Long Term Potentiation (LTP)

Introduction:
One area that seems to separate humans from other animals is intelligence. Part of that
intelligence may be attributed to the size of the human brain, since an increase in brain size
seems to be a ey anatomical difference separating humans from apes and also modern homo
sapiens from earlier hominids, as !udged by fossils. "et any no#ledgeable discussion of
intelligence, perception of emotions, and ability to reason #ill re$uire further ad%ancement of the
no#ledge of brain function.
&arly studies of neuron mechanisms focused on the neurons in%ol%ed in transmitting sensory
information of our fi%e senses bac to the brain to be processed. This led to a good understanding
of the neurotransmitter, acetylcholine. 'o# it is released by an e(cited cell, diffuses across the
synapse to a neighboring cell and binds to the acetylcholine receptor on the ad!acent neuron. This
alters the conformation of the receptor, also a sodium channel, to allo# the free flo# of sodium
ions into the cell, #hich in its normal state has a higher ()) ion concentration inside than out. This
depolarization, %ia the release of *a
+,
ions from %esicles, results in a #a%e of depolarization that
tra%els lie an electric current through the a(on to the other end of the neuron. -lmost
instantaneously causing the release of acetylcholine from this cell etc. *holinergic receptors
e(plain the basic mechanism for the transmission of information from the senses to the brain and
any return messages. These often result in beha%iors re$uiring muscle acti%ity as a response. If
#e smell something good to eat, #e mo%e closer to in%estigate. If #e hear frightful sounds #e
might mo%e to put distance bet#een us and the source. In this type of neuron function #e are not
that much different from other animals. In fact chemical insecticides used to protect crops are
fre$uently acetylcholinesterase inhibitors that interfere #ith the ner%e)brain communication
path#ay and result in paralysis.
*ognition, at least #hat #e understand of it, appears to in%ol%e the same basic mechanism of
electrical and chemical transmission bet#een neurons. 'o#e%er, the brain contains a %ast array
of specialized neurons, containing a %ariety of neurotransmitters, and their corresponding
receptors, that help us to sort out %ast arrays of sensory input, emotional responses, memories of
prior e%ents and associations, to name !ust a fe# of the factors in%ol%ed in brain function.
-lthough humans seem to ha%e an edge in the ability to reason, the biochemical mechanisms for
all of the pre%iously mentioned brain functions are not %astly different in other mammals. .ince
it is unethical to do research on human sub!ects, a lot of #hat #e no# comes from the studies of
these mechanisms in animals. In fact the similarities that #e do obser%e in brain function lead
many to $uestion #hether it is ethical to perform such studies on animals. /onetheless, it is
currently accepted practice to use laboratory animals to study brain function. "ou0%e all heard
the story of Pa%lo%0s dogs, #hich learned to associate a bell #ith dinner, such that the bell alone
could cause them to sali%ate in anticipation of their meal, e%en if it didn0t come.
.ome years ago, an 1IT researcher performed an e(periment that caught the imagination of
the press, in part because of the associations made by the researchers choice of terminology for
the mice used in the study. (Tsien ) /ature, .ept. +, 2333 4 .cience, /o% 25, +555) They #ere
called 6oogie mice after the name of the title character in a T7 sho# about a precocious
teenager #ho attained his 1.6. degree at the age #here most students #ould !ust be finishing
middle school. The sho#0s name #as 6oogie 'o#ser, 1.6. (I can0t recall seeing any more than
25 minutes of one or t#o sho#s, but nonetheless, I remembered the name).
The research sho#ed that o%er)e(pression (by %irtue of additional copies) of a gene called
/8+9, #hich encodes the /16- (/)methyl)6)-spartate) 8eceptor, in mice allo#ed them to
learn faster than a%erage mice. This of course re$uires e(plaining #hat #e mean by learning.
-lthough memorization typically gets a bad name in pedagogical circles, the concept of
intelligence and learning #ithout memory is lie the concept of playing basetball #ithout a ball.
