Molecular mechanisms of memory

• How does the brain achieve Hebbian plasticity?

• How is the co-activity of presynaptic and postsynaptic cells registered and stored?

• Experiments in the 1980’s showed that blockade of a particular type of glutamate receptor prevented the induction of LTP without interfering with synaptic transmission.

• When this receptor was blocked, the synapse still worked (release of transmitter from the presynaptic neuron produced a normal postsynaptic response)

• However, it could be cause LTP.

• A second experiment showed that LTP could not occur if calcium was prevented from rising in the postsynaptic cell during action potentials.

• These two findings converged, because the special glutamate receptor controls calcium in the postsynaptic cell during action potentials.

• Recall that glutamate is the main excitatory neurotransmitter in the brain.

• When it is released from presynaptic terminals and binds to postsynaptic receptors, it increases the likelihood that the postsynaptic neuron will fire.

• There are several types of glutamate receptors.– The AMPA receptor is involved in regular

synaptic transmission– The NMDA receptor is involved in synaptic

plasticity.– There are others, but not involved here.

• Presynaptically released glutamate binds to both AMPA and NMDA receptors.

• Binding of glutamate to AMPA receptors is the normal way that a postsynaptic cell is induced to fire.

• In contrast, when presynaptically released glutamate reaches NMDA receptor on the postsynaptic cell, it has no initially because part of the receptor is blocked.

• However, one glutamate has caused the postsynaptic cell to fire an action potential by binding to the AMPA receptors, the block on the NMDA receptor is rmoved.

• Glutamate can then open the NMDA receptor channel and allow calcium to enter the cell.

• LTP is the result.

• For NMDA receptors to pass calcium, both presynaptic and postsynaptic cell must be active.

• This is the requirement for Hebbian plasticity.

• Why is calcium entry through NMDA receptors a means of forming associations between a strong and a weak input?

• Activity in the weak input pathway results in the release of glutamate and the binding of glutamate to postsynaptic receptors.

• Because the connection is weak, however, the input is not capable on its own of making the postsynaptic cell fire an action potential.

• However, when synaptic activity in the strong pathway activates the postsynaptic cell, the block on NMDA receptors will be removed, even at the weak synapses.

• If the weak pathway releases glutamate at the same time that the strong pathway causes an action potential, the NMDA receptors at both the strong and the weak synapses will be able to bind the glutamate.

• Calcium will flow in through the NMDA receptors, and the weak synapses will be strengthened.

• In summary, the reason that NMDA receptors allow LTP to occur is that they are coincidence detectors: they are able to register that presynaptic and postsynaptic neurons are active at the same time.

• NMDA receptors allow the cell to record exactly which presynaptic inputs were active when the postsynaptic cell was firing.

• This input specificity is key to association, which is exactly what Hebb described.

Long term memory

• The binding of glutamate to its receptors is a brief event.

• Memories can be long term.

• Biological and chemical changes must occur that outlast the synaptic activation by NMDA.

• Changes in synapses have been studied use two procedures– Early LTP is a form of Hebbian LTP that lasts

only an hour or so– Late LTP is more persistent

• Early and late LTP are commonly considered analogs of short-term and long-term memory.

• Short- and long-term memory are distinguished by their chemical requirements, in addition to their longevity.

• Known for several decades that if animals are given drugs that prevent the brain from making new proteins, they are able to learn normally (short term) but are unable to form long-lasting memories.

• If the animals are tested within an our of learning some task, they perform well, but when they are tested the next day, they show no sign of having learned the task.

• This requirement for protein synthesis is true for most if not all kinds of memory, and for most if not all species.

• Blockade of protein synthesis has no effect on early LTP but prevents late LTP.

• These parallels between early LTP and short term memory on the one hand, and late LTP and long-term memory on the other, are consistent with the idea that LTP may mediate memory.

Second messengers in memory

• Neurotransmitters like glutamate are considered first messengers

• They are responsible for signaling between neurons.

• Second messengers initiate chemical reactions within neurons after the neuron is stimulated by the first messengers.

Calcium is a major 2nd messenger

• We saw that, when glutamate binds to its NMDA receptors, calcium flows into a cell (after the block has been removed)

• Once this occurs, calcium directs chemical reactions that strengthen synaptic connections.

• The inflow of calcium activate protein kinases, which are enzymes that activate other proteins.

• Protein kinases phosphorylate their target proteins, which transforms them from inactive to an active state.

• The creation of long-lasting or late LTP, like long term memory, requires synthesis of new proteins.

• This requires activation of kinases, specifically protein kinase A (PKA), MAP kinase (MAPK) and calcium/calmodulin protein kinase (CaMK)

• These activated kinases move to the cell nucleus where they activate another protein, CREB.

• CREB is a transcription factor that causes the expression of specific genes to produce new proteins.

• These proteins strengthen the synapses.

Biochemistry of LTP

• LTP in the hippocampus involves– NMDA receptor activation– consequent post-synaptic increase in

calcium– activation of protein kinases and other

enzymes– a partially-characterized sequence of

events leading to increased synaptic strength

Mutants in genes in this pathway cause changes in learning ability

Gene Targeting:Methods exist to

• add, delete, or modify genes in the mouse genome.

• restrict expression of mouse genes to specific regions of the brain,

• restrict expression to specific experimental conditions: – high/low temperature– presence/absence of antibiotic

• These methods can be used to create mouse models of human disease, e.g., Alzheimer' disease.

• The first gene-targeting study of LTP and learning used mice with a null mutation for the alpha CaMKII gene.

• This gene responds to changes in calcium (Ca) ion changes related to memory formation.

• Alpha CaMKII mutants showed impaired LTP and LTD in the hippocampus and neocortex.

• Although the alpha CaMKII mutant mice were severely impaired in the hippocampal-dependent version of the water maze, they were able to learn the "visible-platform" version of this task, which is known not to depend on hippocampal function.

• alpha CaMKII mutants – can learn that the platform is the only escape

in the pool– have the motivation to escape the water – have the motor coordination and sensory

perception required to efficiently swim to the escape platform,

– but they are unable to learn the spatial relationships required to guide them to the hidden platform.

• CaMKII appears to be involved in the early stages of memory formation (during initial learning), but not in long-term memory formation.