I2 - LTP + LTD Flashcards
(94 cards)
1
Q
what do dendritic spines reveal about inputs to a neuron?
A
how many inputs a principal neuron receives
2
Q
where in the brain that is relevant to LTP receives excitatory inputs?
A
cortex, amygdala + hippocampus
3
Q
what happens to memories in diseases where synapses are non-functional?
A
memory formation, retention or access is cooked
4
Q
what is an engram?
A
theorized physical or chemical change in the brain that represents a memory, a lasting modification in neural tissue resulting from a learned experience
5
Q
how might you create a conceptual engram?
A
make 2 neurons statistically more likely to fire together than other neurons in the network
- change the performance of synapses that connect the 2 neurons
6
Q
how does the hippocampal network work?
A
- 3 cell sets – granule, CA3 and CA1 (trisynaptic loop)
- all are excitatory, with some neuroinhibitory modulation
- ~200,000 cells per layer, ~10k inputs per cell
7
Q
what is an LTP?
A
transformation of an EPSP elicited in one cell by an AP in other from one size to another size
and then maintenance of that increased EPSP magnitude for a long time
8
Q
describe Bliss & Lomo’s 1973 expt that first recorded LTPs
A
- short high freq bursts of neural activity in rabbit DG -> augmentation + long lasting increase in EPSP size
- resembled real life as a short burst is like hearing someone’s name once
9
Q
what was Bliss’ follow up study to the discovery of LTPs?
A
1973
followed potentiation in anaesthetised rabbit for 16 weeks – LTP still observed after 16 weeks
- also phenom sustained for entire mouse life (2 years)
10
Q
what is Hebb’s postulate?
A
When an axon of cell A is near enough to excite cell B and repeatedly takes part in firing it, some growth or metabolic process occurs in one or both cells such that A’s efficiency, as one of the cells firing B, is increased. (1949)
an LTP is Hebbian
11
Q
name some important figures in LTP research in the late 1970s/early 1980s. what did they discover?
A
Malenka
Andersen
McNaughton
Barrioneuvo
discovered you can generate an input-specific LTP, at a single synapse while its neighbour, nor the whole cell, does not express the same LTP
12
Q
who discovered LTP is dependent on NMDAR? how?
A
Collingridge et al 1983
if you block NMDAR with APV (comp inhibitor), does not affect basal transmission
if you try to induce LTP in presence of APV, you can’t, but if APV is washed out, you can again
NMDA must be linked to LTP induction process
13
Q
what is the condition under which NMDARs are functional?
A
membrane of the cell its in is depolarised
has to displace Mg2+ from the mouth
14
Q
why is the Mg2+ held in the NMDAR?
A
-ve internal charge of the cell
can be pushed out electrostatically when the membrane becomes +ve
15
Q
how is a NDMAR-containing cell usually depolarised?
A
- carriage of EPSP mediated by AMPARs
- glut binds AMPA -> current flows down steep ECG for Na+ into cell -> EPSP
16
Q
how does a membrane become depol enough for NMDAR to open?
A
if there are sufficient glutamate releases to produce multiple EPSP (temporal summation)
17
Q
what are the 2 conditions (the gate if you will) for NMDAR to become functional?
A
- glutamate is bound to post-syn
- post-syn depol has occurred
then Ca2+ can flow
18
Q
what is the evidence that Ca is necessary + sufficient for LTP?
A
Lynch 1983: NMDARs are essential for LTP due to the Ca that they allow to flow
- mopped up Ca in the post-syn neuron with EGTA -> LTP blocked
Malenka 1988: if you artificially elevate intracell Ca through photolysis -> induce LTP
19
Q
what happens if CaMKII is inhibited or KO’d?
A
animal cannot learn or form declarative memories: LTP is blocked
20
Q
who made the first use KO animal in LTP studies?
A
Silva et al 1992
KO a-CaMKII
found animal could not learn
21
Q
What did Lledo et al 1995 find wrt LTP and CaMKII?
A
if you provide neurons with a preactivated version of CaMKII, LTP is manifested
22
Q
what is the hypothesis of CaMKII involvement in LTP?
