Synaptic Plasticity Flashcards
What is synaptic development?
The increase in both brain size alongside speed of neural processing.
Specifically the number of synapses in the cerebral cortex peaks within the first few years, declines by about 30% between early childhood & adolescence.
When is the brain fully developed?
- Brain size:
new born brain is 1/4 of the size of an adults
brain size is 80% of an adults at the age of 3 and then 90% by the age of 5
growth is mostly due to changes in individual neurons.
- Speed of neural processing:
a newborn transmitts info less efficiently than an adult therefore their brain is slower
increases dramatically during infancy & childhood, maximum at about age 15.
Brain development: Nature vs Nurture?
Does experience change the actual structure of the brain?
– Brain development is “activity-dependent”
– Every experience–whether it is seeing one’s first rainbow, riding a bicycle, reading a book, sharing a joke–excites certain neural circuits and leaves others inactive
– As neuroscientists sometimes say, “Cells that fire together, wire together.”
What is neuroplasticity?
The brain’s lifelong ability to change its structural & functional architecture in response to learning & experience.”
Post-natal brain development
*overall brain volume quadruples between birth and adulthood
*increase size and complexity of dendritic trees of most neurons- this is called dendritic arborisation
Dendritic arborisation of cells in visual cortex shows the increase
in dendritic length between birth to adulthood
*increase in density of synapses (synaptogenesis)
*increase in fatty sheath around neuronal fibres (myelination)- this increases the efficiency of electrical transmissions
- In the newborn brain there are also regressive changes that occur after birth.
- Synaptic densities undergo a loss of synapses, called pruning.
- The timing of these processes varies between cortical regions.
Synaptic density of visual cortex VS prefrontal cortex
synaptic density in the visual cortex begins to reach adult levels after about 2 years of age, however synaptic density of prefrontal cortex does not reach adult levels until the teenage years.
Define cognition
Processes by which knowledge is acquired and manipulated – i.e., thinking.
All mental activities involved in acquiring, understanding & modifying information.
This separates humans from other species
- A reflection of what is in the mind.
- Not observed directly –inferred from behaviour.
- Includes unconscious and non-deliberate processes involved in routine activity (e.g., reading).
Define cognitive development
Development: Changes in structure or function over time.
Define STRUCTURE with regards to cognitive development
Structure: a substrate of the organism
–e.g., nervous system tissue, muscle, limbs (physical structures) or
–mental knowledge that underlies thinking e.g., schemas or concepts
–hypothetical
Define FUNCTION with regards to cognitive development
Function: actions related to the structure
– Most commonly, something that the child does e.g.retrieving a memory, pressing a computer key, etc.
– Cognitive development; assimilation of info into schemas, performing addition.
Why is structure and function bi-directional?
Structures enable function, and function (e.g., activity) feeds back to
drive further development of structure
Function maintains the structure and allows for proper development
Give an example of when structure and function are bi-directional in newborn infants?
Newborn infants have very poor vision
– Growth of cells in the visual cortex (structure) leads to better visual
acuity
– Better acuity (sharpness) leads the baby to look at more patterns, objects (function)
– More looking stimulates further cell growth (structure)
Most development of the infants visual cortex occurs from birth to 6 months
Dynamic & reciprocal transaction of internal & external factors
Nature (biology) & Nurture (environment)
- Oldest, most fundamental issue in psychology
- Which one drives development? (genes or environment)
Currently, not an either-or issue
Genetic potential for development established at conception
Genotype is not a “blueprint”
Sets a range of potential outcomes
Phenotypic (observed) outcome depends on interaction with environment
New techniques has provided the means to address new questions about cognitive development- such as:
what does a baby know before birth? Does an infant understand the grammar of language?
The nature vs. nurture debate continues … At every stage of development, there are important genetic effects and biological
constraints at work in the unfolding of the human brain and mind. Similarly, at each stage there are critical effects of the surrounding
environment, whether at the level of a cell, a system, or the brain itself.
What is plasticity?
