NMDA mediated learning and memory

From Neural Wiki

From Wikipedia: more

NMDA (N-methyl-D-aspartic acid) is an amino acid derivative acting as a specific antagonist at the NMDA receptor, and therefore mimics the action of the neurotransmitter glutamate on that receptor. In contrast to glutamate, NMDA binds to and regulates the above receptor only, but not other glutamate receptors.

NMDA

[edit] Learning

Synaptic plasticity dependent on NMDA receptors is thought to underlie certain types of learning and receptors. It is known that NMDA receptor dependent LTP can be induced by applying a few trains of high-frequency stimuli to the connection between two neurons.

[edit] How tetanic stimulation induces Long term potentiation (LTP)

  LTP is based on strengthening synaptic transmission, and is often described as wire together fire together 

During synaptic transmission, information is passed from a presynaptic neuron (fires first)to a postsynaptic neuron. This generates an excitatory postsynaptic potential (EPSP). The magnitude of the EPSP determines whether LTP will be induced in the postsynaptic cell.

Here is how it works

• A stimulus is applied to the presynaptic neuron.
• Presynaptic neuron releases a neurotransmitter, usually glutamate, onto the postsynaptic cell membrane.
• Glutamate binds to AMPA receptors embedded in the postsynaptic membrane

AMPA receptors are one of the main excitatory receptors in the brain and are responsible for most of the rapid moment-to-moment excitatory activity (Agranoff et al., 1999).

• Glutamate binding to the AMPA receptors triggers an influx of predominantly sodium ions in the postsynaptic cell
• Influx of sodium ions causes a short-lived depolarization, the EPSP.
• Single stimulus does not generate an EPSP capable of inducing LTP
• Single AMPA mediated EPSP has a rise time-to-peak around 2-5 ms and a duration of approximately 30 ms
• By stimulating at 100 Hz, an EPSP will occur 10 ms after the previous EPSP, and will arrive when that previous EPSP is at its peak amplitude.
• EPSP summation means that the postsynaptic depolarization increases as each EPSP occurs
• This summation drives the membrane potential towards values that cannot be achieved with a single stimulus.
• The summation will approach, but not exceed the reversal potential of the EPSP which is approximately -10 mV

[edit] Role of the NMDA receptor

When the membrane potential is at the resting, or near resting state (-70 mV), the NMDA receptor does not contribute any current to the EPSP. The NMDA channel spans the cell membrane and therefore the electric field generated by the membrane potential.

Glutamate released by synaptic activity binds to the NMDA receptor and causes the NMDA receptor ion channel to open. However, no current flows through the channel, because it is instantly blocked by a magnesium ion (Mg²⁺) that binds "inside" the NMDA receptor channel.

However, magnesium will periodically unbind and leave the channel as the cell depolarizes (positive magnesium is more likely to stay put with more negative membrane potential; basic physics: opposites attract). During the brief time between a magnesium ion leaving and another taking its place, other ions can flow through the channel. The lower the hyperpolarization, the less often magnesium blocks the channel. Though the channel is not voltage dependent, the magnesium blockage means that the NMDA receptor channel is both ligand-gated and voltage gated at the same time (e.g. Engberg et al., 1979). This is critical for the NMDA receptor channel to act as a Hebbian coincidence detector for membrane depolarization and synaptic transmission.

 The Point: Synaptic transmissions produce glutamate, which opens the NMDA receptor channel, which allows 
 ions in based on the membrane depolarization.  Therefore, NMDA receptor channels are a coincidence detector                                                          
 for synaptic transmission and membrane depolarization.

[edit] In vivo Animal Models

[edit] Mice and Rats

Rat swimming in a Morris water maze

Some of the first evidence that LTP was required for the formation of memories was shown by Morris et al. (1986) who induced the NMDA blocker APV which stopped the formation of new spatial memories.

In a follow up to Morris et al.'s watermaze experiment, Bannerman et al. (1995) showed that blocking NMDA receptors caused mice to have trouble learning a new watermaze, but that they had little trouble if they had previously trained (and formed previous memories) on a different watermaze.

Lee and Kim (1998) show that NMDA receptors in the amygdala, which processes emotions, seem to be critical for fear conditioning in naive rats. Blocking NMDA receptors with antagonist DL-2-amino-5-phosphonovaleric acid (APV) blocked fear conditioning in responses to a tone, even though those rats had previously formed fear responses to a light (like a light bulb) stimulus. They were unable to form fear responses to novel stimulus, but retained their fear response to those that they had already learned.

[edit] In vitro Models

[edit] Brain slices

[edit] Dissociated Neural Networks

[edit] References

Agranoff, Bernard W.; Siegel, George J. (1999). Basic neurochemistry: molecular, cellular, and medical aspects. Philadelphia: Lippincott-Raven, p326. ISBN 0-397-51820-X.

Bannerman DM, Good MA, Butcher SP, Ramsay M, Morris RGM (1995) Distinct components of spatial learning revealed by prior training and NMDA receptor blockade. Nature 378, 182 - 186 (09 November 1995); doi:10.1038/378182a0 [1]

Enabera I. Flatman JA. Lambert JDC (1979) The actions of excitatory amino acids on motorneurones in the feline spinal cord. J Physiology(Lond) 288:227-26 1.

Hongjoo Lee and Jeansok J. Kim (1998) Amygdalar NMDA Receptors are Critical for New Fear Learning in Previously Fear-Conditioned Rats. The Journal of Neuroscience, October 15, 1998, 18(20):8444-8454 [2]

Morris R, Anderson E, Lynch G, Baudry M (1986). "Selective impairment of learning and blockade of long-term potentiation by an N-methyl-D-aspartate receptor antagonist, AP5". Nature 319 (6056): 774-6. PMID 2869411.