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26 Learning - Memory2 - LTP1 PDF

The document discusses the neural mechanisms underlying long-term explicit memory mediated by the hippocampus. It describes how long-term potentiation was discovered and its properties, including specificity, associativity, and cooperativity. It explains the role of NMDA receptors in LTP induction and the molecular mechanisms involved in early and late LTP expression and maintenance.

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52 views13 pages

26 Learning - Memory2 - LTP1 PDF

The document discusses the neural mechanisms underlying long-term explicit memory mediated by the hippocampus. It describes how long-term potentiation was discovered and its properties, including specificity, associativity, and cooperativity. It explains the role of NMDA receptors in LTP induction and the molecular mechanisms involved in early and late LTP expression and maintenance.

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What neural mechanisms are responsible for long-term explicit

memory mediated by the hippocampus and its associated structures


in the medial temporal lobe of the mammalian brain?

Bliss and Lomo (1973)


discovered long term
potentiation (LTP):
activity-dependent long-term
plasticity at the perforant path-
DG hippocampal synapses:

brief high-frequency trains of


APs induce an increase of the
EPSP amplitude, that can last
for several hours (in slices) and
for days-weeks in the living
animal.
Late LTP (4 train of pulses, it lasts >24 hours)
% EPSP slope
relative to
control before rly LTP (1 train of pulses
train of pulses
Eatrain of pulses100 Hz for 1 s; lasts 1-3 hour
Early LTP (1
Interesting property of LTP (for its possible role as a cellular mechanism of memory)

LTP:
It is a state-dependent Recording
phenomenon induced
by the coincidence of a
presynaptic event
(neurotransmitter
Stimulus
release) and a
postsynaptic event
(depolarization) Strong depolarizing pulses coupled
to the AP-evoked EPSPs

cf Hebb postulate in one of


the first theoretical models
on synaptic basis of
learning and memory:
coincidence of presynaptic
and postsynaptic events is
necessary
Time
Other interesting properties of LTP (for its possible role as a cellular mechanism of memory)

Specificity Associativity
C) Cooperativity: it is
necessary to
Active Strong
simultaneously activate
stimulation
a large number of
afferents to sufficiently
Potentiated Potentiated depolarize the
synapse synapse postsynaptic membrane
Weak
Inactive stimulation  Only significant
events are memorized
Unaffected Potentiated
synapse synapse

Memory requires selective potentiation of


specific synapses: inputs that convey
information not related to a particular event Cellular equivalent of classical
will not be strengthened to participate in a associative conditioning
given memory
Glutamate NMDA receptor: coincidence detector of presynaptic
release and postsynaptic depolarization
 underlies the state-dependence, specificity and associativity of LTP at
CA3-CA1 synapses

Are permeable to Na+ and K+ Very permeable to Ca2+: PCa =5-10 PNa, K
(some also to Ca2+) Open, close and desensitize more slowly
Open and desensitize rapidly Require glycine as cofactor
Block by Mg2+ confers V-dependence
because Mg2+ block is relieved with increasing
depolarizaton
During normal, low-frequency synaptic
transmission glutamate released from
the terminals of CA3 Schaffer collateral
axons binds to both NMDA and AMPA
receptors in the postsynaptic membrane
of dendritic spines of CA1 neurons.
Sodium and K+ flow through the AMPA
receptors but not through the NMDA
receptors because their pore is blocked by
Mg2+at negative membrane potentials

LTP induction
During a high-frequency tetanus the
LTP induction: large depolarization of the postsynaptic
biochemical postsynaptic membrane relieves the Mg2+blockade
mechanisms elicited by of the NMDA receptors, allowing Ca2+,
Na+, and K+ to flow through these
high-frequency presynaptic channels. The resulting increase of
stimulation that trigger long- Ca2+in the dendritic spine triggers
term changes at the calcium-dependent kinases
synapse calcium/calmodulin–dependent kinase
(CaMKII) and protein kinase C (PKC)—
as well as the tyrosine kinase Fyn,
leading to induction of LTP.

The Ca2+elevation in the spine is vital


to the induction of LTP; injection of a
chemical chelator of Ca2+ into the
postsynaptic CA1 cell blocks the
induction of LTP.

Activation of CaMKII has key role in that


as a consequence of
autophosphorylation its activity
becomes Ca-independent
Early LTP expression
Phosphorylation through activation of
protein kinases, including PKC,
enhances current through the AMPA
receptors, and leads to the insertion of
AMPA receptors in the postsynaptic
membrane from a pool of intracellular
receptors stored in recycling endosomal
vesicles. The fusion of these vesicles
with the plasma membrane is triggered
by the phosphorylation by protein
LTP expression: kinase C of the cytoplasmic tail of the
Long-term changes that endosomal AMPA receptors.
increase the synaptic
efficacy (can be In addition, the postsynaptic cell may
release retrograde messengers that
postsynaptic or presynaptic activate protein kinases in the
depending on the specific presynaptic terminal to enhance
stimulus) subsequent transmitter release. One
such retrograde messenger may
be nitric oxide (NO), produced by the
enzyme NO synthase
Late LTP (4 train of pulses, it lasts >24 hours)
% EPSP slope
relative to
control before rly LTP (1 train of pulses
train of pulses
Eatrain of pulses100 Hz for 1 s; lasts 1-3 hour
Early LTP (1
Late LTP involves recruitment of the
cAMP and PKA signaling pathway, which
recruits the cAMP response element
(CRE) binding protein (CREB)
transcription factor, leading to the
synthesis of new mRNAs and proteins,and
to the formation of new synapses.

The maintenance of late LTP depends on


a novel isoform of protein kinase C termed
PKMζ (PKM zeta) which lacks a regulatory
domain and so is constitutively active.
Levels of PKMζ in the hippocampus are
normally low. Tetanic stimulation that
induces LTP leads to an increase in
synthesis of PKMζ through enhanced
translation of its mRNA. This mRNA is
present in the CA1 neuron dendrites,
enabling its local translation to rap-idly
alter synaptic strength. The persistent
activity of PKMζ leads to the persistent
increase in insertion of AMPA receptors in
the postsynaptic membrane

Blockade of PKMζ with a specific inhibitor


does not block early LTP but does block
late LTP. Moreover, application of the
PKMζ blocker several hours after the LTP
induction protocol can reverse late LTP
after it has been established.
Kandel, 2001 Science
Prior to LTP a CA3 neuron typically forms only one
functional synapse with a CA1 neuron. At this synapse a
presynaptic action potential releases with low probability a
single vesicle of transmitter. Following induction of early
LTP, the probability that a presynaptic action potential will
release a vesicle is increased.

Induction of the late phase of LTP by direct application of


a chemical analog of cAMP dramatically
changes the response to synaptic stimulation. Under
these conditions a presynaptic action potential elicits
a very large EPSP through the release of multiple
quanta of transmitter. Because each release site (active
zone) in the presynaptic terminal releases at most one
vesicle, the increase in the number of quanta indicates
that late LTP recruits new presynaptic release sites
apposed to new clusters of AMPA receptors in
the postsynaptic membrane.

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