-ll intelligence re$uires memory. 1emory, is basically the association of e%ents, sensory input,
emotions, thoughts or ideas, or combinations of these. Learning is the process by #hich these
associations are established, and can sometimes be maintained o%er years. (Just for fun, try to
think back to the very first thing in your life you can remember and recall as much as you can
about the event. It might be interesting to check with your parents or older siblings to see how
accurate your memory of the event matches theirs, assuming its something they may also
remember). I still recall high school cross country training and races at .chenley Par in
Pittsburgh, e%ery time I smell the odor of fallen lea%es in the fall. :ithout that input, I rarely
thin of those e(periences. Thus I al#ays associate the smell of rotting lea%es #ith running (in a
%ery pleasant #ay).
People often discuss short)term %s. long)term memory in taling about tests and
e(aminations. If you tae a single class and do nothing #ith the sub!ect matter for a long time
after, you tend to lose most of your no#ledge from the class. 'o#e%er, if you learn something
and then immediately go out and mae repetiti%e use of the information, you tend to hang unto
that no#ledge for a longer period of time. The theory of ho# #e retain associations for long
periods of time is called long term potentiation (LTP). The 6oogie mouse is only one of many
studies focusing on components of this process.
In simplistic terms LTP theory credits brain neurons for housing memories. These neurons
mae multiple connections #ith other brain neurons in%ol%ed #ith recei%ing sensory input, lie
%ision from the optic ner%e, for e(ample. The more input cells connected to the same memory
cell are stimulated the stronger the connections bet#een these cells become, and the longer
lasting the associations bet#een those inputs are, to the e(tent that at a much later time, one of
the inputs alone #ill allo# us to recreate the emotions from the other input(s). 'o#e%er, if the
senses connected #ith a memory cell are not stimulated #ithin a short time range, then it is liely
that the dendritic connections bet#een these cells #ill be deconstructed and reformed to other
cells in a some#hat random fashion. In essence it is not unlie the immune system #here #e
mae thousands T cells carrying one uni$ue, randomly produced antibody anchored to its
membrane. If that T)cell ne%er encounters an antigen that it binds to, it #ill e%entually die lie
any other cell. Other immune cells #ith a different, random antibody molecule #ill tae its place.
Lie#ise if multiple sensory inputs are #ired to the same ;memory0 neuron and those sensory
inputs are not used, the connections #ill e%entually be broen apart and ne# random connections
#ill be made. 'o#e%er, if an immune cell binds to a foreign antigen it sets in motion a process to
mae many more immune cells that #ill mae and distribute soluble forms of the antibody it
contained. Lie#ise if t#o different sensory inputs in the brain happened to be #ired to the same
;memory0 neuron #hen both of those sensory inputs get stimulated the connections are
strengthened rather than diminished. The more fre$uent the sensory input (still temporally
associated) or the more intense the simultaneous sensory input, the longer lasting #ill the
association become. This is #hy you should study outside of class<
The e(tent to #hich the initial connections are ;hard)#ired0 by genetic information %s. ho#
much is ;learned0 by the random connections fortified by e(periences as #e gro# is hotly
debated. The old philosophical assumption that humans are born #ith ;blan)slate0 brains is
surely incorrect. 'o#e%er, the notion that our no#ledge le%el is 255= genetically
predetermined is e$ually absurd.
:hat maes this theory e(perimentally difficult to test, e%en in animals, is that #e are not
!ust taling about connections of one cell #ith a dozen or so of its nearest neighbors. - single
neuron in the brain can recei%e connections from 25,555 > ?5,555 other cells %ia its dendrites.
The a(ons maing these connections may be as long a meter or as short as 2mm. There are #ays
of checing electrical and metabolic acti%ity in different parts of the brain follo#ing controlled
sensory input, but as far as I no# no#, you cannot %erify cell to cell connections e(cept by
autopsy. @inding %olunteers for such research is problematic<
'o#e%er, there are current methods utilizing non)in%asi%e procedures lie 18I that can
assess the metabolic acti%ity of neurons by gauging their metabolism le%el. Thus #hen certain
en%ironmental stimuli are presented to a sub!ect, the areas of the brain that are most acti%e can be
determined. The biochemistry of brain function #ill be a %ery acti%e and producti%e area of
research in the upcoming decades.
.