A
AMPARs open -> NMDARs open -> CaMKII activated. then:
CaMKII phosphorylates AMPAR -> more likely to be open subsequently -> membrane depol -> Ca influx to same extent as NMDAR without need for NMDAR
but phosph has finite lifetime, so cannot be the full explanation
23
Q
describe Malinow’s 1989 expt on LTP
A
- H-7 (PKC + CaMKII inhibitor) added to brain slice once LTP established
- if repeatedly phosphorylating targets is the answer to LTP, it should disappear
- use this format to test enzymes for responsibility in LTP
- kinase inhibitor makes no difference
24
Q
what enzymes have been demonstrated to play a part in LTP, and by who?
A
- PKC (Malinow 1989)
- PKA (Frey 1993)
- ERK (Winder 1999)
- TK (O’Dell 1991)
25
which enzyme might represent a 'master switch' for LTP?
PKMzeta -- once it is activated it stays activated indefinitely (though has finite lifetime) so phosphorylates for days/weeks once synthesised
could keep activating 2nd messenger cascades once phosphorylated
26
what was the initial evidence for PKMz as a master switch?
Ling 2006:
- staurosporine = conventional PKC inhibitor, doesn't block established LTP
- chelerythrine = atypical PKMz inhibitor, does block LTP
- developed ZIP (z inhibitor peptide), claimed it deleted LTP + learning capacity in mice
27
what was the contradicting evidence against PKMz as a master switch?
Volk 2013:
generated KO for PKMz in mice
LTP is still normal, can PKMz can't be that important
but ZIP still works as inhibitor
- but there might be a compensatory protein filling in the PKMz role (downsides of KO) -- PKM lambda perhaps, but noone convinced
28
how did researchers initially try to measure whether change in EPSP observed with LTP had a pre-syn component?
Catz statistical methods
but too complicated and arbitrary
29
describe optic interrogation
- FM1-43, styryl dye put onto membrane leaflet
- stimulate cell, undergoes endocytosis, dye is now on inner leaflet of the vesicles
- wash off the dye from the outside of cells
- stimulate cell and watch the rate at which dye leaves
- if LTP changes likelihood of vesicles being released, terminal gets dimmer faster
Zakarenko et al 2001: FM1-43 decline is accelerated after LTP induction
30
what is optic quantal analysis?
- load brain slice neurons with Ca reporter dyes
- stimulate input onto individual dendritic spines, image them
- Ca increases within spine
- measure increase with laser beam and plot as a function of time/space
- rise correlates to incidence of EPSP as recorded electrophysiologically
- 2 different optical methodologies point towards involvement of pre-syn locus
31
what did Emptage 2003 discover with OQA?
probability of synapse releasing NT and generating a Ca signal is greater after LTP than before
controls - block NMDAR
32
what is retrograde transmission?
transmission of signal from post-syn to pre-syn neuron
crucial for regulating synaptic plasticity and transmission and overall neuronal circuit function
33
how does the pre-syn neuron know LTP has been induced in the post-syn neuron?
* activation of NMDA also activates enzyme to send signalling entity back to pre-syn
* NO can activate pre-syn cGMP -> modulates NT release probabilities [Schuman & Madison 1991] [Garthwaite group]
34
what is the difference between pre-synaptically and post-synaptically expressed LTP?
pre-syn: changes release probability of vesicles
post-syn: lead to changes in AMPAR performance
[Padamsey 2017 review]
35
how does pre-syn LTP relate to post-syn LTP?
pre-syn LTP engages NO synthase
pre-syn NMDARs are involved
pre-syn neuron regulates release of NT depending on performance of post-syn cell, and is fed back on by NO (retrograde messenger)
- seems to add additional data to the process than just a post-syn LTP
36
what is a silent synapse?
a population of synapses on excitatory CA1 neurons that contain only NMDAR and no AMPARs, but show AMPAR insertion after LTP induction [NMDAR dependent as shown by APV studies]
AMPARs could be unmasked by a random depolarisation of the membrane, or inserted by lateral diffusion/exocytosis
37
how can we make silent synapses show current?
- depol to +30mV -> relieve Mg block artificially under voltage clamp -> synaptic events
- these events must be NMDAR currents since there are no AMPARs
38
what are the 2 forms of hippocampal LTP?
- NDMAR-dependent, rise in post-syn Ca [locus of expression uncertain)
- NMDAR-independent, found at mossy fibre synapses, requires rise in pre-syn Ca
39
is there any anatomical evidence for silent synapses? or is it a weird artefact of the voltage clamp?
