short-term memory Flashcards
what is a memory
change in behavior of the organism = memory of the experience that caused the change
what kind of change must happen so an experience has an impact on future behavior
physical change; molecular or biochemical change in function of the neuron
how can computers make memories (3)
- charging a capacitor
- making a very small magnetic field (hard drive)
- quantum electrical tunneling (USB keys)
biological ways of storing memories (6)
- changes in phosphorylation state
- insertion or removal of membrane proteins
- persistent activation of protein kinases
- production of new proteins
- morphological changes at pre-existing synapses
- new synapses
reductionist approach to discover how biological organisms replicate (4)
- define question: how do biological organisms replicate?
- find simple system that still gives insight into question: 1 bacteriophage infects a bacteria; 20 minutes later, 100 bacteriophages come out
- use system to reduce question as much as possible: what molecules do bacteriophages replicate in the bacteria?
- answer question: DNA
reductionist approach to discover how DNA replicates (4)
- question: what about DNA allows it to replicate?
- simple system: x-ray crystallography of DNA
- reduce question: can’t reduce it further
- answer: double helix
reductionist approach to how memories are made (4)
- question: how are memories made?
- simple system: aplysia have large invariant neurons and they make memories
- reduce question: which neurons store the memory and how do those neurons change after memories are made?
- answer: sensory neurons; change in protein phosphorylation
habituation vs sensitization in aplysia
habituation: decrease in defensive reflex due to repetitive non-noxious stimulation
sensitization: increase in defensive reflex due to noxious stimulus
what kind of stimulus creates habituation and sensitization
conditioned stimulus triggers habituation; unconditioned (shock) stimulus triggers sensitization
what are non-associative memories
learning that doesn’t require association bw conditioned and unconditioned stimuli
change in aplysia behavior when sensitized and habituated
sensitizes: noxious stimulus to head/tail causes increase in time and extent of gill withdrawal to touch to siphon
habituated: repetitive touches to siphon causes decreased gill withdrawal (without shock)
how do you measure synaptic strength
- place electrode in post-synaptic cell
- fire AP in pre-synaptic cell
- measure voltage change (post-synaptic potential) -> measures synaptic strength
EPSP while stimulating siphon of aplysia every 10 min
with every touch (10 min interval), the EPSP decreases -> habituation
EPSP after habituation and coupled with shock
increased EPSP -> sensitization (novel stimulus)
effect of habituation on sensory and motor neuron of aplysia
didn’t decrease the ability of the sensory neuron to fire APs; decreased size of EPSP in motor neuron
effect of sensitization on sensory and motor neuron of aplysia
increased EPSP in motor neuron after single AP in sensory neuron
what mimics shocking the tail/stimulating the nerve of aplysia
application of 5HT
action of 5HT on synaptic strength
sufficient to increase synaptic strength bw sensory and motor neurons
effect of removing 5HT-containing neurons on synaptic strength
reduced sensitization
action of 5HT during sensitization (2)
- 5HT-containing neurons fire during sensitization
- 5HT released during sensitization
circuit underlying sensitization in aplysia (5)
- shock to tail -> activates sensory neuron
- sensory neuron activates 5HT neuron
- release of 5HT on sensory neuron in siphon + motor neuron
- siphon sensory neuron synapses motor neuron
- motor neuron causes gill withdrawal
behavioral habituation and cellular depression
behavioral habituation -> repeated touches leads to decreased withdrawal;
repeated touches = repeated firing of sensory neuron -> leads to less release and decrease of EPSP to motor neuron -> decreased withdrawal
behavioral sensitization and cellular facilitation
behavioral sensitization -> shocking tail/head leads to increase of withdrawal; shocking nerve/adding 5HT -> more release and increase of EPSP to motor neuron -> increased withdrawal
how can synaptic strength be increased (3)
- releasing more transmitter/AP
- increase effect of releasing same amount of transmitter by having bigger post-synaptic response (increase chance of NT release)
- more synapses
M=NPQ: meaning of each letter
M = strength of synaptic connection
N = number of synapses or release sites
P = probability of release of synaptic vesicle after an AP (0 to 1)
Q = amplitude of EPSP from release of 1 vesicle
how can N, P and Q be controlled by proteins (2)
- change which proteins are present (transcription, translation, proteolysis)
- modify proteins that are already there (PTMs)
how do proteins get phosphorylated
protein kinase takes P from ATP and places it on protein (ATP -> ADP)
