NEUS 609 - LTP & LTD

Long term potentiation

aka LTP

long-lasting increase in neuronal response, strengthening of the synapse that follows coincident activation of pre- and post-synaptic neurons

• cellular mechanism by which info is converted from short to long-term memory

• Depends on Ca2+ levels in the POSTSYNAPTIC neuron

• different LTP mechanisms at different synapse working at different time points

hippocampus

LYP happens EVERYWHERE but was discovered in the ___ as it is the region of memory formation

dentate gyrus

inner structure of the hippocampus looking like a little “C”

CA3

structure part of the bigger looking “C” closer to the dentate gyrus

CA1

structure part of the bigger “C”, top of the general hippocampal structure

entorhinal cortex

Thicker region at the top end of the “bigger C” aka at the end of CA1

perforant path

pathway through which info ARRIVES at the hippocampus aka the axons of entorhinal cortex 

direct pathway

layer III of entorhinal cortex to pyramidal cells of CA1

• excitatory input

• lesions in this pathway do not prevent initial learning, but prevent consolidation aka long-term storage

trisynaptic pathway

originates form layer III of entorhinal cortex to granule cells of dentate gyrus

• excitatory input

• aka indirect pathway

• lesion in this pathway limit spatial learning tasks but some learning still possible

mossy fiber pathwayway

from granule cells in DG to the pyramidal cells of CA3

• excitatory input

Schaffer collateral pathway

CA3 pyramidal cells to CA1 pyramidal cells

• become commissural if crossing the midline

• excitatory input

ALL

inhibitory interneurons are found in ___ layers of hippocampus

cell nomenclature letters

location—orientation—projection area(s)

25, subtypes

inhibitory cells represent __% of the population, but have many more ___ compared to excitatory cells

high frequency, tetanus

To experimentally generate LTP, you need intense activation of a pathway increasing the subsequent response

• done via ___ exposition using ___

Testing done after exposition to stimulus in normal setting. Only the pathway exposed to stimulus increases its response to form LTP.

L-Ca2+

Different mechanisms underly LTP at different synapses and different pathways

• usually, postsynaptic ___ channels dependent

Non-associative LTP

Based on following pre-synaptic mechanism:

1. modulator norepinephrine (NE) acts on postsynaptic receptor activating adenylyl cyclase (ADC)

2. ADC convert ATP to cAMP

3. cAMP activates cAMP-dependent kinase A (PKA)

4. PKA phosphorylates additional proteins ultimately ending in increased NT release

Associative LTP

Based on thinking, Pre and Postsynaptic activity must be COINCIDENT

• coincidence detected by NMDA receptor thanks to the Mg2+ blocking the channel until sufficient postsynaptic activity changes the membrane potential enough

activity, NMDA receptors

The 2 factors needed for coincidence to happen are presynaptic ___ (or experimental additional GLU) and postsynaptic ___

induction

transient event that triggers the formation of LTP

• NMDA receptor responsible for this phase

amplitude/initial slope

To measure the expression of LTP, you measure the ___ of EPSP

induction mechanism

1. postsynaptic depolarization

2. activation of NMDA receptors

3. postsynaptic influx of Ca2+ (activates protein kinases)

4. 2nd messenger molecules

AMPA

Expression of LTP characterized by:

• INCREASED NUMBER or SENSITIVITY of ___ receptors

• retrograde messenger nitric oxide (NO)

• increased NT release from presynaptic terminal

expression = addition of __ receptors to membrane and/or phosphorylation of the ones already there

maintenance

persisting biochemical signal in a cell that ultimately results in the expression of LTP

consolidation

aka late LTP

phase lasting beyond 1 hour

requires protein synthesis (& more training/high frequency exposure)

• blocking protein synthesis only block late LTP, thus preventing ___

growth of new synapses

Protein synthesis is needed in late LTP for the ____

mechanism of late LTP

1. Normal LTP initiation as NMDA receptors activate, Ca2+ kinases activate, and there in an increase in number/sensitivity of AMPA receptors

2. Repeated high frequency exposure causes Ca2+ influx which recruits ADC, increasing cAMP levels, activating PKA, which ultimately activates MAP kinase

3. MAP kinase translocated to the nucleus and phosphorylates CREB-1 TF

4. CREB-1 activates transcription of targets leading to growth of new synaptic connections

5. Repeated high frequency exposure also activates translation in dendrites encoding active form of PKC

Long term depression

aka LTD, allows us to forget things

long lasting decrease in magnitude of responses of neurons after afferent cells have been activated with electrical stimuli of relatively LOW frequency

removed, NMDA, Ca2+

LTD ultimately leads to AMPA receptors to be ___ from the membrane

• still requires ___ receptors and postsynaptic __ entry just like LTP

LTD mechanism

Low and prolonged internal Ca2+ entry activates phosphatases (calcineurin for ex) that DEPHOSPHORYLATE the AMPA receptor and lead to the internalization of these receptors.

synaptic strength

BOTH LTP and LTD use the NMDA receptors and Ca2+ postsynaptic activity (high and brief for LTP, low and prolonged for LTD) so the ___ will depend on which process prevails/is more active

timing

As presynaptic and postsynaptic activity need to be associated for any synaptic plasticity mechanism, ___ is an important factor

polarity, magnitude

Timing of pre and postsynaptic activity codes for ___ and ___ of plasticity

• postsynaptic AP occurs after presynaptic activity = LTP

• postsynaptic AP occurs before presynaptic activity = LT

narrow, wider

the window for LTP is quite ___ compared to the __ one of LTD, which is why it is more likely to forget than to remember

Sliding Modification Threshold

aka SMT

phenomenon happening after LTP induction making it easier to produce LTD at the same connection.

• threshold frequency slides to the right after LTP induction, meaning you need higher frequency to induce it again

• threshold frequency slides to the left after LTD induction, meaning you need lower frequency to induce it again

associativity

association of a normally weak stimulus to a stronger one makes it more likely to be remembered

• Like Pavlovian conditioning

cooperativity

2 weak stimuli happening together makes it more likely for each to them to be remembered

• A threshold must be overcome -Ensures only events of significance will the memory get stored.

synapse specificity

More likely to remember information linked to a strong stimulus

• Information not related to a particular event will not get stored.

spatial memory

demonstration of synaptic plasticity using the water maze assay and blockers and enhancers

• preventing autophosphorylation of Ca2+ mediated kinase II = tetanus induced LTD instead of LTP = no learning = no __

• blocking NMDA receptors = no __

• blocking NMDA receptors after LTP = no effect

• blocking active form of PKC in dendrites after LTP = no maintenance = no ___

• deletion of NR1 = no LTP = no ___

• enhancing NR2B enhances ___