Liao 1999:
- fluorescently labelled NR1 [NMDA] (red) and GluR1 [AMPA] (green)
- see loads of NR1 only in dendritic spines (NR1 only synapses)
- also loads of yellow (both), meaning both AMPA + NMDA
- very few green
40
describe Shi et al 1999's expt about AMPAR insertion into dendritic spines
* attached GFP to GluR1 in AMPAR subunits
* induced LTP in neurons by tetanical stimulation, observe where subunit is inserted
* 30 mins post-LTP, see clear fluorescence of dendritic spines -> GluR1 subunits are brought to the surface and can be optically visualised as discrete spines
* does not occur if APV also applied, suggests NMDAR-dependent process
41
how might AMPARs be maintained at the membrane?
by changing subunit composition [think Yo Sushi]
- LTP induces insertion of AMPARS, cell biological machinery keeps them there
- proteins are maintained at the site of insertion until synapse is instructed otherwise
- biological conveyor belt of sustenance
seems like there is diffusional trapping of GluR1 AMPARs by input-specific synaptic activity [Ehlers 2007]
42
how do AMPARs and NMDARs align with each other? who investigated this?
Racca et al 2000 -- immunogold labelling (add gold to receptor via antibody)
- in mature tissue (adult mice), NMDAR + AMPAR are coexpressed at the majority of synapses
- there are few silent synapses in an adult (you need less learning in adulthood??)
43
how might you be able to reset saturation of LTP?
homeostatic plasticity - happens across all synapses as a response to change in activity
- rescaling, patterns are conserved but the memory has a lower magnitude
44
what is Turrigiano's 1999 expt on homeostatic plasticity?
* change activity in cell network via added TTX to block Na channels, or GABA antagonists to increase AP incidence
* if reduce activity, EPSCs incr
* if enhance activity, EPSCs decr
* found that the incr and decr were scaled and not generic
45
what is dendritic democracy?
a normalisation of synaptic inputs so that EPSP value is protected, and is the same as when it was potentiated at the axon hillock
46
why is dendritic democracy needed and how is it achieved?
current decays with distance based on cable diameter -- do the strengths of the initial EPSPs actually matter then as something potentiated further away would have less of an impact on the genesis of AP than something less important but closer
- ion channels in different parts of the dendrites differ, scale the EPSP appropriately
- though many sources of confusion
47
so what is the overall integrative idea of plasticity?
you can turn the synapse on or off
and then tune it by modulating probability of NT release
and also have a dendritic democracy supporting inputs at various distances from the site
and homeostatic plasticity allows synaptic scaling of the whole thing
48
how do you initiate LTD through a stimulus regime?
1Hz 900x
causes synaptic response to decrease stably below baselines
but is there anything in a neural network that's likely to stimulate something 900x
49
what are the 3 methods of LTD induction?
- NMDAR dependent LTD
- Ca2+ dependent LTD
- metabotropic LTD
50
describe properties of NMDAR dependent LTD
induced by: low freq bursts
sensitive to: blockade of NMDAR (eg. AP5)
NMDARs contribute to LTD as they do to LTP
[Dudek & Bear 1992]
51
describe Ca2+ dependent LTD
* synapses weaken in response to specific patterns of activity -- when post-syn neurons receive Ca2+ influx after low-freq stimulation
* arose from a conceptualised renormalising of synaptic weights via mathematical rule (BCM model) to combat Hebbian plasticity saturation
- i.e. if plasticity is saturated, organism cannot learn further
- based off vibes [Bienenstock, Cooper and Munro 1982], but retrospectively correct
52
describe metabolic LTD
metabotropic GluR1 or R5 can be blocked pharmacologically
- LTD observed, linked to IP3, Ca dependent signalling pathway involving Ca stores
- though seems mechanistically different to Ca dependent processes, as Ca does not enter through NMDARs, but Ca flow is supplemented by them [Oliet 1997]
also Otani & Connor 1998
53
what about endocannabinoid involvement in LTD?
- in KOs, antagonists to eCB receptors aren't so good
-when eCB1 deleted, LTD cannot be induced in that pathway -- eCBR-dependent form of LTD
- but expts done in visual cortex not hippocampus
54
what is some evidence for mechanisms of LTD expression?
