[Dissassociatves] NMDA Receptor Function, Memory and Brain Aging

[Chip (OP)]

source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3181613/

Whilst reveiwing how I think memory works (all action sequences or learned behaviour (you don't tend to absorb much when inactive) and stored in lipids such as the brain's fatty tissue), I wondered what may be the key" for coding and accessing *relevant* memories & non-coding then also and discovered the NMDA receptor as a likely candidate.

Anybody familiar with Ketamine or PCP will have an understanding of dissociatives and would "feel" the action of, the N-Methyl-D-aspartate receptor (NMDAR). They are commonly used as anesthetics for animals and humans; the state of anesthesia they induce is referred to as dissociative anesthesia. Druggies can ride this threshold and have fun on there (sub-coma doses can be handy niteclub tools .

I also expect the ion channels (without doubt), genetics, mood, Cortisol and hormones, GABA, Dopamine, Seratonin and Endorphins etc. to be also be significant players of this (think benzo/alcohol/opiod/opiod/accident blackout (OD)) and hold the "keys" to memory functions.

NMDA receptor^Wiki function, memory, and brain aging

Exceprts:

Abstract

An increasing level of N-methyl-D-aspartate (NMDA) receptor hypofunction within the brain is associated with memory and learning impairments, with psychosis, and ultimately with excitotoxic brain injury. As the brain ages, the NMDA receptor system becomes progressively hypofunctional, contributing to decreases in memory and learning performance.

In those individuals destined to develop Alzheimer's disease, other abnormalities (eg, amyloidopathy and oxidative stress) interact to increase the NMDA receptor hypofunction (NRHypo) burden. In these vulnerable individuals, the brain then enters into a severe and persistent NRHypo state, which can lead to widespread neurodegeneration with accompanying mental symptoms and further cognitive deterioration.

If the hypotheses described herein prove correct, treatment implications may be considerable. Pharmacological methods for preventing the overstimulation of vulnerable corticolimbic pyramidal neurons developed in an animal model may be applicable to the prevention and treatment of Alzheimer's disease.

The amino acid glutamate (Glu) plays a central role in both the normal and abnormal functioning of the central nervous system (CNS). Glu is recognized to be the main excitatory neurotransmitter in the CNS, estimated to be released at. up to half of the synapses in the brain.

In addition, Glu is also an excitotoxin that can destroy CNS neurons by excessive activation of excitatory receptors on dendritic and somal surfaces. Two major classes of Glu receptors, ionotropic and metabotropic, have been identified. Glu exerts excitotoxic activity through three receptor subtypes, which belong to the ionotropic family.

These three receptors are named after agonists to which they are differentially sensitive, Ar-methyl-D-aspartate (NMDA), amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), and kainic acid (KA). Of these three, the NMDA receptor has been the most extensively studied and the most frequently implicated in CNS diseases.1

Excessive activation of NMDA receptors (NMDA receptor hyperfunction [NRHyper]) plays an important role in the pathophysiology of acute CNS injury syndromes such as hypoxia-ischemia, trauma, and status epilepticus.

Recently, hyperstimulation of AMPA/KA receptors and consequent excitotoxicity has been proposed to underlie neurodegeneration in amyotrophic lateral sclerosis (ALS, Lou Gerhig's Disease). The role of Glu excitotoxicity in the pathology of several other neuropsychiatrie disorders has been extensively reviewed elsewhere and will not be the focus of this paper. Instead, we will focus on the consequences of underexcitation of NMDA receptors (NMDA receptor hypofunction [NRHypo]).

Edit: Excitotoxicity^Wiki occurs when a person wakes up from a GHB nod (but as the GABA variant).

Progressive increases in the severity of NRHypo within the brain, which can be induced experimentally in vivo using NMDA receptor antagonist drugs, can produce a range of clinically relevant effects on brain function, which are discussed below. In brief, underexcitation of NMDA receptors, induced by even relatively low doses of NMDA antagonist drugs, can produce specific forms of memory dysfunction.

