Transcript Presynaptic Mechanisms

Nens220, Lecture 6
Interneuronal communication
John Huguenard
Electrochemical signaling
Synaptic Mechanisms
• Ca2+ dependent release of neurotransmitter
– Normally dependent on AP invasion of synaptic
terminal
• Probabilistic
Probabilistic release
• Synaptic release is unreliable
– Action potential invasion does not necessary evoke
release
– Net response is product of number of terminals (or
release sites, n ), size of unitary response (q), and
probability (p) of release at each terminal
– N varies between 1 and 100
– p between 0 and 1
– q is typically on the order of 0.1 to 1 nS
Binomial probability
Postsynaptic properties:
ionotropic receptors
• Ligand gated receptors
• Directly gated by neurotransmitter – ion
pores
• Can be modeled analogously to voltage-gated
channels
The probability of a ligand gated
channel be open (Ps) will depend
on:
• on and off rates for the channel
• With the on rate dependent on
neurotransmitter concentration
• This can be approximated by a brief (e.g.
1ms) increase, followed by an instantaneous
return to baseline
Three major classes of ligand
gated conductances: ligands
• Excitatory
– Glutamate
• AMPA/Kainate receptors (fast)
• NMDA receptors (slow)
• Inhibitory
– Gamma amino butyric acid GABAA receptors
AMPA (glutamate)
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•
•
•
Fast EPSP signaling
trise < 1ms
tdecay : 1..10 ms
Cation dependent
EAMPA 0 mV.
2+
Ca
permeability: AMPAR
• Depends on molecular composition
• GluR2 containing receptors are Ca2+ impermeable
– Unless unedited
• Prominent in principle cell (e.g. cortical pyramidal
neuron) synapses
• GluR1,3,4 calcium permeable
– Calcium permeable AMPA receptors more common in
interneurons
AMPAR have significant
desensitization
• Contributes to rapid EPSC decay at some
synapses
Spike/PSP interactions
Hausser et al.
Science Vol. 291. 138 - 141
EPSC/AP coupling
Galaretta and Hestrin
Science 292, 2295 (2001);
EPSP/spike coupling II
Galaretta and Hestrin
Science 292, 2295 (2001);
NMDA (glutamate)
• EPSP signaling, slower than with AMPA
– trise : 2-50 ms
– tdecay : 50-300 ms
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•
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cation dependent
ENMDA 0 mV
Significant Ca2+ permeability
NMDAR - necessary for many forms of
long-term plasticity
NDMAR Blocked by
physiological levels of [Mg2+]o
• Voltage and [Mg2+]o dependent
• Depolarization relieves block
Kainate receptors (glutamate)
• Roles are less well defined than
AMPA/NMDA
Inhibitory ligand gated
conductances
• GABAA
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–
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–
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Fast IPSP signaling
trise < 1ms
tdecay : 1.. 200 ms !, modulable
Cl- dependent
EGABAA range: –45 .. –90 mV
Highly dependent on [Cl-]i
• Which is in turn activity dependent
• NEURON can track this
Metabotropic receptors
• Many classes
• Conventional neurotransmitters, GABA,
glutamate
• Peptide neurotransmitters, e.g. NPY, opioids,
SST
• Often activate GIRKS
– G-protein activated, inwardly-rectifying K+
channels
mReceptors, cont’d.
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•
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Inhibitory, hyperpolarizing responses.
Can be excitatory,
e.g. Substance P closes GIRKS
Slow time course
– e.g. GABAB responses can peak in > 30 ms and
last 100s of ms
• Presynaptic & negatively coupled to GPCRs
Electrotonic synapses
• Transmembrane pores
• Resistive connection between the intracellular
compartments of adjacent neurons
• Prominent in some inhibitory networks
Perisynaptic considerations
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Neurotransmitter uptake by glia or neurons
Diffusion
heterosynaptic effects
extrasynaptic receptors
Hydrolysis
Presynaptic receptor mediated
alterations
• Mainly metabotropic
– An exception is nicotinic AchR
– Homosynaptic “autoreceptors”
– Heterosynaptic receptors
Short term plasticity
• Dynamic changes in release probability
– Likely mechanisms
• Ca2+ accumulation in synaptic terminals
• Altered vesicle availability
– To implement
• update Prel upon occurrence of a spike
• then continue to calculate state of Prel dependent on
P0 (resting probability) and tP(rel)
250 pA
250
pA
2.5 ms
Fran Shen
Dynamic-Clamp: Artificial Autaptic IPSCs
Based on Fuhrmann, et al. J Neurophysiol
87: 140–148, 2002