Lee (1998), Banke (2000) thought as kinases were involved in LTP, phosphatases would be invovled in LTD:
- removing phosphorylation reverses LTP predisposal, reducing sensitivity
Hey-Kyuang 2003:
- removed phosph sites from AMPAR subunit
- double KOs, no phosph sites on GluR1 -> cannot get LTD
Malenka 1993:
- protein phosphatase 1 (PP1) inhibitors vlock induction of LTD
- PP1 not Ca sensitive, but NMDAR + metabotropic LTD has ca-sensitive component
- could be calcineurin (Ca/CaM dependent phosphatase [Mulkey 1994]
cAMP analogues inhibit induction of LTD - cAMP is involved
55
what determines whether LTD or LTP is generated, if they both depend on Ca and NMDARs?
the floating parameter of [Ca]: determines whether phosphatases or kinases are activated
- calcineurin senses Cs and drives PP1 to dephosph relevant synaptic targets
- PKA blocks activation of PP1
* LTP requires lots of Ca for short period to activate Ca-dependent cAMP -> PKA -> blocks PP1 -> cant get LTD when there is a lot of Ca from short bursts of high freq activity
* Low freq activity generates small elevations in Ca over a long period -> doesn't activate cAMP -> PP1 is active -> LTD
56
what happens to AMPARs upon LTD induction?
rapidly internalised
can be lateralised at synapses
AMPAR endocytosis
57
are there pre-syn components to LTD?
yes, in all forms described
Zakharenko et al 2002: NT release decreased when mGluR LTD is induced
FM1-43 destaining is decreased
58
What did Griffiths 2008 argue?
LTD codes different sorts of memories to LTP
we are not convinced
expt doesn't examine memory coding as a balance of synaptic weights e.g. some pathways potentiated and some depressed during learning + memory
this would imply that manipulation of either LTP or LTD would alter the encoding of a memory
59
name post-syn mechanisms of expression of synaptic plasticity
* AMPAR trafficking
* post-translational modification of AMPARs
* structural plasticity
60
name pre-syn mechanisms of expression of synaptic plasticity
* changes in release probability
* regulation of vesicular release
* retrograde signalling
* structural plasticity of pre-syn terminals
61
what are the concepts of plasticity that may co-exist?
homeostatic plasticity, dendritic democracy and synaptic (Hebbian?) plasticity
62
what is the synaptic plasticity and memory (SPM) model?
rooted in Hebbian plasticity 'fire together, wire together'
- 2 types now posited (early and late LTP), LTP is stronger
- synaptic plasticity encodes memory and learning
- supported by the fact it shows input specificity and associativity
63
what is the the synaptic tag and capture model?
if E-LTP and L-LTP are induced a 2 synapses close to each other, synapse experiencing E-LTP will use vital synaptic proteins from L-LTP synapse to form L-LTP connection
- events that occur in temporal proximity are bound in memory together
- thus engrams form - plasticity at specific synapse encodes entire associative memory
64
what is evidence for LTP's involvement in long term memory?
Shema 2007: giving PKMz inhibitor ZIP in rat insular cortex -> forgetting long-term associative memories (conditioned taste association), for upwards of several weeks, maybe permanent
- long term memory is contingent on PKMz long after we would consider it 'consolidated'
- ability to relearn is not hindered
Shema 2011: overexpressing PKMz in rat insular cortex (lentivirus microinfusion) enhances long-term memory compared to dominant -ve version of PKMz
Hayashi-Takagi 2015: optogenetically depotentiating spines of rodents (AS-PaRac1 optoprobe) active during motor learning task erases memory. new motor skill requires formation of task-specific dense synaptic ensemble
65
what does recent data suggest about LTP?
it is the substrate of memory retrieval rather than formation
i.e. does LTP block actually erase a memory, or just prevent it being accessed?
66
what is some evidence that LTP is the substrate of memory retrieval not formation?