More severe NRHypo can produce a clinical syndrome that includes core features of psychosis. Finally, sustained and severe underexcitation of NMDA receptors in the adult brain is associated with a recently discovered and unconventional form of neurotoxicity, with well-characterized neuropathological features. Neuropathological changes that can be associated with sustained NRHypo include the disruption of neuronal cytoskeletons resulting in structures resembling neurofibrillary tangles (NFTs). These NRHypo-induced structures can occur in multiple brain regions, resembling the distribution of NFTs in Alzheimer's disease (AD).

Differences in when NRHypo or an equivalent state is instilled in the brain (eg, early in brain development versus during older adulthood), and differences in the cause of the NRHypo state, can lead to differences in clinical and neuropathological presentations, as discussed in detail elsewhere.

In the following sections, we will describe the role of NMDA receptor function in memory, the effect of NMDA receptor blockade on the expression of psychosis, and the type of neuronal damage produced by severe and sustained hypoactivation of the NMDA receptor.

We will then discuss the complex neural circuitry that, is postulated to be perturbed as a consequence of NRHypo and to underlie the expression of some of the neuropathological and clinical features associated with NRHypo. Next, we will discuss the evidence for decreasing NMDA receptor function in aging, and the role that this may play in the expression of agerelated memory decline. Finally, we describe how agerelated decreases in NMDA receptor activity may also interact with disease-related mechanisms to contribute to the expression of psychosis and to certain neuropathological features in patients with AD.


NMDA glutamate receptors and memory

Hippocampal long-term potentiation

NMDA receptors are now understood to critically regulate a physiologic substrate for memory function in the brain. In brief, the activation of postsynaptic NMDA receptors in most hippocampal pathways controls the induction of an activity-dependent synaptic modification called long-term potentiation (FTP).

The NMDA receptor has been conceptualized as a synaptic coincidence detector that can provide graded control of memory formation. LTP (Lond Term Potentiation) and other forms of activity dependent synaptic modification share important properties with memory function and have been postulated to underlie the brain's ability to store information.

NMDA antagonist drugs can block both in vivo hippocampal LTP induction and spatial learning at intracerebral concentrations comparable to those that block LTP in vitro.

NMDA receptors are heteromeric complexes consisting of an NR1 subunit in combination with one of several NR2 subunits, with the NR2 subunit regulating channel gating. Gene knockout of the NMDA receptor NR2A subunit in mice reduces both hippocampal LTP and spatial learning. NR1-NR2B complexes in vitro have longer excitatory postsynaptic potentials than NR1-NR2A complexes.

This result suggests that increased expression of NR2B subunits and their incorporation into functional receptor complexes in vivo could increase the time period for NMDA receptors to detect synaptic coincidence, increasing synaptic efficacy and also potentially increasing memory function. Consistent, with this hypothesis, investigators have recently reported that overexpression of NR2B receptor subunits in transgenic mice enhances the activation of NMDA receptors, facilitating synaptic potentiation as well as learning and memory.

Psychotomimetic^Wiki effects of NMDA glutamate receptor antagonists

In the 1950s, the dissociative anesthetic, PCP, was observed to induce a psychotic state in human subjects. The syndrome produced by PCP includes hallucinations, delusions, idiosyncratic and illogical thinking, poverty of speech and thought, agitation, disturbances of emotion, affect, withdrawal, decreased motivation, decreases in cognitive function, and dissociation.

However, the link to NMDA glutamate receptors was not suspected until 30 years later when blockade of NMDA glutamate receptors was implicated as the primary mechanism by which PCP disrupts brain function.

Hypofunction of NMDA receptors induced byvarious NMDA antagonist drugs is now known to precipitate a transient psychotic state in normal subjects.

Ketamine^Wiki, a well-studied PCP^Wiki analog still used in human anesthesia, is known to cause emergence reactions similar to, but not as severe as, those caused by PCP and a clinical syndrome at subanesthetic doses that includes mild positive, negative, and cognitive symptoms resembling schizophrenia. Notably, these effects are dose-dependent and memory impairments emerge prior to the expression of psychotic symptoms.

