Dysfunction of NMDA receptors in Alzheimer’s disease

“Following presynaptic neuronal depolarization, calcium channels open, permitting the influx of calcium and triggering the fusion of vesicles with the membrane, resulting in the exocytosis of glutamate into the synapse [15].”

“Tau reductions cannot transport Fyn to dendritic spines, prevent the memory deficits and excitability caused by A b [58].”

“…can also be taken up by the presynaptic terminal or astrocytes by their respective transporters Activation of synaptic NMDARs mediates synaptic plasticity and is thought to be beneficial for neurons, whereas prolonged activation of NMDARs with subsequent overload of Ca 2 ? entry is deleterious [32].”

“More-over, treatment of rat organotypic slices containing pyramidal neurons with A b oligomers decrease dendritic spine density and reduce NMDAR-mediated calcium influx into active spines [50].”

“When applied to cultured cortical neurons, Ab enhances endocytosis of NMDARs and decreases expression of NMDARs [53].”

“The increased influx of calcium transform into chemical signals which in turn, leading to the establishment of LTP, a process believed to underlie learning and memory [18].”

“Tau phosphorylation results in mislocalization of tau from axons to dendritic spines and decreased expression of AMPA receptors and LTP deficits, and subsequently synaptic impairment [56].”

“Phosphorylation of CREB at residue ser-133 is particularly important for its transcriptional activity, which is decreased in AD [36].”

“Besides, Ab is also reported to trigger NMDA-mediated Ca influx, excitotoxicity, and stress-related signaling pathways in neurons which may exacerbate aging-related increases in oxidative stress, impaired energy metabolism, and defective Ca homeostasis [2].”

“On the contrary, both synaptic and extrasynaptic NMDARs are necessary for LTD [31].”

“Activation of GluN2A and decrease in GluN2B subunit may be an attempt to reduce A b induced neuronal dysfunction [52].”

“Over-stimulation can let the synaptic regulation aberrant, leading to alterations in learning and memory, and more serious, neurodegeneration [21].”

“Moreover, A b -induced LTP impairment in AD can be ameliorated by decreasing extracellular glutamate levels and inhibition of p38MAPK or calpain, which are selectively activated by extrasynaptic NMDARs [47].”

“A b induces glutamate release from astrocytes, which in turn activates extrasy-naptic NMDARs on neurons and subsequent decrease in miniature excitatory postsynaptic currents (mEPSCs) which may reflect early synaptic injury [30].”

“…glutamate concentration, including increased stimulation intensities, knockout or inhibition of the glial glutamate transporter can impair LTP and this impairment can be prevented by NMDAR antagonists, suggesting that extrasynaptic NMDARs can obstruct activity-dependent plasticity [29].”

“CREB is the prototypical signal-regulated transcription factor, plays an essential role in the maintenance of LTP [34].”

“A b oligomers is reported to impair NMDARs-dependent LTP at hippocampal CA1 and dentate gyrus synapses [45].”

“So NR2 subunit of NMDARs affected may disturbance electrophysiological balance during development which results in variable neurological phenotypes [14].”

“The re-entrant M2 loop is part of the channel pore and it contains a critical asparagine residue that determines calcium permeability of the channel and mediates the magnesium blockade [4].”

“Within the hippocampus, CREB-mediated gene expression are associated with synaptic plasticity, learning and memory [35].”

“Besides, a portion of native NMDARs are triheteromers assembled by two NR1 and two different NR2 subunits [5].”

“While synaptic NMDARs activation induces ubiquitination and degradation of STEP61 which correlated with the phosphorylation of ERK1/2 [42].”

“However, the acute NMDA receptor-dependent tau phosphorylation is reversible whereas tau phosphorylation after 5 days of A b exposure is not [57].”

“Memantine, a drug that blocks NMDARs, is widely used in treating AD patients, although its mechanism is still in debate [20].”

“Early neuronal dysfunction induced by A b is mediated by an activation of NR2B-containing NMDAR in primary neuronal cultures and hippocampal slices from rat and mouse [49].”

“Calpain, activated by Ca 2 ? influx through NMDAR, degrades tau protein into a toxic N-terminal peptides which leading to cell death [59].”

“According to the latest new model, the function of extrasynaptic NMDARs is related to a variety of locations at different distances from the nearest synaptic active zones and arrangements characterized by close association with different kinds of adjacent processes [33].”

“Activation of NMDARs by A b accumulation may occur at early stages of the disease [44].”

“Moreover, in 3xTg-AD mice, memantine treatment ameliorates cognitive impairment and reduces A b accumulation and tau phosphorylation [63].”

“Alzheimer’s disease is the most common form of dementia and the most prevalent neurodegenerative disease characterized by cognitive disorder and memory dysfunction in the elderly population, affecting almost 40 million people worldwide [1].”

“On the other hand, nonphosphorylated Jacob is translocated after extrasynaptic NMDAR stimulation and is associated with decreased CREB activity, dendritic complexity, and synaptic density [39].”

“In addition, many extrasynaptic NMDARs concentrate at points of contact with adjacent processes including axons, axon terminals, or glia [27].”

“Perturbations in the glutamatergic tri-partite synapse may underlie the pathogenic mechanisms of AD [16].”

