Synaptic Transmission Flashcards
Electrical synapses (gap junctions) allow
- very fast, bidirectional communication between cells
→ useful to generate rhythms (e.g. for breathing) and
oscillations (e.g. interneuron networks). - exchange of small molecules like ATP, cAMP, sugars
→ relevant for large networks of glial cells that control
neuronal metabolism
Function of Electrical Synapes - Gap Junctions
- Allow for direct electrical communication between cells
- Allow for chemical communication between cells, through the transmission of small second messengers, such as inositol triphosphate (IP3) and calcium (Ca2+)
- Metabolic coupling
Chemical synapses
Translating an
electrical signal into a
chemical signal and
right back into an
electrical signal
The most common type is contact between
an axon terminal and a dendritic, somatic, or axonal domain
The Neuromuscular junction (NMJ)
Large postsynaptic cell
* One axon (but about 100 synapses !)
per muscle cell
* Highly reliable
– Most pre-synaptic action potentials lead
to a post-synaptic action potential
* Chemical signaling is simple
– Only one type of ion channel
END PLATE POTENTIAL (EPP)
Stimulation of the motor fiber
generates a synaptic potential in the post-synaptic muscle cell.
~40-50mV amplitude
Action potentials synchronize the release of many transmitter quanta
Miniature End Plate Potentials (MEPPs)
very small (miniature) potentials (~1 mV) occur even in the absence of stimulation
Eliminated in instances with redued extracellular Ca2+
EPPs are multiples of MEPPs
(Spontaneous) Neurotransmitter release occurs in quantal packets
Quantal release theory
Key variables that characterize quantal (vesicular) release:
- the number of release sites (N)
- the probability of a quantal release (p)
- the size of the quantal response (q)
Quantal analysis
the distribution of amplitudes of
the postsynaptic response can be
fitted to a binominal distribution
→ From this, the best-fitting values of N, p, and q can be extracted
Morphological correlates of Katz’s variables
the number of release sites (N)
number of active zones/synapses
Morphological correlates of Katz’s variables
the probability of a quantal release (p)
number of docked vesicles
Morphological correlates of Katz’s variables
the size of the quantal response (q)
single vesicle and/or the response to a single vesicle (receptor sensitivity)
____is required for transmitter release (influences the probability of release)
Calcium
Presynaptic action potentials open
voltage-gated Ca2+ channels.
Ca2+ allows vesicles
to fuse
with the membrane
2-fold increase in Ca2+ can
increase
transmitter release 16-fold
Infusion of a
Ca2+ chelator such as BAPTA
reduces Ca2+
release
Action-potential triggers
Ca2+ influx into presynaptic terminal via voltage-gated Ca2+ channels (N- and/or P/Q type)
In the active zone, Ca2+ currents are
10x larger
than elsewhere.
In the active zone, Ca2+ can rise
1000-fold (to ~100 µM)
SNAREs (SNAp REceptors)
group of proteins that promote
fusion of the vesicle and presynaptic membrane.
Steps involved in vesicle release and recycling
- Trafficking
- Tethering
- Docking and Priming
- Fusion
- Endocytosis
Trafficking
target vesicles to
the active zone
Tethering
restrain vesicles in reserve pool
Docking and priming
vesicles to active zone
Fusion AKA
exocytosis
Endocytosis
retrieve fused
membrane (recycling)
4-AP blocks K+ channels and prolongs the
action potential and thus
tincreases the
amount of Ca2+ that can enter
→ leads to more quanta released per AP
→ Correlates perfectly with number of fused vesicles counted in EM
The fusion of a transport vesicle with its target
involves 2 types of events:
The transport vesicle must recognize the
correct target membrane.
* Second, the vesicle and target membranes must fuse,
so that the content of the vesicle can be delivered to the target organelle (within the cell) or into the synaptic cleft.