PCP and related ligands act at a “PCP” receptor located in the ion channel of the NMDA subtype of glutamate receptor to effect a noncompetitive blockade of NMDA receptor function. In addition, CPPene (3-[2carboxypiperazine-4-yl]propenyl-1-phosphonate), CPP (3-[2-carboxypiperazin-4-yl]propyl-1-phosphonicacid), and COS 19755 (cis-4-[phosphonomethyl]-2-piperidine-carboxylic acid), agents that block NMDA receptors competitively by acting at the NMDA recognition site outside the NMDA ion channel, have all been shown to cause a similar PCP-like psychosis in normal human volunteers.

When PCP and Ketamine, the most extensively studied of these agents, are administered to healthy subjects, they better mimic a broad range of psychotic symptoms than amphetamine, lysergic acid diamine (LSD), barbiturates, or N,N-dimethyltryptamine. Indeed, PCP-induced psychosis can be clinically indistinguishable from an acute presentation of schizophrenia, complicating appropriate clinical care.

Additional observations have strengthened interest in the effects of NMDA receptor function in relation to adult-onset psychoses. Patients with schizophrenia are unusually sensitive to pharmacological blockade of NMDA receptors, in that administration of PCP to stabilized chronic schizophrenia patients can trigger a recrudescence of acute psychotic symptoms lasting for up to several months. In contrast, LSD causes only a brief hallucinogenic state that does not appear to last longer in schizophrenia patients than in normal healthy subjects.

Another important observation is that many adults have displayed agitation and psychotic symptoms upon awakening from PCP- or ketamine-induced anesthesia, whereas pediatric patients at any age prior to adolescence show little or no susceptibility to this NRHypoassociated phenomenon. It would appear that humans become susceptible to NRHypo-induced psychotic reactions around the same age that various adult-onset psychotic syndromes (eg, schizophrenia) can begin to present. These parallels between the drug-induced NRHypo state and adult-onset psychoses have fueled the hypothesis that an NRHypo-related mechanism may contribute to the pathophysiology of psychosis.

On the basis of this evidence, as well as postmortem evidence of changes in glutamate metabolism96 and receptor expression97,98 in schizophrenia, several authors have recently developed theoretical positions regarding the relative roles of NRHypo and dopamine (DA) receptor hyperfunction as causal factors in schizophrenia.

The NRHypo hypothesis

Recent novel approaches to the treatment and prevention of drug-induced and idiopathic psychoses have emerged from the NMDA glutamate receptor hypofunction hypothesis. Simply stated, the hypothesis proposes that NRHypo, the condition induced in the human or animal brain by an NMDA antagonist drug, might also be viewed as a model for a disease mechanism which could explain the expression of psychosis, cognitive impairments, and certain neuropathological findings in patients with neuropsychiatrie disorders like schizophrenia and AD.

The disease mechanism itself might involve dysfunction of the NMDA receptor or downstream effects that can be modeled by blocking NMDA receptors. An important consequence of blocking NMDA receptors is excessive release of Glu and acetylcholine^Wiki (ACh) in multiple brain regions. It has been proposed that this excessive release of excitatory transmitters and consequent, overstimulation of postsynaptic neurons might, explain the cognitive and behavioral disturbances associated with the NRHypo state. It. is assumed that both genetic and nongenetic factors can contribute to the NRHypo state, and that NRHypo can interact with a variety of other disease mechanisms.


Neurotoxic effects of NMDA glutamate receptor antagonists

In order to better understand the mechanisms underlying the clinical effects of NMDA antagonist drugs and the clinical consequences of an NRHypo state, several research groups have begun examining the consequences of drug-induced NRHypo and have shown that one typical consequence is excessive release of Glu and Ach in the cerebral cortex^Wiki.

Therefore, a concerted effort is being made to understand the mechanism by which NRHypo triggers excessive release of excitatory neurotransmitters in the hope that this may provide new insights into the pathophysiology of psychosis and certain cognitive impairments. While moderately increased neurotransmitter release and associated overstimulation of postsynaptic neurons can produce certain cognitive and psychotic symptoms, unremittingly severe and chronic NRHypo and associated excitatory transmitter release can lead to neurodegenerative changes in the brain.

