The NMDA Receptor is an ion channel which is activated by Glutamate. The NMDA Receptor is involved in the response of neurons to ischaemia. The NMDA Receptor is also involved in memory formation in a process referred to as Long Term Potentiation.
There is an interesting paper by Lai, Zhang and Wang on excitotoxicity and stroke. The authors look at the targets for neuroprotection following a stroke. Excitotoxicity is related to the NMDA Receptor. This in turn is relevant to the Brain Hypometabolism Hypothesis.
Lai, Zhang and Wang outline the role of Monosodium Glutamate in their paper. Monosodium Glutamate is a food additive. In a paper published in 1957, Lucas and Newhhouse reported the results of their study looking at the effects of Monosodium Glutamate (MSG) when applied to the mouse retina. The researchers found evidence of neurotoxicity. Further findings confirmed that Glutamate (MSG dissociates into Sodium and Glutamate in solution) is excitatory (i.e. increases the chance of a neuron firing).
In their paper Lai, Zhang and Wang reference a classic study by Olney and colleagues (Olney et al, 1974). This study involved Kainic acid which is an analogue of Glutamate. This paper generated the hypothesis that
‘excitotoxicity is “in essence, an exaggeration of the excitatory effect”’
Professor John Olney and colleagues conducted research in 1971 into the excitotoxic effects of Glutamate analogues (Olney et al, 1971). They found that analogues which were excitatory were excitotoxic and those which were not excitatory were not excitotoxic. Contextualising this – the effects of Glutamate are mediated via the NMDA Receptor and excitotoxicity is a pathological process which can result from reduced energy metabolism. This in turn is relevant to the Brain Hypometabolism Hypothesis.
In their paper Lai, Zhang and Wang write that although excitotoxicity was initially investigated in relation to the properties of Monosodium Glutamate it plays an important role in brain trauma and a number of neurodegenerative conditions including
- Huntington’s Disease
- Alzheimer’s Disease
- Amyotrophic Lateral Sclerosis
In their paper Lai, Zhang and Wang cite research by Berdichevsky and colleagues (Berdichevsky et al, 1983) identifying the N-Methyl-DL-Aspartate receptor as the most potent inducer of excitoxocity and facilitator of Calcium influx. This leads to the following hypothesis.
The N-Methyl-DL-Aspartate receptor (NMDA Receptor) is a potent inducer of excitotoxicity and Calcium influx. The NMDA Receptor mediates Glutamate induced excitotoxicity.
Lai, Zhang and Wang discuss the regulation of Calcium. They refer to the Sodium-Calcium Exchanger as an important regulatory of Calcium influx into the neuron. This is turn is relevant to Excitotoxicity. NCX removes Calcium from the cell in exchange for Sodium entering the cell. The authors state cite evidence that shows NMDA receptor mediated dysfunction in NCX and that Glutamate induced Calcium influx is associated with a reversal of the action of NCX.
Lai, Zhang and Wang discuss the regulation of Calcium by the Sodium Calcium Exchanger (NCX). They reference a study (Bano et al, 2005) in which it was demonstrated that substituting an NCX isoform that was not influenced by the NMDA receptor avoided subsequent excitotoxicity. This reinforced the importance of the NMDA receptor for excitoxicity.
Lai, Zhang and Wang provide evidence that the Mitochondria play a key role in Calcium homeostasis.
Calcium plays a role in NMDA Receptor mediated excitotoxicity. This in turn is relevant to the Brain Hypometabolism Hypothesis as hypometabolism can lead to excitotoxicity.
‘Glutamate induces Calcium influx in excitoxicity.
The Mitochondria incorporate Calcium ions resulting from the Calcium influx.
The Mitochondria produce reactive Oxygen species‘
Lai, Zhang and Wang examine the effects of Glutamate induced excitotoxicity on the Mitochondria. They cite research evidence that the Calcium influx leads to the permeability transition pore opening and a subsequent depolarisation of the Mitochondrial membrane.
‘Glutamate induced excitoxicity leads to Calcium influx into the neuron.
This leads to Calcium influx into the Mitochondria.
This leads to opening of the permeability transition pore.
This leads to depolarisation of the Mitochondrial membrane’
Lai, Zhang and Wang examine the effects of Glutamate induced excitotoxicity on the Mitochondria. They cite research by (Stout et al, 1998) providing evidence that the Mitochondria mediates neuronal cell death.
