NEUROPLASTICITY-LTP
Dr. vishnu prasad. P
Moderator: Dr. Ch. V. N. Saritha
Total no of slides : 48
Total duration: 30 min
First year pg
Dept of psychiatry
SRMC nandyal
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NEUROPLASTICITY
• The ability of the brain to change and adapt itself as a result of
one’s experience.
• The ability of neural circuits to undergo changes in function or
organization due to previous activity.
• It plays a role in adaptation to sensory inputs and transient
changes in behavior and short lasting memory.
• Long term changes in neuroplasticity play a role in neuronal
development during the growth and formation of long term memories.
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Applications of Neuronal Plasticity
• ‘Learning new things’
• ‘Making new memories’
• ‘Rewiring circuits’
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Basis of plasticity:
- Hebb’s Rule :
“Neurons that fire together, wire together.”
”Neurons that fire apart, wire apart.”
- When one cell repeatedly assists in firing another, the axon of the first
cell develops synaptic knobs (or enlarges them if they already exist) in
contact with the soma of the second cell."
- Hebb postulated that this behavior of synapses in neuronal networks
would permit the networks to store memories.
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Types of Neuroplasticity
Type
Mechanism
Duration
1. Enhancement of existing connections
Synapse development
Physiological
ms-1 to hours
Synapse strengthening
Biochemical
hours to days
Unmasking
Physiological
minutes to days
Sprouting
Structural
days to months
2. Formation of new connections
3. Formation of new cells
Self-replication
stem cell
variable
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Enhancement of existing connections
- Synapse development
- Synapse strengthening:
1. Facilitation (10-100 ms):
o The increase in amplitude of a postsynaptic potential due to rapid repeated activation.
o The facilitated neuron returns to its resting potential between activations, and its enhanced postsynaptic
response is fleeting.
2. Augmentation (several seconds)
3. Potentiation (seconds to minutes):
o Potentiation, in contrast, is a special type of facilitation in which an increased postsynaptic potential
persists after the facilitating stimulus has subsided.
o A high frequency burst of presynaptic impulses lasting several seconds, called a tetanic stimulus, can
cause a posttetanic potentiation, (PTP) lasting several minutes.
o Extended tetanization engenders long-term potentiation, (LTP) which can result in elevated postsynaptic
activity for hours or days. LTP is sustained, in part, by molecules called retrograde messengers.
- Increased use of a synapse in existing pathways
• e.g. Learning a new task
- Alternative pathways following damage
- Cortical re-mapping (phantom limb)
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➢ Formation of new connections:
- Unmasking of pre-existing pathways
o Possible reasons why some synapses could be ‘silent’
o On distal dendrites
o Inhibited by dominant pathways
o Too little transmitter
o Too few receptors
o Don’t fire with other inputs
- Sprouting of new pathways
➢ Formation of new cells: self replication, injury --- nerve growth
factors
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LONG TERM POTENTIATION
• Long-term potentiation (LTP) is a long lasting enhancement in signal
transmission between two neurons that results from stimulating them
synchronously.
• LTP is roughly defined as an increase in the strength of a synapse that
lasts from minutes to several days and is widely considered one of the
major mechanisms by which memories are formed and stored in brain.
• In contrast, a period of stable low-frequency stimulation of the
glutamatergic axons results in a persistent reduced efficacy of synaptic
neurotransmission, a phenomenon known as long term depression (LTD).
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• Classical properties:
• Cooperativity: probability of LTP,
magnitude of change increases with
number of stimulated afferents
• Associativity: LTP only induced at weak
input when associated with activity in
strong input
• Input specificity: Unstimulated weak
pathway not facilitated after tetanus of
strong pathway
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Figure 17.22 Roles of NMDA and AMPA Receptors in the Induction of LTP in CA1 Region (Part 1)
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Figure 17.22 Roles of NMDA and AMPA Receptors in the Induction of LTP in CA1 Region (Part 2)
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Roles of NMDA and AMPA Receptors in the Induction of LTP in CA1 Region (Part 3)
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• But for long term potentiation :
• To increase the synaptic strength and for long period of time.
• We have to :
• 1. increase the amount of neurotransmitter release from pre synaptic
neuron.
• 2.increase number of receptors for the neurotransmitters on the post
synaptic membrane.
• 3.increase the number of synapses or formation of new synapses.
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• LTP is produced in different parts of brain.
• LTP in hippocampus ( part of limbic system ).
• Phenomenon of LTP in hippocampus explains the mechanism of long
term memory.
• LTP IS IMPORTANT FOR BOTH LEARNING AND MEMORY.
• As LTP is produced it leaves traces of previous stimuli (memories) at the
synapses which persists for mins, hours, days and even years which
help in recollection.
