suggesting that chronic block in postnatal period may permanently affect cortical circuits so that they cannot produce significant LTP in adulthood.
 ...
PMID:Early chronic blockade of NR2B subunits and transient activation of NMDA receptors modulate LTP in mouse auditory cortex. 1645 85

NMDA-type glutamate receptors (NMDARs) contribute to many forms of long-term potentiation (LTP) and long-term depression (LTD). NMDARs are heteromers containing calcium-permeating neuronal receptor 1 (NR1) subunits and a variety of NR2 subunits. Evidence suggests that, in the CA1 region of the hippocampus, NR2A-containing NMDARs promote LTP whereas NR2B-containing receptors promote LTD. However, the calcium sensors that distinguish between these signals to promote the appropriate form of synaptic plasticity are not known. Ras-guanine nucleotide-releasing factor 1 (Ras-GRF1) and Ras-GRF2 are highly similar calcium-stimulated exchange factors that activate Ras and Rac GTPases. Here, using a set of Ras-GRF knock-out mice, we show that Ras-GRF2 contributes predominantly to the induction of NMDAR-dependent LTP, whereas Ras-GRF1 contributes predominantly to the induction of NMDAR-dependent LTD in the CA1 region of the hippocampus of postpubescent mice (postnatal days 25-36). In contrast, neither Ras-GRF protein influences synaptic plasticity in prepubescent mice (postnatal days 14-18). Ras-GRF2 mediates signaling from (R)-[(S)-1-(4-bromo-phenyl)-ethylamino]-(2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl)-methyl-phosphonic acid-sensitive (NVP-AAM077-sensitive) (NR2A-containing) NMDARs to the Ras effector extracellular signal-related protein kinase 1/2 (Erk1/2) mitogen-activated protein (MAP) kinase, a promoter of NMDAR-induced LTP at this site. In contrast, Ras-GRF1 mediates signaling from ifenprodil-sensitive (NR2B-containing) NMDARs to the Rac effector p38 MAP kinase, a promoter of LTD. These findings show that, despite their similar functional domain organization, Ras-GRF1 and Ras-GRF2 mediate opposing forms of synaptic plasticity by coupling different classes of NMDARs to distinct MAP kinase pathways. Moreover, the postnatal appearance of Ras-GRF-dependent LTP and LTD coincides with the emergence of hippocampal-dependent behavior, implying that Ras-GRF proteins contribute to forms of synaptic plasticity that are required specifically for mature hippocampal function.
 ...
PMID:Distinct roles for Ras-guanine nucleotide-releasing factor 1 (Ras-GRF1) and Ras-GRF2 in the induction of long-term potentiation and long-term depression. 1646 20

To investigate the involvement of different types of glutamate receptors in recognition memory, selective antagonists of NMDA and kainate receptors were locally infused into the perirhinal cortex of the rat temporal lobe. Such infusion of a selective kainate receptor antagonist produced an unusual pattern of recognition memory impairment: amnesia after a short (20 min) but not a long (24 h) delay. In contrast, antagonism of perirhinal NMDA glutamate receptors by locally infused AP-5 (2-amino-5-phosphonopentanoic acid) impaired recognition memory after the long but not the short delay. For both drugs, impairment was found when the drug was present during acquisition but not when it was present during retrieval. Experiments in vitro indicate that selective antagonism of NMDA receptors containing NR2A subunits blocks perirhinal long-term potentiation (LTP), whereas antagonism of NMDA receptors containing NR2B subunits blocks long-term depression (LTD). However, recognition memory after a 24 h delay was impaired only when both an NR2A and an NR2B antagonist were infused together, not when either was infused separately. These results establish that kainate receptors have a role in recognition memory that is distinct from that of NMDA receptors, that there must be at least two independent underlying memory mechanisms in the infused region, that this region and no other is necessary for both short-term and long-term familiarity discrimination, and that perirhinal-dependent long-term recognition memory does not rely solely on processes used in NMDA-dependent LTP or LTD (although it might be independently supported by components of each type of process with one substituting for the other).
 ...
PMID:The different effects on recognition memory of perirhinal kainate and NMDA glutamate receptor antagonism: implications for underlying plasticity mechanisms. 1657 64


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>