Lai, Zhang and Wang examine the effects of Glutamate induced excitotoxicity on the Mitochondria. They cite research which identifies the Mitochondrial Calcium Uniporter as necessary for excitotoxic cell death. The sequence of events can be summarised as
‘Mitochondrial Calcium Uniporter imports Calcium into the Mitochondria in response to Glutamate.
This leads to Mitochondrial depolarisation.
This leads to Excitotoxic cell death‘
Lai, Zhang and Wang examine the effects of Glutamate induced excitotoxicity on the Mitochondria. They cite research (Qiu et al, 2013) showing that Mitochondrial Calcium Uniporter overexpression leads to an increase in Calcium influx into Mitochondria and an increase neuronal injury.
Lai, Zhang and Wang examine the effects of Glutamate induced excitotoxicity on the Mitochondria. They note that there are separate Calcium pathways. Some pathways are neurotoxic and others play a role in the protection of neurons.
Lai, Zhang and Wang examine the effects of Glutamate induced excitotoxicity on the Mitochondria. The authors reference a set-point hypothesis which states that there is an optimum intracellular Calcium range. Outside of this range there is an increased risk of neuronal toxicity. It is useful to note that extracellular Calcium is maintained within a narrow range as a result of Calcium homeostasis. The authors also suggest that there are subpopulations of NMDA receptors which determine the effects of the Calcium influx into the cell.
Lai, Zhang and Wang examine the effects of Glutamate induced excitotoxicity on the Mitochondria. As per the previous posts, the authors have noted that there is a set-point hypothesis which effectively states that NMDA receptor mediated Calcium influx into the cell is associated either with excitotoxicity or else the promotion of neuronal survival. The authors cite studies on Cerebellar Granule cells which show that low levels of NMDA stimulation of NMDA receptors promotes neuronal survival in contrast with high levels of NMDA stimulation which leads to excitotoxicity.
In the section on neuronal survival and synaptic NMDA receptors, the authors cite research evidence of environmental stimulation reducing excitotoxic injury. The key reference they cite is (Young et al, 1999).
What is interesting to note is that the NMDA receptor is involved in both long term potentiation (memory formation) and excitotoxic injury. The authors hypothesise that these pathways are mediated by different receptor subpopulations. More specifically they suggest the hypotheses that
- Synaptic NMDA receptors mediate neuronal survival
- Extrasynaptic NMDA receptors mediate excitotoxic injury
In their paper, they suggest that extrasynpatic NMDA receptors are stimulated when there is an excess of Glutamate resulting from causes such as ischaemia.
Lei et al cite a number of studies which demonstrate a difference between synaptic and extra-synaptic NMDA receptors dating back to 2001 (Lu et al, 2001).
With reference to the synaptic NMDA receptor they note that this mediates
- The activity of the Extracellular Signal Regulated Kinase (ERK)
- An increase in Calcium in the nucleus which leads to the activation of CREB (a transcription factor) and BDNF production
They note that extrasynaptic NMDA receptor activation
- Reduces Extracellular Signal-Related Kinase (ERK) activity
- Decreases CREB production
- Decreases BDNF production
The authors distinguish between synaptic and extra-synaptic NMDA receptors. The authors note that a global activation of NMDA receptors can lead to excitoxicity and that this can be inhibited by inhibiting the activation of NMDA receptors containing the N2B subunit (which occur extrasynaptically) (Hardingham et al, 2002).
Lai et al have outlined a broad division between synaptic and extra-synaptic NMDA receptors. They describe
- Synaptic NMDA receptors are pro-survival (of neurons)
- Extra-Synaptic NMDA receptors are excitotoxic
They also provide evidence that this division is not so straightforward. There are several lines of evidence that suggest that there is overlap in the NMDA receptor functions across locations.
Thus for example they note that synaptic NMDA-receptor induced Glutamate release is associated with primary hippocampal neuronal death secondary to hypoxic ischaemia and cite (Rothman, 1983 and 1984).
They identify several subunits of the NMDA Receptor
- GluN1: Found in multiple locations in the Brain
- GluN2A: Located in the Forebrain and Cerebellum
- GluN2B: Located in the Forebrain
- GluN2C: Located in the Cerebellum
They note that two NMDA Receptor subunits – GLU2NA and GLU2NB interact with proteins involved in synaptic plasticity – in Long Term Depression (LTD) and Long Term Potentiation (LTP).
