Writeup | Exploring NMDA-NR2B (&CDK5) - The most promising nootropic/learning pathway?
This post will go into the potential of NR2B and how potentiating it can be significantly pro-cognitive. This post will also talk about some potential issues and some ideas to ameliorate them.
NR2B (AKA GluN2B/GRIN2B) is a subunit of NR2 which is part of NMDA receptors. NMDA receptors play a critical role in synaptic plasticity and learning and memory. Blocking NMDA receptors prevents the induction of long-term potentiation (LTP), a cellular model of learning and memory. However, potentiating NMDA generally without being selective to a subunit is not that desirable due to excitotoxicity and other concerns. [1] As a subunit, NR2B brings a lot of interest.
NR2B is found throughout the cortex, however, the visual cortex is much more dependent on AMPA than NR2B, while the dorsolateral PFC (dlPFC) is much more dependent on NR2B for function. This is thought to be the case because the visual cortex is more dependent on fast kinetics, while the dlPFC is more dependent on slow kinetics. [3]
Primate cortical circuits - https://www.frontiersin.org/articles/10.3389/fpsyt.2021.654322/full
NR2B-containing NMDA receptors have slower kinetics compared to receptors with NR2A. This impacts channel opening, closing, desensitization, and calcium influx. [2]
Due to its involvement in plasticity and learning, NR2B is a target for cognitive enhancers, but enhancing it may also increase adverse effects like excitotoxicity and increased pain perception. This is a common theme with enhancing NMDA subunits, so combination with analgesic pathways should be explored when enhancing NR2B. [2]
Interestingly, NR2B is also highly relevant to BA24/25 (part of the cingulate cortex), which means it also has implications on mood and emotional regulation directly. [4] Differences in GRIN2B expression have been found in persons with bipolar disorder in studies, which is definitely interesting, and needs more investigation. [5]
NR2B throughout development
NR2B expression is high early in development, especially in the forebrain, and decreases into adulthood in many brain regions. This developmental shift in subunit composition alters NMDA receptor properties.
NR2B is very relevant for the mechanism of learning, even more than memory storage/expression. Studies suggest that NR2B antagonists generally do not affect the expression/recall of already formed spatial or fear memories, but halt the acquisition of new ones, meaning NR2B is critical for the process of learning. [6]
NR2B decreases as we transition into adulthood, however by enhancing NR2B, we could possibly bring back childlike learning. Then brings the question, how do we increase NR2B?
Methods of enhancing NR2B
The goal is to enhance NR2B without going into the realm of excitotoxicity. For those unaware, excitotoxicity is a process observed in many disease states by which an excessive synaptic excitation causes neuronal death. If NR2B or any glutamate subunit is potentiated too much, it can cause excessive synaptic excitation. This is a major limiter for glutamate enhancing compounds, so with this in mind, NMDA enhancement must be approached intelligently.
To limit this potential issue, the first thing that comes to mind for me is a NR2B PAM (Positive Allosteric Modulator). In simple terms, an agonist directly drives receptor activation, while a PAM amplifies the effect of an agonist. This is desirable because rather than causing a large surge in NR2B activity that does not correlate with endogenous activity, a PAM will only enhance endogenous activation.
However, the research into NR2B allosteric modulators is quite limited. The only selective NR2B PAM known right now is an experimental compound mentioned in this study ("compound 2"), which has not been studied upon further as far as I can tell.
The more studied upon (and proven) method of increasing NR2B and cognition is through interrupting NR2B-Cdk5 interaction. Cdk5 directly phosphorylates NR2B at Ser1116, meaning that Cdk5 inhibits NR2B activity. Therefore, by using a Cdk5 inhibitor, NR2B expression can be enhanced, and cognition can be enhanced.
Figure. 2 - https://www.sciencedirect.com/science/article/pii/S0896627314000531#fig2
In the same study as the above image, they tested how CDK5 inhibition effects NR2B expression within the brain. Inhibiting CDK5 significantly potentiates NR2B and it increased cognition.
Figure. 6D - https://www.sciencedirect.com/science/article/pii/S0896627314000531#fig6
A small interfering peptide (siP) was designed to disrupt NR2B-Cdk5 binding. Application of this siP to brain slices reduced S1116 phosphorylation, increased NR2B surface levels, and enhanced NMDA receptor synaptic currents.
The study showed significant improvements in enhancement of fear memory (a common test of memory for rodents) and learning. The mice showed a reduced threshold for induction of LTP, which is desirable as LTP is one of the major cellular mechanisms that underlies learning and memory (as discussed in my last post on NR3A).
Studies showing NR2B over-expression also show similar results, with enhancements to memory and spatial cognition. [8]
Potential leads for CDK5 inhibitors:
- CP681301 (not that selective)
- NR2B small interfering Peptide (siP) [ RRPPRSPDHKRYFRDKE ]
- CDK5i-FT Peptide
All known selective CDK5 inhibitors are experimental.
Attenuating disadvantages of NR2B over-expression
As shown, studies show that increasing NR2B levels enhances working memory and cognitive performance. This demonstrates the critical role of NR2B for PFC function.
However, too much NR2B also confers disadvantages. The prolonged activation of NR2B-containing NMDA receptors results in greater calcium influx, which makes neurons more vulnerable to excitotoxic damage. Therefore, approaching NR2B enhancement with a holistic approach is required to minimize excitotoxicity and downsides.
This may not be as big of an issue as it seems however, as increasing NR2B in adulthood boosts synaptic plasticity and cognition without the same level of excitotoxic vulnerability seen in early development. [7]
Enhancing NR2B while also using a compound/method to reduce excitotoxicity (such as with GCP-II inhibition (?)) seems like an interesting and novel approach to increasing the brain's potential.
For those with chronic inflammatory pain or seizures, enhancing NR2B should likely be avoided, however in healthy people, when done correctly, NR2B enhancement is likely to be a potent nootropic factor.
Some other notable things NR2B enhancement may contribute to is: increased hunger (?), attentuating autism (?), attenuating chronic stress (?), positively and negatively modulating hedonism (dlPFC mediated), and more. It seems GCP-II inhibition (mGluR3 enhancement) would pair well with NR2B enhancement for multiple reasons (protective against seizures, analgesic, anti-addictive, limits excitotoxicity/glutamate over-activation, etc).
There is definitely more to talk about regarding NR2B, so I will likely extend this post at some point. Thank you for reading.
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