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Hebbian Mechanism
• Donald Hebb (1949):
‘When an axon of cell A is near enough to excite a cell B and repeatedly or persistently takes part
in firing it, some growth process or metabolic change takes place in one or both cells such that A’s
efficiency, as one of the cells firing B, is increased.’
• ‘Cells that fire together, wire together’
• Coincident activity in two synaptically coupled neurons
increases the synaptic strength between them
• Not all forms of LTP obey Hebb’s law:
e.g. Mossy fiber-CA3 synapse
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• Hebbian theory is a theory in neuroscience which proposes an
explanation for the adaptation of neurons in the brain during the learning
process.
• It describes a basic mechanism for synaptic plasticity, where an increase
in synaptic efficacy arises from the presynaptic cell's repeated and
persistent stimulation of the postsynaptic cell.
• Introduced by Donald Hebb in his
1949 book
The Organization of Behavior.
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LTP (E-LTP; L-LTP)
• Mechanism:
Repeated activation
NMDA-receptor releases Mg2+
‘early ‘LTP (< 90 min)
[Ca2+] ↑ ↑
AMPA-receptors ↑ and ionic conductance ↑
‘late’ LTP (> 90 min)
Protein synthesis
POSTSYNAPPTISCH
Glutamate, depolarization
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LTP: mechanisms for induction,
expression and maintenance
• Multiple mechanisms for induction
• Increased [Ca2+ ]I
• AMPA and NMDA (Hebb)
• Cooperativity : strong
synaptic input necessary to
depolarize membrane,
AMPAR)
• Associativity/input selectivity:
weak input in itself does not
relieve Mg2+ block
• VGCC (voltage gated calcium
channel)
• Mechanisms for L-LTP highly
conserved across species
(cfr Aplysia)
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LTP maintenance
• E-LTP: phosphorylation of substate protein
• L-LTP: alteration in gene expression
•
•
•
•
•
•
Transcription factors (fos, zif268)
Cytoskeletal proeins (arc)
Signal transduction molecules (CaM kinase II)
Critical time window (<2h)
Synapse specificity: tagging by kinase(s)
Positive feedback/re-activation of L-LTP mechanisms
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Long term depression
Repeated activity
(Hippocampus: 10 min, 1 Hz)
NMDA-receptor releases Mg2+
[Ca2+] ↑
AMPA-receptor defosforylatie
internalisation AMPA-receptors
• Learning mechanism in cerebellum
(eye-blink reflex: decrease in synaptic strength in a postsynaptic
inhibitory neuron)
• Reversal of LTP
• NMDA-dependent and – independent mechanisms
POSTSYNAPPTISCH
Depolarization
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LTP or LTD
Depends on:
- Brain region/type of neuron
- Increase in [Ca2+]
- mild -> LTD (protein phosphatase)
- high-> LTP (protein kinase)
- Characteristics of repeated activity
- High frequencies-> LTP
- Low frequencies (≤ 1Hz) -> LTD
• Long-term potentiation (LTP) is the long-lasting strengthening of the
connection between two neurons
• can last from hours to days, months, and years.
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• LTP was discovered in the rabbit hippocampus by Terje Lømo in 1966 .
• tetanic stimulation consists of a high-frequency sequence of individual
stimulations of a neuron.
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dentate gyrus (1)
cornu ammonis (2)
Their three layered cortex is
continuous below with the
subiculum (3) which has four,
five then six layers as it
merges with the
parahippocampal gyrus (4).
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• Schaffer collateral synapse on the hippocampal
CA1 pyramidal cell, showed that a brief period of
intense stimulation of the Schaffer collateral (100
Hz) resulted in a subsequent persistent increase in
the efficacy of synaptic neurotransmission at
these synapses.
• This phenomenon is known as long term
potentiation (LTP) and is quite widespread with
regard to glutamaergic synapses.
• LTP IS PRODUCED IN MANY PLACES.
• MANY EXCITATORY NEUROTRANSMITTERS
(Ach…GLUTAMATE…aspartate)
• SCHAFFER COLLATERALS (between CA 3 and CA
1) AND GLUTAMATE.
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• PROCESS OF FORMATION OF LTP:
• 1. HIGH FREQUENCY (100 Hz) stimuli to the
Schaffer collaterals at CA3 zone.
• 2.increased production and release of glutamate
from pre synaptic neuron( ie from schaffer
collaterals axon terminals).
• 3.depolarization of post synaptic neuron ( CA 1
ZONE : dendrites of pyramidal neurons).
• 4.increase production of receptors on post synaptic
membrane.
• 5.increase production or formation of new synapses
(ie increase in dendritic spines)
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• After Ca 2+ influx into post
synaptic neuron.
• It acts as a important secondary
messenger and activates many
other
pathways.
• LTP:
• EARLY LTP : modulating proteins
already at the synapse.
• LATE LTP : new protein synthesis.