aa which are phosphorylated (3)
serine (S), threonine (T) and tyrosine (Y)
types of kinases (2)
- kinase that phosphorylates serines and threonines
- kinase that phosphorylates tyrosines
effect protein kinases inhibitors in sensory and motor neurons
sensory neurons -> blocks facilitation
motor neurons -> no effect
what causes changes in P & Q
changes in P -> changes in presynapse
changes in Q -> changes in postsynapse
changes in P & Q in 1st few minutes of facilitation
P changes; Q (EPSP) doesn’t change
how can we control P (3)
- modulating amount of calcium entering with AP
- number of vesicles ready to release
- coupling calcium entry to fusion of vesicle (calcium-secretion coupling)
short-term facilitation by phosphorylation of potassium channels by PKA (6 steps)
- 5HT activates GPCR to activate Gs
- Gs activates adenylate cyclase to make cAMP from ATP
- cAMP activates PKA
- PKA phosphorylates potassium channels (that regulate length of AP)
- longer AP -> longer activation of v-g calcium channels
- more calcium entry -> more transmitter release
STF is caused by
phosphorylation of potassium channels by PKA
what is the specific physical change underlying memory that naturally decays
PKA phosphorylation of potassium channels
how long does a memory that naturally decays last
as long as the potassium channel is phosphorylated
dephosphorylation of potassium channel (4)
- STF lasts 20-30 min
- cAMP is degraded
- PKA no longer active
- phosphatase removes phosphate
summary of how experience changes the brain: STF (4)
- experience does something -> release of 5HT
- 5HT activates PKA
- PKA phosphorylates protein that regulates synaptic strength (potassium channel)
- experience changes the brain
aspects of associative memories (3)
- CS doesn’t lead to response
- US leads to response
- pairing of CS and US leads to response to CS alone
neuronal aspects of associative memories (3)
- weak connection bw neurons encoding CS and response neurons
- US leads to depolarization of response neurons
- pairing of CS and US leads to strengthening of connection bw neurons encoding CS and response neurons
hebbs rule
when presynaptic neuron participates in firing of postsynaptic neuron, strength of connection should increase
what does an associative protein sense
pairing of CS and US
examples of associative proteins and what do they do (3)
- calcium-sensitive adenylate cyclase -> GPCR activation by 5HT (shock; US) + calcium entry (touch; CS)
- NMDAR -> depolarization of post-synaptic cell (US) + glutamate release of presynaptic cell (CS)
- PKC -> depolarization of post-synaptic cell (calcium entry; US) + glutamate release of presynaptic cell (DAG; CS)
characteristics of LTP (3)
- requires firing of presynaptic cell (glutamate release) and depolarization of post-synaptic cell
- requires calcium entry through NMDAR
- synapse specific (glutamate release from presyn cell)
cellular model of synaptic plasticity in vertebrate brain
LTP
mechanism of NMDARs (6 elements)
- AMPARs are ionotropic and let glutamate into the cell
- glutamate makes cell more positive (depolarizes)
- NMDAR blocked by magnesium ion
- magnesium released by depolarization of cell by glutamate
- allows calcium influx into cell when glutamate binds
- NMDAR externalize AMPAR = increased synaptic strength
potentiation vs faciliation
same thing -> increase in synaptic strength
ways to regulate Q (3)
- number and efficacy of post-synaptic receptors
- amount of transmitter in vesicle
- changing driving force for ion carried by channel (amount of sodium or chloride influx/efflux)
how does calcium entry through NMDAR increase Q (4)
- requires calcium-activated kinases (CAMKII) and PKC
- phosphorylation of AMPARs only account for short period of LTP
- increase in AMPAR number involved in later phase of LTP
- Q increases because of increase of AMPARs
exocytosis and endocytosis of AMPARs regulated by
exocytosis -> multiple kinases (PKA, PKC, CAMKII)
endocytosis -> phosphorylation
endocytosis of AMPARs important for
LTD and reversal of LTP
blocking endocytosis of AMPARs inserted during memory formation is a model for
how persistence of memory is encoded
organization of AMPARs and regulation
- tetramer of different subunits
- different subunits regulated in different ways in different parts of the brain
what controls number of AMPARs at synapses (4)
- anchoring proteins retain receptor at synapses: TARPs
- exocytosis of receptors from storage vesicles
- phosphorylation of both AMPARs and anchoring proteins
- regulation of endocytosis
what are TARPs
transmembrane AMPA regulatory proteins that couple AMPARs to post-synaptic density protein through PSD-95
what is PSD-95
protein that anchors synaptic proteins and keeps PSD
effect of PSD-95 KO on NMDARs
no effect
what are the phosphorylation events that cause LTP
don’t know -> leading candidate is CAMKII phosphorylation of TARP proteins
what causes LTD