They discuss the NMDA Receptor Glu2NBR and Glu2NAR subunits
They cite evidence to suggest that NMDA Receptor GLU2NBR antagonists are neuroprotective and the opposite may be the case for GLU2NAR antagonists.
They note that the C-Terminus of the NMDA receptor subunits Glu2NA and Glu2NB mediates function and swapping the C-Terminus between the subunits changes the functional properties.
The authors cite an important study by Harreveld which identifies a role for Glutamate and led to the suggestion that Glutamate mediates stroke related brain injury (Harreveled, 1959). This study provided evidence that an extract from the Pallium induced Cortical depression and muscle contraction.
The authors cite evidence that excitotoxicity is mediated via the synaptic Glutamate receptor
- Cultured Hippocampal neurons without synapses can remain unaffected for up to 24 hours in comparison with Hippocampal neurons with synaptic connections.
- Increased intracerebral Glutamate and Aspartate levels have been identified following ischaemia.
- The findings in 2. are reduced by a reduction in afferent glutaminergic neurons.
- There is experimental evidence from AP7 studies
The authors cite a number of studies dating back to (Benviste et al, 1984) which provide evidence for an elevation of Glutamate following Stroke. The authors suggest that this rapid increase in Glutamate is the initial step that leads to excitotoxicity.
The authors note that the NMDA receptor activates the protein kinase Akt. This is done via two mechanisms
(1) Phosphorylation of Insulin Receptor Substrate-1
(2) Activation of Akt via the protein kinase CaM-KK
The authors note that there is activation of Akt via Protein Kinase CaM-KK as one of two mechanisms for the activation of Akt.
The authors note that the activation of calcium–calmodulin dependent protein kinase kinase (CaM-KK) is independent of PI3K which is involved in the other pathway.
The authors note that there is activation of Akt via PI3K is one of two mechanisms for the activation of Akt.
The authors note that NMDA receptor activation leads to calcium dependent Tyrosine phosphorylation of Insulin Receptor Substrate-1 which in turn binds and activates PI3K (phosphatidylinositol 3-kinase) which in turn leads to the activation of Akt.
The authors note the actions of Phosphatase and Tensin Homolog (PTEN) as involved in NMDA receptor mediated death signalling and can be mutated in many types of cancer cells.
The authors outline a number of properties of Phosphatase and Tensin Homolog (PTEN).
- PTEN interacts with the GluN1 subunit of GLU2NBR
- PTEN doesn’t interact with the GluN1 subunit of GLU2NAR (which is implicated in neuronal survival pathways).
- The lipid phosphatase activity inhibits the Akt activation pathway
- The protein phosphatase activity potentiates the NMDA receptor mediated current extrasynaptically
The authors note that the NMDA receptor can cause nuclear translocation of PTEN via the GluN2B subunit. In nuclear translocation, Cytoplasmic proteins are transported into the nucleus where they can modify cell function. The authors also note that GluN2A impairs nuclear translocation.
They note that another PIK3 product – PtdIns(3,4)P2(Phosphatidylinositol 3,4-bisphosphate) potentiates excitotoxicity via the NMDA receptor. PtdIns(3,4)P2 is a phospholipid and secondary messenger in the cell.
D.R. Lucas, J.P. Newhouse. The toxic effect of sodium l-glutamate on the inner layers of the retina. AMA Arch. Ophthalmol., 58 (1957), pp. 193–201
S. Rothman. Synaptic release of excitatory amino acid neurotransmitter mediates anoxic neuronal death
J. Neurosci., 4 (1984), pp. 1884-1891
S.M. Rothman. Synaptic activity mediates death of hypoxic neurons
Science, 220 (1983), pp. 536-537
A.K. Stout, H.M. Raphael, B.I. Kanterewicz, E. Klann, I.J. Reynolds. Glutamate-induced neuron death requires mitochondrial calcium uptake. Nat. Neurosci., 1 (1998), pp. 366–373
A. Van Harreveld. Compounds in brain extracts causing spreading depression of cerebral cortical activity and contraction of crustacean muscle. J. Neurochem., 3 (1959), pp. 300-315.
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