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• ROLE OF NO (NITRIC OXIDE) :
• Calcium helps in production
of NO from arginine, as NO
is soluble gas, it diffuses
from post synaptic neuron
to pre synaptic neuron
and in pre synaptic neuron
it increases the production
of glutamate.
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• Role of CO (CARBON MONOXIDE ):
• Carbon monoxide is produced during the metabolism of heme by the
action of heme oxygenase (HO).
• Carbon monoxide has been implicated in the development of
hippocampal LTP, although lines of evidence are contradictory. Carbon
monoxide and tetanic stimulation of nerves leads to increased excitatory
postsynaptic potentials (EPSPs).
• HO inhibitors that block carbon monoxide production lead to impaired
induction of LTP and reduced calcium-dependent release of glutamate
neurotransmitter.
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Role of glutamate
• Glutamate clearance by high affinity transporters is essential for the maintenance
of glutamate homeostasis, which requires a functional level of expression of
glutamate transporters at the membrane level of both astrocytes and neurons.
• Glutamate uptake is not a static process and can be finely adjusted in accordance
to synaptic needs.
• Glutamate transporters are able to control the level of activation of glutamate
receptors by controlling the level of glutamate present at the synaptic level.
• These changes can be achieved either by an over or under expression of
glutamate transporters, altered cellular trafficking or changes in the transporter
conformation, all processes that affect the affinity of these transporters for
glutamate.
• For LTP, glutamate uptake needs to be enhanced when compared to basal levels
(Pita-Almenar et al., 2006, 2012)
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Neurons and glial cells are produced by asymmetric
divisions of self-renewing neural progenitor cells (NPC)
Glutamate may influence NPC either directly or
indirectly by stimulating the production of neurotrophic
factors and other signalling molecules in neurons.
An example of evidence supporting a direct action of
glutamate on NPC comes from studies of cultured
human NPC which respond to glutamate by increasing
their proliferation rate, and by increasing their
potential for neurogenesis.
Glutamate stimulates the production of BDNF in
neurons, and BDNF promotes neurogenesis
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Associative learning
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• APPLICATIONS :
• 1.LTP requires the activation of NMDA receptors
as demonstrated by the fact that it is blocked by
NMDA receptor antagonists such as the
dissociative anesthetics ketamine and
phencyclidine (PCP).
• Conditions resulting in blockade of LTP in the
hippocampus are associated with impairments
in the formation of new memories.
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• The extinction of conditioned fear has been shown to be an active
process mediated by the activation of NMDA receptors in the
amygdala.
• Treatment of rats with NMDA receptor antagonists prevents the
extinction of conditioned fear whereas treatment with the glycine
modulatory site partial agonist D-cycloserine facilitates the extinction
of conditioned fear.
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• (D-Cycloserine is an antibiotic used to treat tuberculosis that has 50
percent of the efficacy of glycine at the NMDA receptor.)
• To determine whether the phenomenon generalizes to humans,
patients with acrophobia were administered either placebo or a single
dose of D-cycloserine along with cognitive behavioral therapy (CBT).
• D-Cycloserine plus CBT resulted in a highly significant reduction in
acrophobic symptoms that persisted for at least 3 months as compared
to placebo plus CBT.
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• Fragile X mental retardation protein (FMRP), which is deficient in individuals
with fragile X syndrome, appears to be synthesized locally within the spine
during times of NMDA receptor activation and also plays a role in transporting
specific mRNAs to the spine for translation.
• Notably, mice in which the FMRP gene has been inactivated through a null
mutation as well as patients with Fragile X syndrome have fewer dendrtic
spines, the preponderance of which have an immature morphology.
• In mice with a selective deletion of NMDA receptors in the CA1 field of the
hippocampus, many aspects of CA1 physiology remain intact, but the CA1
neurons do not exhibit LTP, and memory impairment is observed in behavioral
tasks.
.
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• The role of LTP in disease is less clear than its role in basic mechanisms
of synaptic plasticity.
• However, alterations in LTP may contribute to a number of neurological
diseases, including depression, Parkinson's disease, epilepsy, and
neuropathic pain.
• Impaired LTP may also have a role in Alzheimer's disease and drug
addiction.
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Role of plasticity in psychiatric disorders:
•
•
•
•
-
Stress:
Stress is a known contributor to psychological and physical disorders.
Stressful life events have been related to occurrence of mood disorders in those vulnerable to it.
Stress leading to excess release of glucocorticoids results in pyramidal cell loss in hippocampus, a
postmortem finding in depression.
Schizophrenia:
In cases of schizophrenia, dendritic spine density is found to be lower in areas like Dorso-lateral
Pre Frontal Cortex (DLPFC) and there is a reduction of Cortical Dopaminergic (DA) signals.
Depression:
In depression, there is a prominent deficit of explicit memory which is a function of
hippocampus and medial temporal lobe.