The SNARE hypothesis describes
vesicle fusion via the interaction between specific
pairs of transmembrane proteins, called SNARES
(SNAP [Soluble NSF Attachment Protein] Receptor)
Two (main) types of SNAREs
vesicle or v-SNAREs (or R-SNAREs),
target or t-SNAREs (or Q-SNARES)
vesicle or v-SNAREs (or R-SNAREs)
incorporated into the membranes of transport
vesicles during budding
Example of a v-SNARE
- Synaptobrevin sits in the vesicle membrane
target or t-SNAREs (or Q-SNARES)
located in the target membranes
Examples of t-SNAREs
- Syntaxin and SNAP-25 are anchored in the presynaptic membrane (T-SNAREs)
Calcium sensor (not a SNARE) involved in Exocytosis
Synaptotagmin
or VAMP (vesicle associated membrane protein)
Functions of Synaptotagmin-1
Calcium Sensor
– Releases clamp on release, or facilitates release.
Involved in docking and
vesicle fusion via
interaction with βneurexin or SNAP-25
Also aids in recycling
– binds clathrin
Neurexins
interaction with synaptotagmin
leads to fusion
The SNARE complex binds
directly to N-type Ca++ channels
Two neurotoxins that effect SNAREs
Botulinum neurotoxin and Tetanus neurotoxin
Botulinum neurotoxin
cleaves SNARE proteins
Tetanus neurotoxin
cleaves Synaptobrevin
The “classic” synaptic vesicle cycle
Duration
~ 1 min
Two key proteins for Endocytosis
- Clathrin
- Dynamin
clathrin
forms coated pits by curving the membrane
dynamin
pinches of coated vesicle
Synaptotagmin I is involved in
both sides of the vesicle cycle.
Synaptotagmin serves as anchor for AP2.
Clathrin attaches to AP2 or synaptotagmin itself
Four different modes of endocytosis
- “kiss and run”
- Clathrin-mediated
- Bulk endocytosis
- “Ultrafast”
Duration of “kiss and run” endocytosis
1 sec
Duration of Clathrin-mediated endocytosis
tens of seconds
Duration of Bulk endocytosis
tens of seconds, requires strong stimulation
Duration of “Ultrafast” endocytosis
50-100 ms
Function of Synapsin
keeps vesicles tethered in the
reserve pool
* cross-links vesicles to
cytoskeletal filaments (f-actin)
Synapsin is regulated by
Ca2+/Calmodulin-dependent kinase (CaMKII) and PKA
Phosphorylation of Synapsin
frees
vesicles to move.
Rab proteins
(members of the Ras superfamily of G-proteins)
Small GTP-binding protein
mark transport vesicles
* interact with v-SNAREs to initiate fusion
Rab GTPases regulate
many steps of membrane traffic, including vesicle formation, vesicle movement along actin and tubulin networks, and membrane fusion
more than __ different Rab proteins are involved in vesicle transport
60
Neurexins (NRXN) are
presynaptic cell adhesion proteins.
The intracellular portion of NRXN interacts with SNAREs, while
their extracellular domain interacts with proteins in the
synaptic cleft, most notably neuroligin.
Neuroligin 1 (NLGN1) is
enriched at excitatory
synapses
NLGN2 is
enriched
at inhibitory, dopaminergic
and cholinergic synapses
NLGN3 is
found at both
excitatory and inhibitory
synapses,
Neurexin and neuroligin
“shake hands,” resulting in the
production of a synapse
Neurexin (presynaptic); Neuroligin (postsynaptic)
An EPSP has a reversal potential more
positive than the AP threshold
an IPSP has a reversal potential more
negative than threshold
Post-synaptic responses
Excitatory Input
- often glutamate or ACh
- permeable to both Na+ and K+
Post-synaptic responses
Inhibitory Input
- usually GABA
- permeable to Cl-
Direction of post-synaptic potential determined by:
- The ionic identity
- The equilibrium (reversal) potential of that ion
Two types of post-synaptic receptors
- Ionotropic
- Metabotropic
Ionotropic Receptors
ligand-gated channels
→ receptor IS channel;
immediate conductance change
Metabotropic receptors
G-protein-coupled receptors
→ receptor modulates channel, or other
intracellular effects; delayed, longer lasting response
Binding of ligand (e.g. ACh) to receptor has
similar effects as changes in membrane potential on voltage-gated channels.
The reversal potential can be used to
determine which ions flow
during synaptic currents
Because under physiological conditions the
driving force for Na+
is much higher,
activation of the receptor typically results in
an inward current and an EPSP