The ability to adapt to our environment & store information
Useful for:
1. Development
2. Learning & Memory
3. Disease & Addiction
Plasticity suggests that the nervous system is modifiable
What are the 2 areas where plasticity play an important role
- Macroscopic
Lesion studies – areas of brain damaged by injury (e.g. stroke, head injury) or surgical procedures (e.g. tumour removal, treat epilepsy) lead to changes in brain function and memory/learning
- Microscopic
a. How do individual brain areas encode new information?
– brain made up of neurones so likely that change in neuronal
function involved
b. What can we change?
–Action potentials
* APs are ‘all or nothing’ so can’t change size
* Could change probability of action potential being fired
–Synaptic transmission
Donald Hebb’s Postulate: “When an axon of cell A is near enough
to excite cell B or 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.”
State a case study that support the idea of plasticity on a macroscopic level
Patient HM (Henry Molaison)
- Developed epilepsy at age of 16
- Seizures increased in severity & frequency until he was suffering
around 11 seizures per week - Decision made to remove region of temporal lobe (where seizures
originated) - Fist-size area removed, including hippocampus, amygdala,
entorhinal and perirhinal cortices. - Epilepsy cured
- But HM lost ability to form new memories
- Researchers concluded that hippocampus is involved in learning &
memory
– Declarative – episodic and semantic (facts and events)
– Spatial (based on rodent studies) but HM had more than hippocampus removed
Why use the hippocampus to study learning & memory?
– has an identified role – spatial learning in rodents
– has a “simple” neuronal structure
check slide 30
Long term potentiation LTP (Slide 31)
Bliss & Lomo (1973)
Recorded from hippocampus of anaesthetised rabbits in vivo
Stimulation of axons at a low basal rate produced a stable synaptic response
Application of a single high frequency stimulus train resulted in a persistent increase in response size - LTP
Basal stimulation – e.g. one stimuli every 15s
*LTP induction: high frequency stimulus train
State the important basic properties of hippocampal LTP
- Long Lasting
- Input specificity
If you stimulate two independent inputs and deliver a high frequency
stimulus to one input, only that input shows LTP.
HEBBIAN PLASTICITY - Cooperativity
There is a threshold for LTP induction
e.g. 20 stimuli @ 100 Hz doesn’t induce LTP but 100 stimuli @ 100 Hz does induce LTP - Associativity
If a weak tetanus, which does not induce LTP, is delivered to one input at the same time as a strong tetanus is delivered to a second
input, the subthreshold tetanus now induces LTP – the two sets of
synapses act associatively. - Can be reversed
- Can be saturated
Induction on LTP
*CA3-CA1 hippocampal synapse is glutamatergic
* Different classes of glutamate receptors
AMPA receptor – responsible for basal transmission at this synapse
NMDA receptor – responsible for LTP induction
(also kainate and metabotropic glutamate receptors)
γDGG = AMPA and NMDA receptor antagonist
APV = NMDA receptor antagonist
When NMDA receptor binds glutamate and channel opens, magnesium ions block the channel unless the cell is depolarised.
When cell is depolarised magnesium is expelled from the channel and sodium and calcium ions enter cell
Depolarisation needed to remove magnesium is achieved by activating synapse repeatedly
Expression of LTP
Calcium influx through NMDA receptor is essential
for LTP induction
Calcium activates intracellular signalling molecules
–e.g. calcium calmodulin dependent protein kinase II - CaMKII
How is transmission increased?
– increased amount of glutamate release
– increase in the number of AMPA receptors
– increase in the current passing through each AMPA receptor
– increase in the number of synapses
Variety of mechanisms, dependent on developmental stage,
brain region, induction parameters
Does LTP = learning?
*It is Detectable
*Anterograde alteration
*Retrograde alteration
*Mimicry
Can you observe LTP after learning? (is LTP detectable?)
