Groundbreaking new research challenges decades of accepted neuroscience dogma on how memories are formed in the brain.
The study provides strong evidence that the induction of long-term potentiation (LTP), widely believed to be the cellular mechanism underlying memory formation, relies on structural changes in neurons rather than enzymatic activity as long thought.
Key Takeaways:
- LTP induction requires structural rather than enzymatic functions of CaMKII, an enzyme critical for LTP and memory.
- CaMKII binding to NMDA receptors is necessary and sufficient for LTP induction.
- Pharmacological or genetic manipulation to enable CaMKII binding rescued LTP when enzymatic activity was blocked.
- Findings upend the central dogma that CaMKII enzymatic activity is required for LTP and memory formation.
Background on LTP and Memory Formation
For over 30 years, the prevailing theory has been that formation of new memories relies on LTP – persistent strengthening of synapses between neurons that occurs with neuronal stimulation.
Specifically, LTP induction was thought to require enzymatic activity of CaMKII, an enzyme that plays a key role in LTP and memory.
CaMKII enzymatic activity refers to its ability to add phosphate groups to target proteins, modifying their function.
The widely accepted model posited that CaMKII enzymatic activity was essential to phosphorylate downstream substrates critical for establishing LTP and storing memories.
However, new findings from a collaborative research team challenge this central dogma, demonstrating that structural changes mediated by CaMKII binding to NMDA receptors, rather than enzymatic activity, are responsible for LTP induction.
Teasing Apart Structural vs Enzymatic Roles of CaMKII
To dissect the relative contributions of CaMKII’s structural versus enzymatic roles in LTP induction, the researchers utilized an array of pharmacological and opto/pharmaco-genetic approaches.
They identified a novel CaMKII inhibitor, AS283, that blocks its enzymatic activity without disrupting binding to NMDA receptors.
Using AS283, they showed CaMKII enzymatic activity was not required for LTP induction in hippocampal slices, contradictory to accepted theory.
In a parallel approach, the team employed a photoactivatable CaMKII to directly initiate CaMKII binding to NMDA receptors with light.
This photo-induced binding was sufficient to elicit LTP-related structural and functional changes in neurons even when enzymatic activity was blocked.
CaMKII Binding Restores LTP When Enzymatic Activity Blocked
In the most compelling experiments, the researchers leveraged pharmaco-genetic techniques to rescue LTP when enzymatic CaMKII activity was rendered impossible.
By genetically manipulating CaMKII to enable its binding to NMDA receptors only in the presence of specific inhibitors, they could restore LTP induction even when CaMKII was enzymatically “dead.”
These findings provide powerful evidence that CaMKII binding to NMDA receptors is both necessary and sufficient for LTP, independent of its enzymatic function.
Implications for Understanding Memory Formation
The study fundamentally shifts the model of how memories form in the brain via LTP.
Rather than phosphorylating downstream targets, CaMKII instead appears to induce LTP through structural reorganization enabled by regulated receptor binding.
As senior author Dr. K. Ulrich Bayer states, “the sole contribution of kinase activity was autoregulation of this structural role via T286 autophosphorylation, which explains why this distinction has been elusive for decades.”
While further research is needed, these breakthrough findings open exciting new directions for investigating the molecular underpinnings of memory formation.
They may also have important implications for developing novel therapeutics that target CaMKII binding rather than activity to modulate LTP in disease states.
Diving Deeper into the Study
The researchers utilized multiple approaches to convincingly demonstrate the insufficiency of CaMKII enzymatic activity for LTP induction.
Here are more details on some of the key experiments:
Testing a New CaMKII Inhibitor – AS283
- AS283 inhibits CaMKII enzymatic activity without blocking binding to NMDA receptors
- In hippocampal slices, AS283 failed to block LTP induction despite inhibiting CaMKII activity
- Suggests CaMKII activity is not required for LTP induction
Restoring LTP in “Kinase-Dead” CaMKII Mutant Mice
- T286A mutation prevents CaMKII autophosphorylation needed for activity
- In T286A mutant mice, AS283 enabled LTP induction by enhancing CaMKII-NMDA receptor binding
- Binding alone can induce LTP when kinase activity is eliminated
Using Pharmaco-genetic Approach
- Introduced point mutation enlarging CaMKII ATP binding pocket
- Mutation prevented nucleotide binding required for kinase activity and receptor binding
- Small molecule NM-PP1 restored binding and enabled LTP without kinase activity
Activating CaMKII Binding Optically
- Engineered photo-activatable CaMKII (paCaMKII)
- Light-induced paCaMKII binding to NMDA receptors induced LTP-related structural changes
- Binding was sufficient to elicit LTP independent of kinase activity
Updated understanding of memory formation
The new research represents a seismic shift in the model of how memories are encoded and stored in the brain via LTP induction.
Using an impressive array of techniques, the authors provide convincing evidence that structural changes mediated by CaMKII appear both necessary and sufficient, independent of its canonical enzymatic activity.
While further work is needed to elucidate the precise structural mechanisms, these findings fundamentally update and improve understanding of the molecular underpinnings of memory formation.