The 6oogie 1ouse &(periment
The ;smart0 mice in Tsien0s e(periment had e(tra copies of the gene encoding the /16-
receptor added. 9ut, ho# do you test the intelligence of a mouseA Tsien performed the follo#ing
three types of e(periments for this purpose.
2) Place a mouse in a cage #ith three ob!ects. The time the mouse spends ;interacting0 #ith
each ob!ect is charted. /o# change one of the ob!ects. If the mouse has a good memory it #ill be
already familiar #ith the usual ob!ects and #ill thus spend more time ;interacting0 #ith the
ne#er ob!ect. The 6oogie mice did indeed spend more time e(amining the ne#er ob!ect relati%e
to control mice.
+) Place a mouse in a certain en%ironment. This en%ironment may be supplemented #ith a
particular sensory input, lie a tone. /o# shoc the mouse #hile in this en%ironment. -fter a
certain number of days return the mouse to the same en%ironment. The mouse that remembers
the shoc #ill display higher le%els of an(iety. The 6oogie mice began to display an(iety signs
after fe#er shoc e(posures that the control mice. 'o#e%er, if the shocs #ere discontinued they
also lost their an(iety more $uicly than control mice that had de%eloped the same le%el of
an(iety due to longer e(posure.
?) Thro# a mouse into a pool #ith a submerged platform. The mice s#im randomly until
they find the platform. The number of tries before the mouse immediately s#ims to the platform
is noted. The 6oogie mice a%eraged ? tries #hile the control mice a%eraged B.
The added /16- receptors of the 6oogie mice #ere designed to be deacti%ated by the drug
do(ycycline, #hich could be added to their drining #ater. 6eacti%ating the added receptors
after the learning too place did not remo%e the gained ability. This supports the aspect of
learning theory that in%ol%es the increase in the number of dendritic connections bet#een the
associated memory cells.
I #ill insert a fe# notes of caution here. The /16- receptor gene is not the intelligence
gene. 1ice #ith enhanced genetic predisposition for ner%e gro#th factors #ere also better in
de%eloping LTP. The list could probably e(tend $uite a bit. It should also be noted that maing
associations too easily or remembering too #ell might be detrimental to sur%i%al. If fear
moti%ates action it can enhance sur%i%al. If fear causes a type of paralysis, because #e can0t deal
#ith the intensity of percei%ed memory, it might be detrimental to sur%i%al. .cientists should
display e(treme caution before !udging that increased e(pression of ;intelligence0 genes is a
good thing.
Long Term Potentiation > The basic mechanisms
*ertain molecular aspects of neuron functions and memory are beginning to clear up a bit.
@or a re%ie# of this topic see 1alena 4 /icoll > .cience (2333) .eptember 2C, %olume +DE
2DC5)2DCF
The hippocampus is the brain0s center for forming ne# memories. The parts of the neurons
that are stimulated by the release of neurotransmitters from neurons that recei%e sensory
information in the brain are called dendrites. They are referred to as post)synaptic. The cell
releasing the neurotransmitter does so through the ends of its a(ons. These are referred to a
presynaptic. The presynaptic a(ons mae and release neurotransmitters (#hen stimulated by
sensory input). The post)synaptic dendrites contain the receptors that the neurotransmitters bind
to. /eurons are connected by short synapses bet#een the a(ons and dendrites. This space is
typically on the order of CE G, on the order of the thicness of a lipid bilayer. The dendrites of the
memory neurons contain t#o inds of receptors in%ol%ed in memory. The -1P- receptors
respond to the neurotransmitter, glutamate, or the agonist, )amino)?)hydro(y)E)methyl)F)
iso(azoleproprionic acid (-1P-). They contain a channel permeable to /a
,
and H
,
that mostly
create in#ard flo# of /a
,
ions upon acti%ation. This depolarization is the reason for .TP (short
term potentiation). If you only stimulate these receptors the associations made bet#een the
stimulating sensory neurons #ill be short li%ed, decaying to baseline le%els in about E)+5
minutes.