– initial studies showed an increase in EPSPs recorded in vivo after a
learning task, but later studies showed this was largely due to an
increase in brain temperature during learning task
– if animals are reared in a complex rather than simple environment
they show increased EPSP size
– some studies have shown an increase in glutamate release after
LTP & learning
– paper by Whitlock et al (Science, 2006, 313:1093-1097) shows an
increase in fEPSP after learning, and LTP is occluded after learning
Anterograde alteration
Do manipulations that block the induction or expression of LTP impair learning?
– blocking NMDA receptors block spatial learning (Morris watermaze)
– knockout mice lacking certain enzymes show a lack of LTP &
learning
– animals expressing reduced level of NMDA receptor subunit NR1
show decreased hippocampal LTP & reduced spatial learning
NMDA receptor antagonist AP5 blocks LTP in vitro & learning in
the Morris water maze in vivo
Retrograde alteration
Does reversing LTP cause forgetting?
– give drugs which cause LTP to be erased and see if forgetting occurs
* ZIP, an inhibitor of a protein kinase, reverses LTP and causes forgetting
* Rat hippocampus
* Spatial memory
Mimicry
*Induce LTP –should lead to formation of new memories
Other forms of synaptic plasticity
Other forms of synaptic plasticity
* Synaptic plasticity differs in different brain regions
* Long-term depression as well as long-term potentiation occur
Long term depression
Low frequency stimulation (LFS) induces LTD at CA3-CA1
synapses
Typical LFS used to induce LTD – 900 stimuli delivered
at 1 Hz (1 per second)
LTD is input specific
LTD at this synapse is dependent on NMDA receptor activation
It is also dependent on calcium influx
LTD at CA3-CA1 synapse
- NMDA receptor-dependent LTD is only seen in slices prepared from
young rats – up to about 30 days of age - Is dependent on activation of phosphatases
- Can be saturated and reversed
- Different LTD mechanism may exist in adults
Mechanisms of hippocampal LTD
Synaptic silencing may be a way of pruning synapses during development
Slide 59 for diagram
Mechanisms of hippocampal LTD
Synaptic silencing may be a way of pruning synapses during development
Slide 59 for diagram
How can LTP and LTD both be dependent on NMDA
receptor activation?
The size and time course of NMDA receptor activation and calcium influx differ between LTP and LTD induction
- LTP produces a large intracellular calcium rise for a short period of
time - LTD produces a smaller rise in calcium over a longer time scale
- Enzymes have different sensitivities to calcium
*Deliver 900 pulses at a range of frequencies
*Low frequencies = LTD
*As frequency increases magnitude of LTD decreases
*High frequencies = LTP
Describe LTP and LTD with respect to Hebb’s postulate.
*LTP = Hebbian plasticity
Synapses are strengthened when both postsynaptic & presynaptic cell are active during the induction protocol
NMDA receptor acts as a coincident detector – needs postsynaptic depolarisation and presynaptic release of glutamate
*LTD = anti-Hebbian
Synapses are weakened when both presynaptic & postsynaptic cells are active during the induction protocol
Synapses are bidirectionally modifiable
Cerebellum VS Perirhinal cortex- does LTD occur here? is so where?
Cerebellum – LTD occurs, and is involved in motor learning
Perirhinal cortex – LTD is probably involved in object recognition
Cerebellar LTD
Stimulate parallel fibres coupled with depolarisation of Purkinje cell produces LTD
ANTI-HEBBIAN
Mechanisms of cerebellar LTD
Needs activation of both AMPA & metabotropic glutamate receptors
Activation of protein kinase C essential
AMPA receptors are internalised, reducing number expressed at
cell surface
Perirhinal cortex
*Involved in object recognition memory
Record from perirhinal cortex neurones
Measure action potential firing
Present picture of a novel object, neurones increase AP firing
Present same image again, response of neurone is much reduced
LTD-like effect?
LTD in perirhinal cortex brain slices
Induced by Low Frequency Stimulation
Input specific
Dependent on NMDA receptor activation
LTD can be blocked by putting a peptide into the postsynaptic cell that interferes with removal of AMPA receptors from the cell surface
Study to support and provide as evidence:
Using a virus to express same peptide in perirhinal cortex of alive animals blocks recognition memory
Rats allowed to explore a novel and a familiar object. They will spend more time exploring the novel object.