phosphorylation of AMPARs causes them to be removed from membrane
neuronal pathway of CS in cerebellum (3)
mossy fibers from pontine nucleus -> granule cells -> (via parallel fibers) purkinje neurons
neuronal representation of US in LTD
climbing fibers (one input) coming from inferior olive
how does combination of CS and US affect CS in LTD
depression of CS
effect purkinje cells have on neurons
prevent output neurons from firing (because are GABAergic)
how does depression of CS lead to increase in eyeblink response (4)
- depression of CS -> depression of inputs from granule cells
- less firing onto purkinje cells
- increased firing of output neurons (less inhibitory tone from purkinje cells)
- increased eyeblink response
what causes LTD in purkinje cells
pairing firing of climbing fibers (US) with parallel fibers (CS) leads to decrease in synaptic strength in parallel fiber input
effect on eyeblink response when purkinje cells are silenced with picrotoxin
eyes still close, but at the wrong time
how can we mimic LTD in cultured purkinje cells
with glutamate (CS) -> activation of GPCRs; and depolarization (US) -> calcium entry
associative molecule in LTD
PKC
phosphorylation mechanism of LTD (4)
- calcium entry (depolarization) + DAG from mGPCRs activate PKCa
- PKC phosphorylation AMPARs at identified site
- phosphorylation reduces binding to GRIP and allows internalization of PICK
- decreased receptor = LTD
PKCa KO phenotype
no LTD
PKCa associates with which protein/receptor
AMPARs
what is GRIP and PICK
PDZ proteins that bind to GLUA2
regulation of AMPAR endocytosis (GRIP and PICK) (4)
- GRIP bound to GLUA2
- when serine of GLUA2 phosphorylated, GRIP leaves because doesn’t like P (GRIP requires unphosphorylated serine)
- PICK doesn’t care so replaces GRIP on GLUA2
- stimulates endocytosis
roles of GRIP and PICK
GRIP -> PDZ-stabilizer (like PSD-95)
PICK -> stim endocytosis
binding site on GLUA2 for PDZ proteins
SLKI-COOH (end of GLUA2)
actions of phosphorylation and effects (3)
- adds negative charge -> causes conformational shift in protein (change in function)
- adds site for protein:protein interaction
- removes a site for protein:protein interaction
which mutation will mimic the addition of negative charge by phosphorylation
serine/threonine mutated to negatively charged aa (glutamic acid/aspartic acid)
which mutation blocks effect of adding negative charge by phosphorylation
serine/threonine mutated to uncharged aa (like alanine)
which mutation blocks effect of adding a site for protein:protein interaction by phosphorylation
serine/threonine mutated to glutamic acid, aspartic acid or alanine (E doesn’t look like phosphoserine other than charge)
which mutation will mimic the effect of removing a site for protein:protein interaction by phosphorylation
serine/threonine mutation to glutamic acid, aspartic acid or alanine
ex of roles of phosphorylation (3)
- conformational change due to charge -> CAMKII activation
- creates binding site with phospho-amino acid -> CREB phosphorylation
- destroys binding site by phospho-amino acid -> GRIP binding to GLUA2
role of phosphorylation in GRIP binding and effect of mutating serine
- serine important for GRIP binding -> phosphorylation causes destruction of binding site (GRIP can’t bind anymore)
- S -> A mimics phosphorylation role (serine isn’t present anymore so binding site is destroyed)
how does K -> A mutation in SLKI affect phosphorylation and LTD
prevents PKC from phosphorylating because SxK fits into substrate binding pocket of PKC, but SxA doesn’t -> no GLUA2 phosphorylation, no LTD (blocks LTD)
what event is required for LTD
phosphorylation of GLUA2
summary of how experience changes the brain: LTD (4)
- experience does something -> causes coincident firing of granule cells and climbing fibers
- activation of PKC
- PKC phosphorylates protein that regulates synaptic strength (AMPAR)
- experience changes brain
what would lead to the belief that phosphorylation of GLUA2 is required for eye-blink conditioning
- eye-blink conditioning causes LTD
- LTD is caused by phosphorylation of GLUA2
- could infer that GLUA2 is involved in eye-blink conditioning
is phosphorylation of GLUA2 required for eye-blink conditioning and why
GLUA2 with mutation preventing its phosphorylation = no LTD when climbing fibers and parallel fibers fire together; but mice have normal eye-blink conditioning -> cellular plasticity of LTS is not necessary for timing of eye-blink conditioning
conservation of phosphorylation sites/mechanisms across species
phosphorylation sites/mechanisms for STM (change in synaptic strength) are not conserved across species; other phosphorylation mechanisms (not STM) are conserved across species
what is a molecular memory trace
physical manifestation of a memory
what does the length of time a memory lasts depend on
stability of the molecular memory trace (phosphorylation)
what is short-term synaptic plasticity due to
transient activation of protein kinases