For research purposes, creating a drug-induced NRHypo state in the rodent brain provides an excellent means of identifying neuronal populations that are at risk of being hyperstimulaled and potentially injured as a consequence of the NRHypo state. Described below, our findings indicate that a protracted NRHypo state can trigger neuronal injury throughout many corticolimbic brain regions.

resumably any of these hyperstimulated neurons can be instrumental in producing NMDA antagonist-induced psychotic symptoms or cognitive impairments. In addition, this animal model provides an opportunity to test pharmacological approaches for pre venting the NRHypo state from hyperstimulating and injuring neurons. Finally, a careful analysis of the pharmacological interventions that are protective can provide insights into the circuitry and receptor mechanisms that, mediate this pathological process.

In experimental animal studies, we have found that, if the increased release of Glu and ACh is pronounced, certain postsynaptic neurons can develop either reversible or irreversible morphological changes, depending on the duration and severity of the NRHypo state. Low doses of NMDA receptor antagonist drugs, such as Ketamine, MK-801, tiletamine, PCP, CPP, and CPPene, reliably injure certain ccrcbrocortical neurons.

At. these doses, the injury is confined to the posterior cingulate and retrosplenial (PC/RS) cortex and consists of the formation of intracytoplasmic vacuoles in layer III-IV pyramidal neurons. These changes are transient and resolve by 24 hours. While these neurons will continue to express the 72-kDa form of heat shock protein (HSP-72) for up to 2 weeks, they do not become argyrophilic^Wiki (de Olmos cupric silver method) or die. In contrast, administration of an NMDA antagonist in high dosage or by continuous infusion for several days induces a prolonged NRHypo state, which causes irreversible injury involving the death of neurons in many cerebrocortical and limbic brain regions.

Large to medium-sized pyramidal and multipolar neurons are preferentially affected, although smaller neurons are also involved. The full pattern of damage includes the PC/RS, frontal, temporal, entorhinal, perirhinal, piriform, and prefrontal cortices, the amygdala, and hippocampus.

At 4 hours, the reaction in PC/RS cortex consists of intracytoplasmic vacuole formation, but in other brain regions a spongiform reaction featuring edematous swelling of spines on proximal dendrites is the most prominent cytopathological change.

At 24 to 48 hours, the affected neurons become argyrophilic and immunopositive for HSP-72 and begin to display cytoskeletal abnormalities, including a conspicuous corkscrew deformity of their apical dendrites.

In the 72- to 96-hour interval many of the degenerating neurons display conspicuous fragmentation, but cytoplasmic organelles and cytoskeletal elements within the cell body and mainstem dendrites of some cells continue to show mixed signs of viability and degeneration for at least 10 days. Over this period, the degenerative reaction does not elicit a robust glial or phagocytic response and the overall appearance is one of a subacute protracted neurodegenerative process.

Neural circuitry that is disturbed by NRHypo

In a series of recent studies, our group and others have found that, several different classes of drugs effectively block the PC/RS neurotoxic action of NMDA antagonist drugs. These findings, in conjunction with other work, indicate that, a surprisingly complex neural circuitry is involved in NRHypo neurotoxicity (Figure 1). In a series of recent, studies, we have found that a key feature of the circuitry that mediates the NRHypo neurotoxic process is that Glu, acting at N.M.DA receptors, functions in this circuit, as a regulator of inhibitory tone. Glu accomplishes this regulatory function by tonically stimulating NMDA receptors on GABAergic interneurons (GABA: gammaaminobutyric acid), which, in turn, inhibit, excitatory projections that, convergently innervate vulnerable cerebrocortical neurons. NMDA receptor-blocking drugs prevent Glu from driving GABAergic inhibitory neurons, and this results in a loss of inhibitory control over two major excitatory projections to the cerebral cortex, one that, is cholinergic and originates in the basal forebrain, and one that is glutamatergic and originates in the thalamus.