Discrimination ratio is a measure of this – a ratio of 0 means the rat spends equal time exploring the two objects
So peptide that blocks LTD in vitro also blocks learning in vivo
Evidence that LTD = learning
Synaptic plasticity and disease
As well as being involved in learning & development, some neurological diseases involve alterations in synaptic plasticity
*Alzheimer’s disease
– problems with memory
– LTP in the hippocampus may be reduced
Are researchers looking for the right effect? LTP = learning but how do we recall information
*In animal models of Parkinson’s disease there is a loss of LTD in the striatum
*LTD in the striatum linked to motor control, which is affected in Parkinson’s disease
*Schizophrenia may involve a reduction of NMDA receptor function
*Changes in plasticity?
*Many drugs of abuse (ethanol, cocaine, amphetamines) alter synaptic transmission in brain reward pathways
*Hijack normal synaptic plasticity mechanisms?
*Multiple forms of plasticity exist
*Both LTP and LTD important for learning
*The mechanisms of LTP or LTD often differ between brain regions
*Plasticity is involved in neurological diseases
*Not all plasticity NMDA receptor dependent
*Plasticity occurs at inhibitory as well as excitatory synapses
Synapse
*transduction
*neurotransmitter
How do neurons communicate? (Visual)
Light hits the Rod and Cone cells at the back of the eye, activating the threshold value of the cell causing individual action potentials to be fired.
The more visual input (the more light) the more the cells are activated thus more action potentials fired
Learning and Memory: Neural Mechanisms
- Changes in Synapses May Be Mechanisms of Memory Storage
- The Nervous System May Form & Store Memories in Various Ways
- Cerebral Changes Result from Training
Nervous System May Form and Store Memories in Various Ways
- Physiological changes at synapses may store information.
- Changes can be presynaptic, or postsynaptic, or both.
- Changes can include increased neurotransmitter release, or
effectiveness of receptors. - Changes in the rate of inactivation of transmitter would increase
effects. - Inputs from other neurons might increase or decrease
neurotransmitter release. - Structural changes at the synapse may provide long-term storage.
- New synapses could form or some could be eliminated with
training. - Training might also lead to synaptic reorganisation.
Strengthening synapses
*Three synaptic modifications will support LTP
–Addition of receptors
–Addition of synapses
–Increased glutamate release from the presynaptic
membrane
Synaptic modifications supporting LTP – Increased receptors
- Individual synapses are strengthened by an increase in AMPA
receptors on the post-synaptic membrane
– Increases the cell’s response to glutamate release
Hypothesized mechanism:
1. Calcium activates the CaMK enzyme
2. Activated CaMK binds to an intracellular portion of the NMDA
receptor
3. Linking proteins bind to the CaMK
4. AMPA receptors bind to the linking proteins and are embedded into the cell membrane
Nervous System May Form and Store Memories in Various Ways
Structural changes at the synapse may provide long-term storage.
New synapses could form or some could be eliminated with training.
Training might also lead to synaptic re-organisation.