Nabavi 2014: optogenetically-induced CS-US (conditioned stimulus-unconditioned stimulus) tone-footshock can be caused to be forgotten by LTD induction, and retrieved again by LTP
Ryan 2015: using protein synthesis inhibitor anisomycin after a task could cause memory 'loss' but could be retrieved if these cells in the engram were optogenetically activated again
Bannerman 2012: hippocampal GluN1 KO mouse inhibits CA1 LTP. [more evidence see other card]
plasticity does not seem to store the memory itself but allow access to it
67
describe Bannerman's 2012 expts in hippocampal GluN1 KO mice
* mice just as good as controls in Morris water maze learning: NMDA-dependent LTP not necessary for learning
* had deficit in reversal learning when platform moved (animals kept returning to original platform)
* spatial discrimination task: shown 2 black footballs, use spatial cues to dissociate which was 'escape' ball, KO mice went to wrong ball first when placed near it
* problems with disambiguation of competing spatial memories -> plasticity necessary for memory retrieval
68
what is habituation?
the diminishing of an innate response to a frequently/recently repeated stimulus
69
how might plasticity be linked to habituation? what are some expts?
plasticity plays a role in some form of learning + memory encoding but the SPM hypothesis doesn't stand
Sanderson 2011: GluA1 KO mice in operant boxes, show light then 30s later the same or a different light. KO mice show less interest in different light
Zamanillo 1999: WT show increased exploration of novel arm of Y maze, while KOs for GluA1 don't -- AMPAR plasticity has a role in behaviour??
70
what does GluA1 KO model?
GluA1 receptor of AMPAR has been removed, no LTPs
71
what are other options for the cellular substrate of learning + memory encoding/storage?
DNA methylation ***
poly-ADP-ribosylation
matrix metalloproteases altering ECM -> neurons can form more physical contacts
- combines with and facilitates RNA release during transmission?
72
what is evidence for DNA methylation's involvement in learning + memory storage?
Biergans 2015: DNA methyl patterns change in bees after they were trained on a task
Halder 2016: methyl changes after contextual learning in mice
but you would expect plasticity (which alters gene expression) to alter methylation, so does not indicate methylation is responsible + there is also no mechanism
Miller 2010: inhibition of DNA methylation 1 month after association learning disrupts memory (DNA is maybe the 'memory trace' then)
in aplysia (sea slug), PARP-1 is activated in neurons that mediate long term memory
73
what was the expt in Aplysia by Bedecarrats 2018?
injection of RNA from trained animal to naive animal could successfully transfer the memory of sensorimotor reflex
genetic material is in some way linked to memory formation, though this is very simple model of learning
74
what is evidence of polyADP-ribosylation involvement in memory formation?
Cohen-Aromon 2004: suggested that fast and transient decondensation of chromatin structure by polyADP-ribosylation enables the transcription needed to form long-term memory without strand-breaks in DNA
later reiterated in mice by Goldberg [2009]
75
how might DNA methylation model account for input specificity?
Arc protein? Arc mRNA can be translated upon arrival into post-syn neuron
changes AMPAR trafficking by modifying cytoskeleton of dendrite, altering post-syn excitability -- but no evidence for alteration of methylation to maintain a 'trace'
maybe release of miRNA, circRNAs in synaptic endosomes during transmission
76
how can we reconcile the plasticity and DNA methylation models?
plasticity may facilitate the retrieval and habituation aspects of memory while methylation encodes the memory trace
synaptic plasticity must be important in driving changes in DNA methylation itself, so memory as a whole relies more on this process
other mechs involved?
77
how does experimental induction of LTP differ to physiological?
LTP expt: hundreds of high freq, quick succession bursts
phys: 2 or 3 APs through spike-time dependent plasticity (STDP)
early expts may have missed pre-syn mechanisms
78
give a concise conclusion to the question 'is LTP a pre-syn or post-syn phenomenon?'
* evidence suggests LTP is governed by increased trafficking + insertion or de novo synthesis of AMPARs in dendritic spines after LTP -> sets new basal level for AMPAR recycling
* for the same release of glut you get more inward current due to more AMPARs available on post-syn mebrane
* but must match pre-syn, bc there might then not be enough glut to bind all of them to cause EPSP
* both pre-syn and post-syn loci are therefore important for induction + maintenance
79
what do silent synapses demonstrate?
phosphorylation pathways may not only drive modulation of channel activity but phosphorylation of enzymes involved in AMPAR insertion pathway
80
what are the limitations of the silent synapses study?
basically looked at some synapses and kept reducing the stimulation intensity until they couldn't see anything at -60mV, so how physiological it is we do not know
81
how was LTP shown to be dependent on NMDAR? what does this suggest about LTP?