“Glutamate is cleared from the extracellular space via excitatory amino acid transporters 1/2 (EAAT1/2) by astrocytes and EAAT2/5 by the presynaptic terminal and then stored into vesicles [17].”

“And the inhibition of LTP induced by A b can be prevented by GluN2B-selective antagonist at low concentrations [46].”

“GluN1 mRNA levels are significantly lower in AD, moreover, GluN2A and GluN2B levels are decreased in susceptible regions of postmortem human AD brain, such as the hippocampus and the cortex [51].”

“Synaptic NMDARs activate ERK whereas the extrasynaptic NMDARs promote ERK inactivation [43].”

“Synapse-specific presynaptic NMDARs activation could provide an important mechanism for governing information processing in neocortical columns during high-frequency firing [25].”

“A number of studies suggest that extrasynaptic NMDARs function may depend on the receptor type as well as that of associated proteins [28].”

“Memantine unable to attenuate A b -induced potentiation of extracellular glutamate levels but protects neurons by attenuating tauphosphorylation [60].”

“NMDARs are the primary channel that mediates Ca 2 ? signals in hippocampal neurons and contribute to the expression of long-term potentiation (LTP) and long-term depression (LTD) and for synaptic plasticity [8].”

“…such as AD, Parkinson’s disease and schizophrenia and as a potent therapeutic tool in depression. rTMS enhance the LTP at hippocampal CA3-CA1 synapses and increase NR1 and NR2B expression resulting in improving spatial learning and memory abilities in the rat model of vascular dementia [67].”

“NR3A levels are low in embryonic day, increases rapidly after birth and declines gradually into adulthood [7].”

“The expression of glutamate transporters is reduced significantly both in human tissue from AD patients [54] and animal models of AD [55].”

“More-over, presynaptic NMDARs may play a role in mediating spontaneous transmitter release that can dynamically alter the synaptic efficacy at inhibitory synapses [26].”

“Dysfunction or reduced expression of GLT-1/EAAT-2 has been documented in both chronic and acute neurodegenerative disorders [22].”

“Synaptic NMDAR activity suppresses FOXO activity by promoting the Akt-mediated phosphorylation whereas extrasynaptic NMDAR activity stimulates FOXO nuclear import and leads to excitotoxic cell death [41].”

“, leading to mitochondrial functional impairments characterized by activation of the permeability transition pores in the inner mitochondrial membrane, cytochrome c release and depletion of ATP, and simultaneous formation of ROS [3].”

“A b decreases the phosphorylation of CREB through inactivation of PKA and thus inhibits LTP generation [37].”

“Low-frequency rTMS reverse the decreased NMDAR levels and deficits in LTP and spatial memory in A b induced AD mouse models [68]. rTMS treatment also improve the cognitive ability and language performance in AD patients suggesting that rTMS may be a effective therapeutic technique in the treatment…”

“Although the investigation into the role of tau in glutamate excitotoxicity is a relatively nascent field, tau play a role in mediating A b -induced neuronal death and can induce synaptic dysfunction independently [62].”

“In clinical trials, memantine has shown significant benefits in aspects of cognition such as language, memory, praxis, functional communication and in activities of daily living for AD patients [64].”

“Both NR2A and NR2B subunits are critical for the induction of LTP and LTD [9].”

“NR2B subunit is mildly expressed in the hippocampus and the temporal region of the cerebral cortex in fetal brain, becomes hardly expressed in adults [6].”

“…NMDAR levels and deficits in LTP and spatial memory in A b induced AD mouse models [68]. rTMS treatment also improve the cognitive ability and language performance in AD patients suggesting that rTMS may be a effective therapeutic technique in the treatment of neurodegenerative diseases [69].”

“Statistical indicate that multiple coding variants on the risk haplotype containing rs1806201 may play a role in mediating susceptibility to AD [10].”

“And the GRIN3A R480G variant showed strong association with schizophrenia [13].”

“GluN2A-contained NMDA receptor induces reduction of tau phosphorylation by a PKC/GSK3 pathway [61].”

“In interneuron–Purkinje cell synapse, the NMDA induce an increase in miniature inhibitory postsynaptic currents (mIPSCs) frequency suggesting the presynaptic NMDARs present on inhibitory axon terminals [24].”

“NMDARs are also located presynaptically where they mediate synaptic transmission and activity-dependent synaptic plasticity in developing neural circuits [23].”

“And also the frequency of Ht2-AG haplotype in GRIN3A gene is higher in AD patients indicates that GRIN3A variant may represent a risk in the development of AD [11].”

“People carrying insCGTT which is a genetic variation of the NMDAR NR3B subunit that inserts four bases within the coding region have a predisposition to schizotypal personality traits [12].”

“Neramexane, a non-competitive NMDAR antagonist, has shown to be efficient in enhancing long-term memory in adult rats as memantine, suggesting that this antagonist may have a potential therapeutic applications [ 65].”

“The relevance of NMDAR in AD lends support from studies showing that partial blockade of NMDAR overstimulation with NMDAR antagonists rescues Aβinduced LTP impairment and cognitive function in various animal models [69].”

“In case of hippocampus, TRPC6 and Orai2 were recently identified as SOCE-forming channels in hippocampal neurons (Zhang et al., 2016a).”