1 bi / cns 150 lecture 11 synaptic inhibition; cable properties of neurons wednesday, october 15,...
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Bi / CNS 150 Lecture 11
Synaptic inhibition; cable properties of neurons
Wednesday, October 15, 2013
Bruce Cohen
Chapter 2 (p. 28-35); Chapter 10 (227-232)
-Aminobutyric acid (GABA)
2
Crystal structure of GABAA Receptor (Miller et al, 2014)
• Homomer of 5 GABAA β3 subunits
• Overall structure similar to nicotinic receptor
• Positive charges in vestibule contribute to anion selectivity
The pentameric GABAA and glycine receptors resemble ACh receptors;
but they are permeable to anions (mostly Cl-, of course)
1. -amino-butyric acid (GABA) is the principal inhibitory transmitter in the brain.
2. Glycine is the dominant inhibitory transmitter in the spinal cord & hindbrain.
GABAA receptors are more variable than glycine receptors in subunit composition and therefore in kinetic behavior.
. . Cation channels become anion channels with only
one amino acid change per subunit, in this approximate
location
A Synapse “pushes” the Membrane Potential Toward the Reversal Potential (Erev) for the synaptic Channels
4
At Erev , the current through open receptors is zero.
Positive to Erev, current flows
outward
Negative to Erev, current flows inward
ACh and glutamate receptors flux Na+ and K+,
(and in some cases Ca2+),and Erev ~ 0 mV.
-20
-50
-80
-100
-5
+20
+40
+60
+80Membrane potential
Resting potential
EK
ENa
At GABAA and glycine receptors,
Erev is near ECl ~ -70 mV
Like Figure 10-11
5
Benzodiazepines (= BZ below):
Valium (diazepam), (Ambien, Lunesta are derivatives)
Pharmacology of GABAA Receptors: activators
phenobarbital site is unceratin
The natural ligand binds at subunit interfeces
(like ACh at ACh receptors)
(Miller et al, 2014 Nature)6
The GABA agonist benzamidine also makes cation-p interactions with its binding site
GABAA and Glycine blockers bind either at the agonist site or in the channel
Agonist site
Picrotoxin
(GABAA & glycine
receptors)
Strychnine
(glycine receptor)
Bicuculline
(GABAA receptor
8Like Figure 2-1
(rotated)
Parts of two generalized CNS neurons
synaptic cleft
direction of information flow
apicaldendrites
Excitatoryterminal
cell body
(soma)
nucleus
axon
presynaptic terminal postsynaptic
dendrite
Inhibitoryterminal presynaptic
terminal
axon hillock
neuronPresynaptic
neuronPostsynaptic
basaldendrites
initialsegment
node of Ranvier
myelin
(apex)
(base)
little hill
9
Types of synapses
• Synapses can form on dendrites, axons, soma, and even the presynaptic teriminals
• Two types of dendritic synapses are shown, one on spines, the other on the shaft
• Type 1 synapses tend to be excitatory
• Type 2 tend to be inhibitory
Figure 10-3
10
Concentration of acetylcholine at
NMJ(because of
acetylcholinesterase,turnover time
~ 100 μs)
Number of open channels
ms
0
high closed open
State 1 State 2
k21
all molecules begin here at
t= 0
units: s-1
Duration of postsynptic current
11
How are glutamate & GABA cleared from the
synapse?
• Na+ -coupled transporters
for glutamate & GABA
are present at densities of >
1000 / μm2 near each
synapse
• This density is probably
high enough to sequester
each transmitter molecule
as it leaves a receptor
• At the nerve-muscle synapse,
acetylcholinesterase is present at densities
of > 1000 / μm2 near each synapse
• This density is high enough to destroy each
transmitter molecule as it leaves a receptor
13
Membrane capacitance integrates the current that goes across it
This integration slows down voltage changes across the membrane
C
C
dVI C dT
IV
C
Figure 9-6
Capacitive current is proportional to the derivative of voltage with respect to time
Integrating both sides and solving for voltage we get,
14
1B. Temporal Summation 2. Spatial summation
Recording Recording
SynapticCurrent
SynapticPotential
Long time constant(100 ms)
Short time constant(20 ms)
Axon Axon
SynapticCurrent
SynapticPotential
Long length constant(1 mm)
Short length constant(0.33 mm)
Vm
Vm
2 mV25 ms
Figure 10-14
~ 100 pA
15
1. Passive dendrites act like leaky cables
Gulledge & Stuart (2005) J. Neurobiol 64:75,
V
EPSP measured in soma
V
EPSP measured in dendrite
Excitatory synapses
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Temporal and spatial integration of the EPSP from two synapses
Gulledge & Stuart (2005) J. Neurobiol 64:75,
Δt = 0
Simultaneous,colocalized
EPSPs(two individual trials)
V
Nearly simultaneous,colocalized
EPSPs(two individual trials)
V
Δt = 5 ms
Simultaneous,Spatially distinct
EPSPs
V
Δt = 0
Prolonged rising phase
http://www.neuron.yale.edu/neuron/static/about/stylmn.html
Inspect the simulation, and run the movie, at
17
Active propagation in dendrites
• Patch-clamp recordings from dendrites in brain slices show that dendrites can generate action potentials
• A neuron was filled with a fluorescent dye
• Voltage was recorded at two sites in current clamp mode, one in soma, one in dendrite
• The occurrence of action potentials at the dendritic site shows that action potentials can actively propagate in dendrites
Gulledge & Stuart (2005) J. Neurobiol 64:75,
18
immunocytochemistry
25 μm
Whitaker, Brain Res, 2001
Magee & Johnston, J Physiol (1995)
Now break the patch, to fill the cell with dye:
Averaged traces
Voltage-gated Na+ channels in a dendrite
• Voltage-gated Na+ channels were recorded from a patch of membrane on the apical dendrite of a pyramidal neuron (left traces)
• Step depolarization of the membrane patch opened the channels
• The traces at the bottom left show the ensemble currents evoked by repeated voltage steps
• Image in the middle shows the location of the recording site in a cell filled with fluorescent dye
19
Back propagation of the action
potential
• The existence of voltage-gated Na+ and
Ca2+ channels in dendrites means that
action potentials initiated at the axon
hillock can “back propagate” to the
dendrites
• The back propagation of action
potentials into the dendrites can have
an important effect on synaptic signaling
at excitatory synapses because NMDA
receptors act as co-incidence detectors.
Gulledge & Stuart (2005) J. Neurobiol 64:75,
brain slice
20
3. Excitatory-inhibitory integration:
The “veto principle” of inhibitory transmission
Inhibitory synapses work best when they are “near“ the excitatory event they will inhibit.
“Near” means < one cable length.
A. Inhibitory synapses on dendrites
do a good job of inhibiting EPSPs on nearby spines
B. Inhibitory synapses on cell bodies and initial segments
do a good job of inhibiting spikes
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