Chemical Synapse Plasticity
Vocabulary:
Short-term synaptic plasticity: Last less than a few minutes, has presynaptic changes
Facilitation: Stimuli must be ms apart, potentiation lasts for ms. Ca2+ that is lingering in cytoplasm causes more vesicles to be released (synaptotagmin easier to bind to)
Augmentation: Has short interstimulus intervals repeated multiple times, potentiation can last for several seconds. Thought to result for increased active zone primed vesicles due to Ca2+ alternating munc13 activity (which regulates SNAREs)
Posttetanic Potentiation (PTP): A tetanus (rapid stimulus) lasts for 10-20 seconds, causing potentiation for minutes after the stimulus ends. May result from increased Ca2+ activating PKC to modify proteins like synapsin
Depression: Decreased neurotransmitter release during a sustained activity, degree varies with amount of neurotransmitter previously released. Lower external Ca2+ decreases release and slows rate of depression. Depression increases when the reserve pool size is decreased by impairing synapsin. May result from depletion of the pool of releasable synaptic vesicles
Long-term synaptic plasticity: Lasts over 30 minutes, has postsynaptic changes. Early on is protein modification, later changes in gene expression. May be the mechanism behind memory and learning
Potentiation (LTP): Occurs at excitatory synapses in the hippocampal pathway, cortex, amygdala, and cerebellum. Makes EPSPs easier to fire
Depression (LTD): Decreased sensitivity over time, still uses NDMA receptors, along with calcineurin (PP1) which has a higher affinity for Ca2+ than LTP mechanisms
Hippocampus: Used in memory allocation and storage, involved in LTP and LTD. Damage interferes with declarative memory. LTP can last over a year
Schaffer’s collateral: Axons projecting from CA3 → CA1
Dendrites from CA1 pyramidal cells: Form a thick band
Hippocampal LTP (know it all I’m too burnt out to highlight): Generally a neuron is depolarized, and then another signal comes in and further depolarizes it, which opens calcium channels. This activates thinks like CamKII, eventually inserting more receptors
Two Schaffer collaterals synapse on the same CA1 pyramidal neuron, releasing glutamate onto CA1 pyramidal neuron AMPA/Kainate and NMDA receptors. Low frequency stimulation of Schaffer collaterals leads to moderate EPSPs in each CA1 pyramidal neuron.
With different stimuli, activity is paired in synaptic neurons, postsynaptic CA1 pyramidal neurons are depolarized by injecting current and presynaptic Schaffer collaterals are stimulated once, leading to enhanced EPSP in the postsynaptic neuron. This requires the NMDA coincidence detector and simultaneous activity in pre/postsynaptic neurons, expelling Mg2+ and Ca2+ entering the CA1 neuron, “neurons that fire together wire together”
Pathway 1: After sufficient depolarization NMDA receptors expel Mg+, leading to a Ca2+ influx and enhanced EPSPs for subsequent stimuli. This only applies for
Pathway 2: Little EPSP changes
Late stage: Also activation of adenylyl cyclase, along with all early LTP markers. cAMP activates PKA and phosphorylates CREB
Hippocampal LTD: Schaffer collaterals synapse on CA1 pyramidal neurons and release glutamate onto CA1 AMPA/kanaite and NMDA receptors. Low frequency stimulation has low probability of NMDA unblocking leading to a tiny influx of Ca2+. Initial EPSP and facilitation increase but afterwards there is depression (where stimulation is random)
Cerebellum: Used during LTD
Aplysia californica: A 5” sea slug, has several hundred large neurons with defined circuits. Exhibits learning/memory behaviors when its tail is touched (gill reflex withdrawal)
Gill withdrawal reflex: In Aplysia, motor neurons innervate gills with ACh, mechanosensory neurons innervate the siphon, interneurons receive excitatory input from mechanosensory neurons which then form excitatory synapses onto motor neurons
Habituation: The mechanosensory neuron will release less glutamate to the interneuron and motor neuron (due to fewer vesicles, short-term depression), leading the motor neuron to not reach threshold. Motor neuron gets direct and indirect (from interneuron) stimulus
Sensitization: Strengthening of the response after aversive stimuli. Same circuit as habituation but adds sensory neurons (modulatory) innervating the tail. A modulatory neuron is stimulated by the tail sensory neuron, which causes the siphon sensory neuron to release more glutamate. Serotonin→ Gs receptor → cAMP → PKA → phosphorylation of voltage-gated K+ channels (reducing opening) → prolonged depolarization → longer opening of Ca2+ channels → more glutamate release.
LTP: Initial gene transcription involves CREB. Ubiquitin hydrolase synthesis results in the destruction of PKA regulatory subunits and leads to persistent PKA activity. New synapses form
Hippocampal LTP mechanism:
Early phase: Ca2+ (secondary messenger) influx through NDMA receptors after depolarization. The Ca2+ will insert more AMPA receptors via PKC activation, synaptotagmins, and CamKII activation
There is an increased response to glutamate in spines
CamKII causes a genetic deletion, inactivation of CamKII blocks LTP
Late phase: Caused by protein synthesis, new dendritic spine growth, possibly new synapses
Hippocampal LTD mechanism: Low Ca2+ activates phosphatases like calcineurin (PP2B and PP1). These dephosphorylate proteins in pathways that typically result in endocytosis of AMPAR specific to activated synapses, leading to no more receptors being made. Long-term requires transcription/translation change. Climbing fibers and parallel fibers synapse onto a neuron and release glutamate, depolarizing to open AMPA receptors allowing Na+/K+ in, through mGluR phospholipase is activated to activate DAG and IP3, releasing Ca2+. This Ca2+ and DAG activate PKC which inhibits AMPA receptors
Cerebellar LTD: Purkinje fibers are the output source in the cerebellar cortex, innervated by climbing fibers and parallel fibers from granule cells. Purkinje EPSP strength is decreased, may be the mechanism for motor learning. Parallel fivers fire quickly and release small amounts of glutamate. Glutamate → AMPAR → Gq of Purkinje cells → mild depolarization and IP3/DAG. IP3 and Ca2+ trigger further Ca2+ release from the ER, with DAG the Ca2+ can activate PKC. Here the coincidence detector is the Ca2+ from climbing fibers, they are excitatory and signals depolarize and open voltage-gated Ca2+ channels letting in Ca2+. Along with the DAG from parallel fiber synapses, PKC is activated. PKC targets AMPA receptors and phosphorylates them to be endocytosed (opposite of how it works in hippocampal LTP). Late phase includes protein synthesis
Spike-timing dependent synaptic plasticity: Timing of presynaptic stimulation and when there is an AP in the postsynaptic neuron determine whether LTP of LTD occur, LTP if the AP follows presynaptic stimulation (priming occurs, Mg2+ expelled). LTD occurs if the AP proceeds presynaptic activity, it is ‘worn out’ and Mg2+ stays
Interactions between LTP and LTD can “erase” each other. They are synapse-specific, and require NMDA activation to allow in at least some Ca2+.