Synaptic modifications supporting LTP – Synaptogenesis
- LTP results in the multiplication of synapses
– Most synapses are located on dendritic spines
– LTP results in division and multiplication of these spines
Mechanism:
1. Postsynaptic density expands until it perforates – splits into multiple densities
2. Following perforation, the presynaptic active zone splits into corresponding regions
3. Perforated synapse further divides, until the spine branches
4. Branched spine ultimately becomes two spines, each containing a synaptic region
Synaptic modifications supporting LTP –Synaptogenesis
- Results in the terminal button of one presynaptic neuron synapsing
with multiple spines on the postsynaptic neuron
– Increases communication potential between the two cells - Threefold increase in synapses has been found experimentally
Synaptic modifications supporting LTP – Presynaptic changes
- LTP is associated with an increase in glutamate release by
the presynaptic neuron
–Influenced by retrograde messengers - Nitric oxide – major retrograde signal from NMDA receptors to the presynaptic membrane
- lNO is synthesized in the postsynaptic membrane in response to
calcium influx - Unstable and short-lived, can only diffuse across the synapse before
breaking down - Acts as a limited, direct messenger
slide 89 for image
Long-term depression
- Opposite of LTP, long-term depression is a long-lasting weakening
of synapses that are not associated with strong inputs/production
of action potentials– Seen when two inputs are stimulated at significantly different times, or when a synapse is activated while a cell is weakly depolarized or hyperpolarized – Results in the removal of AMPA receptors from the synapse
- Weakening of synaptic strength may be necessary when new
learning eliminates the need for previously established synaptic
modifications– Ex. Remembering a new locker combination
CREB a molecular switch for long term memory??
- Several intracellular signalling pathways are induced by neural
activity but CREB phosphorylation seems to be important to
convert memories into long term storage. - Behavioral experiments carried out in Drosophilia established
that over expression of CREB activator enhances long term
memory. - When the CREB pathway is stimulated repeatedly, it regulates the
expression of genes involved in a synaptic growth process, which
ultimately changes the connections among neurons in the circuit.
These changes in synaptic connections, distributed throughout the circuit, represent the physical basis of long-term memory.
slide 92 & 93 for diagram
Draw the: Hypothesized Memory Processes
Memory can be subdivided into 4 main categories & involve distinct brain regions.
What are they?
Short-term memory
* Prefrontal cortex, sensory association areas
Declarative long-term memory
* Hippocampus
Procedural long-term memory
* Basal ganglia, motor association areas, cerebellum
Emotional long-term memory
* Amygdala
LY filled pyramidal cell
Analyses of spine density, size, & shape in LY-filled pyramidal neurons in Layer 3 of area 46 in the same monkeys that underwent assessment of cognitive function.
These neurons have been directly linked to cognitive tasks mediated by area 46 (Goldman-Rakic) and are vulnerable to AD in human.
Why is spine size, shape & spine density important?
The importance of spine size as a reflection of plasticity:
Spine size and shape are linked to synaptic plasticity, spine stability, memory & learning.
In vivo imaging in rodent cortex shows that large spines persist and small, thin spines are transient. (e.g., Svoboda, Kasai, Gan).
Kasai’s group: Large spines (“mushroom”) have large AMPA-mediated currents & contribute to strong, stable synaptic currents. Small, thin spines are unstable, motile, weakly activated, NMDAR-dominated. Small spines can expand and stabilize or retract.
Large spines are “memory” spines, small spines are “learning”spines (Kasai, TINS, 2003).
NeuronStudio (Wearne and colleagues): Automated spine size & shape in minutes with higher quality data than manual analyses.
Spine analyses of layer 3 neurons in dlPFC (area 46) in young & aged rhesus monkeys: 33% of the spines are lost with ageing (36% by EM). Size profile shows that small spines are vulnerable to ageing.
Spine number, size classifications, and cognitive performance in dlPFC
All age- related spine loss in dlPFC is accounted for by the loss of highly plastic small, thin spines, and the smallest are the most vulnerable.
This same spine class is responsive to estrogen (estradiol). The loss of these spines is highly correlated with cognitive decline. Preservation of mushroom spines may be related to retained expertise.
Spines on Dendrites
They become less dense and lose spines
Summary
- Brain development is a dynamic, adaptive process.
- Different kinds of process are involved in memory formation (STM
or LTM). - Memory consolidation is proposed to happen by molecular
pathways involving CREB and gene expression - Age-related cognitive decline is likely associated with a loss of
spine/synapse formation, turnover, and structural plasticity.
Current hypothesis: Cognitive performance requires new spines and
synapse turnover, whereas the memory demands of hippocampus are more closely related to stabilisation of existing synapses and molecular alterations of relatively stable synapses.