The second type of receptor is the /16- (/)methyl)6)aspartate) receptor. These receptors
contain a *a
,,
channel, #hich is typically bloced by 1g
+,
under normal conditions and
contributes %ery little to the basal postsynaptic response. 'o#e%er, if the -1P- receptors
produces a significant enough depolarization, the 1g
+,
is remo%ed and *a
+,
influ( into the cell
!oins the /a
,
influ(, triggering LTP. .upporting this model is the fact that /16- receptor
antagonists ha%e little effect on .TP but bloc LTP. @urther support of the
*alcium role comes from the fact that LTP can also be bloced by the addition of *a
,,
chelators.
.ub)threshold concentrations of *a
,,
can either cause .TP or LT6 (long term depression) in
#hich the effects of LTP are re%ersed.
The signal transduction cascade set in motion by the calcium influ( in LTP is not #ell
understood. :hat does seem clear ho#e%er, is that one ma!or component of this cascade is )
calcium calmodulin)dependent Protein Hinase II. (*a1HII). One of the ey e(planations of the
longer term effects of LTP, is that once *a1HII is phosphorylated on Thr)+DB it no longer
re$uires *a
,,
for acti%ation. Thus the signal transduction cascade remains acti%e long after the
I*a
,,
J has returned to baseline. In addition the -1P- receptors appear to be both upregulated
and phosphorylated, so that a future stimulatory e%ent elicits a stronger basal response from
them. This #ill enhance the response of these memory cells to normal le%el stimulation in the
future. In other #ords your response to a particular sensory input might be much greater than
someone else #ho has not had the same pre%ious e(periences that you ha%e. :e #ill not discuss
other components implicated in this cascade.
9ut ho# does this account for memory of e%ents many years into the futureA The #oring
model in%ol%es the building of additional dendritic spines bet#een memory and sensory cells
that ha%e undergone LTP (1uller, Tony, and 9uchs > 'ippocampus (+555) 25(E), E3B)B5F). In
essence these cells become hard #ired together lie cable attachments bet#een a net#or of
computers. It is no#n that the spines containing the dendrites that mae the post)synaptic
connections bet#een cells can be rapidly built, causing an increase in the postsynaptic density
(P.6). :ith disuse, they can be taen apart. The stronger the LTP, the more highly connected
the associated cells.
.ummary ) *hronology of LTP:
2. .timulus triggers acti%ation of -1P- receptors. /a
,
4 H
,
enter the cell reducing the cell0s
polarization (&). This produces the basal synaptic transmission.
+. If the stimulation has sufficient durationKintensity the depolarization results in acti%ation of
the %oltage gated /16- receptors. 1g
,,
is released from its position blocing the /16-
receptor channel. *a
,,
enter the cell (I*a
,,
J ). &%idence: /16- receptor antagonists bloc
the generation of LTP but ha%e no effect on basal synaptic transmission.
?. -ssociati%ity occurs in part because the strong acti%ation of one set of synapses depolarizes
ad!acent regions of the dendritic tree.
F. CaMKII ()calcium)calmodulin)dependent protein inase II) phosphorylates and causes
clustering of the -1P- receptors. -1P- receptor response in the post)synaptic cell is also
enhanced, due to up)regulation of the receptor. .ynapses that had e(pressed only /16-
receptors no# contain -1P- receptors as #ell.
E. *a1HII is also auto)phosphorylated at Thr)+DB. 9ecause of the auto)phosphorylation, *a
,,

ele%ation is no longer re$uired for its acti%ation #hich is #hat maes the cells acti%ation
long)term. LT6 (long)term depression) in%ol%es the dephosphorylation of the -1P-
receptors and *a1HII.
B. - retrograde messenger (unno#n but possibly /O, *O, arachidonic acid, or platelet
acti%ating factor) released from the post)synaptic cell modifies the pre)synaptic function of
the signaling cell. The cell is no# responding more readily to neurotransmitters, recei%ing
more neurotransmitter, and maintaining its responsi%e state for a longer period of time. In
addition a single stimulus is lined to a different stimulus that need not be present.
C. - signal transduction cascade is stimulated such that the neuron acti%ely constructs ne#
dendrites and connects them to the cells that carried the original stimuli signals. These
stimuli no# become ;lined0 such that a only one of the stimuli present in the en%ironment
#ill elicit a memory of other associated stimuli.