Antidepressant use reverses the loss of spine density in various brain areas.
Chronic antidepressant administration leads to neurogenesis in hippocampus and increase in
Brain Derived Neurotrophic Factor (BDNF) expression in hippocampus and Prefrontal Cortex
(PFC).
Drug abuse:
Increased Brain Derived Neurotrophic Factor BDNF levels in ventral tegmental area and Nucleus
Accumbans are associated with behaviors like drug seeking and withdrawal state.
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Role of plasticity in psychiatric disorders:
•
-
Synaptic Plasticity Can Be Measured in Simple Hippocampal Circuits
The post-synaptic region has both NMDA and AMPA receptors.
Glutamate first activates AMPA receptors.
NMDA receptors do not respond until enough AMPA receptors are stimulated and the neuron is partially
depolarized.
NMDA receptors at rest have a magnesium ion (Mg2+) block on their calcium (Ca2+) channels.
After partial depolarization, the block is removed and the NMDA receptor allows Ca2+ to enter in
response to glutamate.
The large Ca2+ influx activates certain protein kinases – enzymes that add phosphate groups to
protein molecules
These effects all increase the synaptic sensitivity to glutamate.
The activated protein kinases also trigger protein synthesis
Strong stimulation of a postsynaptic cell releases a retrograde messenger that travels across the
synapse and alters function in the presynaptic neuron.
More glutamate is released and the synapse is strengthened.
Somatic intervention experiments –
• pharmacological treatments that block LTP impair learning.
Behavioral intervention experiments – show that training an animal in a memory task can induce LTP.
In neuroscience, long-term potentiation (LTP) is a long-lasting enhancement in signal transmission
between two neurons that results from stimulating them synchronously.
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• CONCLUSION:
• LTP is roughly defined as an increase in the strength of a synapse that lasts
from minutes to several days.
• Widely considered one of the major mechanisms by which memories are
formed and stored in brain.
• Study of LTP is required for study of many diseases related with memory
and learning.
• It is important for invention of new psychiatric and neurology drugs.
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REFERENCES
• CTP 10TH
•
Neural_Plasticity_and_Disorders_of_the_Nervous_System
• http://dx.doi.org/10.1155/2016/6053871
• Abraham, W.C., Jones, O.D. & Glanzman, D.L. Is
plasticity of synapses the mechanism of long-term
memory storage?. npj Sci. Learn. 4, 9 (2019).
https://doi.org/10.1038/s41539-019-0048-y
• https://doi.org/10.3389/fncel.2019.00357
• THANK YOU
• READ
• REPEAT
• REMEMBER
LTP
MEMORY
• doi: 10.1196/annals.1418.005
• https://doi.org/10.1111/gbb.12363
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Alcohol‐dependent molecular adaptations of the NMDA receptor system
Genes, Brain and Behavior, Volume: 16, Issue: 1, Pages: 139-148, First published: 01 Decem ber 2016, DOI: (10.1111/gbb.12363)
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Role of glutamate in neuroplasticity
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The NS is a series of connections
• Birth = 100 billion
neurons
• 6 year old has twice as
many synapses as an
adult
• By late adolescence,
synapses begin to
disappear
http://www.eng.yale.edu/synapses.htm
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More dendritic spines on dendrites where
new synapses are made
Dendritic spines from a
cerebellar Purkinje cell, drawn by Cajal
(Ramón y Cajal, 1899b).
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LTP expression
• CA3-CA1 synapse:
• (5) increase of functional AMPA
• (4) P of AMPA receptor: increased conductance
• (4) TARPs: AMPA receptor trafficking
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Synaptic Plasticity Can Be Measured in
Simple Hippocampal Circuits
• The large Ca2+ influx activates certain protein kinases – enzymes that
add phosphate groups to protein molecules.
• One protein kinase is CaMKII – it affects AMPA receptors in several
ways:
• Causes more AMPA receptors to be produced and inserted in the
postsynaptic membrane.
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Synaptic Plasticity Can Be Measured in
Simple Hippocampal Circuits
• CaMKII :
• Moves existing nearby AMPA receptors into the active synapse.
• Increases conductance of Na+ and K+ ions in
• membrane-bound receptors.
• These effects all increase the synaptic sensitivity to glutamate.
• The activated protein kinases also trigger protein synthesis
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Synaptic Plasticity Can Be Measured
in Simple Hippocampal Circuits
Strong stimulation of a postsynaptic cell
releases a retrograde messenger that
travels across the synapse and alters
function in the presynaptic neuron.
More glutamate is released and the
synapse is strengthened.
58
Synaptic Plasticity Can Be Measured
in Simple Hippocampal Circuits
• Somatic intervention experiments –
pharmacological treatments that block
LTP impair learning.
• Behavioral intervention experiments –
show that training an animal in a
memory task can induce LTP.
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