1983: administered APV (NMDAR blocker) to a synapse, did a 100Hz stimulation for 1s and saw no LTP
if APV was washed out, LTP was induced
suggests LTP is a post-syn mechanism, though may cause retrograde transmission leading to pre-syn plasticity + LTP maintenance. NMDARs are also pre-syn.
82
what is the disadvantage of not using optical quantal analysis?
- recording EPSPs in the CNS is non-specific, you don't know if the EPSP is being caused by that synapse or by one of the 10,000 synapses the neuron has
- cannot be sure that the EPSP you record is big bc the electrode is close to the synapse or the synapse has released LOADS of NT
- need something more refined
83
what does 'caging' a molecule mean?
rendering it inactive by attaching a light-sensitive 'cage' molecule, preventing it from activating its receptors
cage can be broken down by light exposure
84
briefly summarise the conclusions of Padamsey 2017 and explain significance
* concludes changes in glut release probability (Pr) are determined by 2 opposing processes at active pre-syn terminals: Hebbian activity promote LTP(pre), while glut release promote LTD(pre)
- promote LTP(pre) -> does not need glut release, involves post-syn depol triggering L-type VGCCs -> NO synthesis and retrograde action on pre-syn terminals that WERE ACTIVE DURING NO RELEASE (Hebbian). suggests role of post-syn NMDARs is indirect
- promote LTD(PRE) -> transiently elevated synaptic glut (e.g. high freq bursts or photolysis) triggers this. mediated by action of pre-syn NMDARs, blocking them abolishes LTD(pre), while blocking post-syn NMDARs does not prevent LTD(pre)
net change in Pr is result of balance between these 2 opponent processes. allows presyn terminal to tune release probability, as influenced by its own activity
85
what does Padamsey 2017 suggest the outcome of LTP(pre) in the CA3-CA1 connection is?
to match up pre- and post-syn signalling
- pre-syn has +ve influence on Pr via retrograde NO (Hebbian), but -ve influence via NMDA autoreceptors
- balance of pathways matches glut release with post-syn depol to ensure balanced system through synaptic trial and error (?)
86
what molecules other than NO are proposed to be retrograde signallers?
CO, arachidonic acid, PAF
87
is there any proposed loci of NMDA-independent presyn plasticity?
mossy fibres connecting dentate gyrus to CA3 neurons hypothesised to have only this pathway
each DG mossy fibre only connects to ~50 CA3 neurons
88
how do you determine if LTP is pre-syn or post-syn?
pre-syn: caused by increased in transmitter release
post-syn: caused by insertion of AMPARs due to 2ry messengers
89
is LTD just the converse of LTP?
certainly it is the conceptual opposte:
- kinase vs phosphatase
- AMPAR insertion vs extraction
- spine heads grow vs shrink
- level + timing of Ca influx determines whether LTD or LTP is induced
together they allow for activity-dependent bidirectional modification of synaptic strength, both have pre and postsyn expressions
does LTD encode different sorts of memories to LTP?
clearly not a simple mirror image/reversal
- differences in induction rules (STDP timing, location dependence)
- interplay of opposing forces, Hebbian potentiation and glut's depressing effect on Pr
LTD is a distinct form of synaptic modificatin, but not negation of LTP
90
is homeostatic plasticity involved in encoding memory content?
not directly
but suggested to contribute to dynamic control system which governs how info if extracted from or hidden within neurons depending on the state of the network
- i.e. could influence accessibility or retrievability of memory
- also homeostatic replenishment of steady state components could contribute to maintaining specific configurations (actin polymers, scaffold proteins) that support memory
91
what signalling casades does CaMKII actvate?
Rho family GTPases
* primarily RhoA and Cdc42
* regulate actin-binding proteins such as cofilin and profilin
* converge on LIMK1
* LIMK1 phosphorylates ADF/cofilin, inhibiting actin depolymerization, expanding dendritic spine volume, and contributing to the induction of LTP.
92
what 2 things influence changes in release probability (Pr)
* Hebbian activity (increases Pr)
* glutamate release (decreases Pr)
net changes depend on relative strength of these
93
why and how does glut release cause decrease in Pr?
* glut activates pre-syn NMDARs (uniquantal release detectors) [**McGuiness 2010**]
* this is regardless of level of post-syn depol
* this appears to rely on NMDAR's ionotrpic signalling
94
how does Hebbian activity increase Pr?
* through L-VGCC and NO-dependent signalling
* i.e. coincident pre and postsyn firing