In addition to these basic features, the NRHypo circuitry includes noradrenergic and serotonergic neurons that, are driven by Glu through NMDA receptors and also perform an inhibitory function so that when NMDA receptors are hypofunctional the inhibitory restraint, contributed by these elements is also lost. One final aspect. that may be quite important for understanding how disinhibition of this circuitry can trigger psychotic reactions is that the vulnerable cerebrocortical neurons are glutamatergic neurons that ordinarily control their own firing by activating an NMDA receptor on a GABAergic neuron in an inhibitory feedback loop.

When the NMDA receptor in this feedback loop is hypofunctional (eg, blocked by NMDA antagonist drugs), GABAergic inhibition is lost and the cerebrocortical neurons' control over their own firing is lost at the same time as these neurons are being hyperstimulated by disinhibited glutamatergic^Wiki and cholinergic^Wiki excitatory inputs. The expected result, under these conditions would be that the overstimulated cerebrocortical neurons could bombard many other neurons in their projection fields with unmodulated output (ie, noise).

This provides a credible hypothesis for the psychotomimetic reactions and working memory impairments induced by NMDA antagonist drugs, and we propose that a similar NRHypo mechanism could contribute to the expression of psychosis and memory impairments in a variety of neuropsychiatrie disorders, including AD.

Age-related decreases in NMDA receptor function may explain age-related decreases in memory

At least, four different laboratories studying three different nonhuman species (mice, rats, and monkeys) have reported that the NMDA receptor transmitter system becomes markedly hypofunctional with advancing age. Several different age-related changes can contribute to this decrease in function. The most consistently reported decrease in binding parameters has been an age-related decrease in binding to the NMDA site, using agonists and antagonists, in the neocortex and hippocampus of rodents and primates.

Depending on the species, this generally appears to reflect a decrease in the number of binding sites, rather than changes in affinity, and generally reflects greater decreases in the cortex than in the hippocampus. Variable age-related changes in binding to the glycine site have been observed. Age-related decreases in binding to the PCP site have also been observed across multiple species, again greater in the neocortex than the hippocampus. This again generally appears to reflect decreases in the number of binding sites, rather than changes in affinity. In humans, a 36% decrease in Bmax for [3H]MK-801, reflecting a decreased number of PCP binding sites, was observed comparing 10 to 20 year olds and individuals in their 90s.

NMDA receptor subunit expression also changes with aging. NR1 expression has been reported to be decreased in the dentate of aged macaques and in the cortex and hippocampus of rodents. NR2B expression also decreases with aging in the hippocampus and cortex of rodents. It should be recalled that NR1-NR2B complexes in vitro demonstrate longer excitatory postsynaptic potentials than NR1-NR2A complexes21 and that an increased presence of NR1-NR2B complexes in vivo could increase the time period for NMDA receptors to detect, synaptic coincidence, potentially increasing synaptic efficacy and memory function.

Thus, an age-related decrease in NR2B expression could account for agerelated shortening of the excitatory postsynaptic potential duration of the NMDA channel. As mentioned above, overexpression of NR2B receptor subunits in transgenic mice enhances the activation of NMDA receptors, facilitating synaptic potentiation as well as learning and memoor. This overexpression has also been reported to prevent, age-related decreases in memory and learning performance. These results support, the hypothesis that age-related decreases in NMDA receptor function could account for age-related decreases in memory and learning. This suggests that strategies to prevent, those agerelated changes, or strategies to prevent, downstream or other events related to those changes, could have important therapeutic implications for the prevention or treatment of age-related memory impairments.

Selected abbreviations and acronyms

Ach   acetylcholine
AD   Alzheimer's disease
ALS   amyotrophic lateral sclerosis
AMPA   amino-3-hydroxy-5-methyl-4-isoxazole propionic acid
GABA   gamma-aminobutyric acid
Glu   glutamate
KA   kainic acid
LTP   long-term potentiation
NFT   neurofibrillary tangle
NMDA   N-methyl-D-aspartate
NRHyper   NMDA receptor hyperfunction
NRHypo   NMDA receptor hypofunction
PCP   phencyclidine
PC/RS   posterior cingulate and retrosplenial (cortex)

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