lecture 11: pre synaptic mechanisms Flashcards
what is the hippocampus involved in
learning and memory
presynaptic mechanisms
- botulinum toxin
- tetanus toxin
- a-latrotoxin
- schizophrenia
botulinum toxin features
- a neurotoxin produced by bacterium clostridium botulinum
- many different forms
- contains heavy and light chains
- effects last about three months
function of botulinum toxin
–> blocks release of neurotransmitter acetylcholine, at the neuromuscular junction
= causes paralysis
impact of the heavy and light chains
- heavy chain of the toxin binds selectively and irreversibly to presynaptic receptors on cholinergic neurons
- the toxin is endocytosed
- light chain is cleaved and released
- light chain binds to SNAP25 and results in cleavage of SNAP25
- preventing exocytosis/fusion of synaptic vesicles with the membrane
- no ACh is released therefore muscles do not contract
impact of botulinum toxins on synaptobrevin
- the cleavage of synaptobrevin, a vesicle associated membrane protein (VAMP), by the toxin inhibits vesicle fusion and neurotransmitter release into the synapse
how does tetanus toxin impact release mechanisms
–> impairs ability to dock to membrane and release neurotransmitter
how does tetanus toxin cause muscle spasm
- tetanus neurotoxin (TeNT) binds to the presynaptic membrane of the neuromuscular junction
- endocytosed
- travels to the cell body, in spinal cord
- released
- selectively binds to inhibitory neurons
- endocytosed
- cleaves synaptobrevin
- inhibitory neurons are inactivated which allows excitatory pathway to dominate
what is the source of tetanus neurotoxin
clostridium tetani
BoTox vs TeNT
BoTox:
Normal
- SNARE proteins secrete AcH
- causes muscle contraction
Impaired
- no SNARE proteins
- AcH isn’t secreted
- flaccid paralysis
TeNT:
normal
- synaptobrevin secretes glycine or GABA
- AcH not secreted
- muscle contraction halted
impaired
- no synaptobrevin = no glycine or GABA secreted
- AcH secreted
- spastic paralysis
flaccid paralysis
muscle is never activated because AcH is never released
- leads to weak, limp muscles and a lack of muscle tone
spastic paralysis
spasms and then muscles are locked in an active form
Neurexin
- ligand
- draws two cells together to allow for synaptic transmission
- presynaptic
- binds neuroligand
- receptors for a-latrotoxin
what does a-latrotoxin enhance
neurotransmitter release through:
- ca2+ pore formation
- G-protein coupled receptor
Ca2+ pore formation
- binds neurexin
- forms a Ca2+ pore in the presynaptic membrane (allows for widespread release of calcium)
- phosphorylation of SNARE proteins
G-protein coupled receptor
- activates phospholipase C
- mobilization of intracellular Ca2+ stores
- phosphorylation of SNARE proteins
what does a-latrotoxin cause a massive release of
SSV but not LDCV
why does a-latrotoxin cause a large release of SSV and not LDCV
because the release of small synaptic vesicles and large dense core vesicles are controlled in different ways
neuromodulation
low frequency action potentials:
- limited release of SSVs containing classical neurotransmitters
high frequency action potentials:
- increased release of SSVs containing classical neurotransmitters
and
- release from LDCVs containing neuropeptides
synapsin def
reserve pool of synaptic vesicles
what other impact does Ca2+ influx have
not only stimulates exocytosis but also releases vesicles from the reserve pool
–> thus rapidly replacing neurotransmitter supply
synapsin features
- an abundant evolutionary conserved phosphoprotein
- found at nearly all synapses
- three distinct SYN genes
SYN1, SYN2, SYN3 –> encodes 3 different types of synapsin
multiple isoforms: I/IIA, IIIA, and IIIB
Synl = the most abundant isoform in mature neurons - associated with cytosolic face of small synaptic vesicles (not LDCVs)
- controls synaptic vesicle mobility and exocytosis (priming and fusion with the membrane)
- ca2+ dependent phosphorylation following strong depolarization
where does synapsin bind
actin cytoskeleton
what is synapsin phosphorylated by
CAMKII
