Synaptic modification rules ?

Matthew Kirkcaldie m.kirkcaldie at removethis.unsw.edu.au
Tue May 18 19:47:41 EST 2004


In article <ec29a509.0405181329.2a3c48a7 at posting.google.com>,
 nettron2000 at aol.com wrote:

>  Matthew,could you please explain further what you meant by "As far as
> "rules" go, there are no rules, just consequences of particular firing
> patterns for cells which have particular membrane properties and
> biochemistry."
>  Are you saying that the spike firing pattern determines the mechanism
> ( or means) used for modification ? In otherwords, if a particular
> firing pattern is present in a cell assembly then some , as yet,
> imagined molecular mechanism "kicks-in" and modification takes place ?
> If not ,well, sounds interesting. :)

It's not imagined - many of the molecular details are actually quite 
well known and have been experimented on.  In general, the main process 
is that patterns of firing in pre- and post-synaptic (receiving) cells 
combine to allow calcium entry to the post-synaptic cell via the NMDA 
receptor.

Excitatory synapses in the central nervous system usually use glutamate 
as a neurotransmitter.  Release of glutamate causes sodium ions to enter 
the post-synaptic cell via glutamate receptors, which are ion channels 
that open when they bind to a glutamate molecule. The two main glutamate 
receptors are AMPA and NMDA (named for chemicals which were found to 
activate them in pharmacological studies). The entry of sodium ions 
depolarises the membrane, which makes the post-synaptic cell more likely 
to fire, depending on the amount of sodium which enters and hence the 
size of the depolarisation.  If you want to change the strength of a 
synapse, you have to change the amount of depolarisation it produces.

The NMDA receptor is a glutamate-activated channel which allows sodium 
*and* *calcium* into the postsynaptic cell when it binds to glutamate; 
however, it is normally blocked by being bound to a magnesium ion. If 
the post-synaptic cell fires, however, the magnesium is displaced, and a 
subsequent release of glutamate at the synapse, within a defined time, 
will allow calcium to enter the postsynaptic cell. Calcium is a very 
potent activator of kinases and phosphatases, enzymes which act to 
chemically activate/deactivate other proteins in the near vicinity. 
Depending on the timing relationship between successive firings, 
calcium-dependent kinases and phosphatases are activated and in turn 
activate or deactivate mechanisms which cause endocytosis (removal of 
membrane from the surface) or exocytosis (fusion of internal membrane 
packages with the surface membrane). The membrane which is removed or 
added is packed with AMPA receptors, which are sodium channels activated 
by glutamate in the synapse.

The more AMPA receptors, the more channels to permit sodium entry when 
the synapse fills with released glutamate.  That means a given release 
of glutamate will have a greater or lesser effect on the postsynaptic 
cell depending on whether AMPA receptors have been added to, or removed 
from, the post-synaptic membrane.

Thus glutamate at the NMDA receptor will, according to the recent 
activity of the postsynaptic cell, allow a little burst of calcium to 
enter the post-synaptic cell at a certain time after its activity.  
Depending on the timing this will activate biochemical pathways which 
cause AMPA receptors to be added to or removed from the membrane, which 
alters the strength of the synapse.

Of course this is a simplified picture.  Most of the enzymes involved in 
moving the receptors are known or strongly hinted at, but any other 
biochemical interaction with these processes will also alter the 
receptor trafficking (as it is called) and hence synaptic modification 
processes.  Have a look at a 2002 review by Malinow and Malenka in Ann 
Rev Neurosci 2002;25:103-26 if you would like (A LOT) more detail!

> BTW, thanks, eagerly await your reply.

My pleasure, I tend to run on a bit though I'm sorry.

      Cheers,

         Matthew.



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