Transcript Document

LECTURE 9: INTEGRATION OF SYNAPTIC INPUTS (Ionotropic Receptors)
REQUIRED READING: Kandel text, Chapter 12
At neuromuscular synapse, single axonal action potential generates a muscle action potential.
The large arborized endplate contains 500,000 acetylcholine receptors generating
500 nA IEPSP sufficient to depolarize muscle past threshold.
Individual neuron-to-neuron synapses are much smaller
and do not generate sufficient IEPSP to trigger action potential in postsynaptic cell.
Neuronal excitation requires near-simultaneous inputs from multiple excitatory synapses.
E.g., a motor neuron will need 20-30 excitatory inputs to give EPSP beyond threshold.
Neurons also have synapses which mediate inhibitory postsynaptic potentials (IPSPs).
IPSPs oppose depolarization generated by EPSPs.
Neurons continuously integrate inhibitory and excitatory synaptic inputs to determine
whether to fire action potentials and with what frequency.
THE IPSP DETECTED IN MOTOR NEURON BY INPUT FROM INTERNEURON
TWO FUNCTIONS OF IPSPs
I.
IPSPs counteract EPSPs to reduce or abolish neural firing triggered
by excitatory synaptic inputs.
II.
IPSPs can interfere with the rhythmic spontaneous firing of neurons.
The pattern of inhibitory synaptic inputs “sculpts” the
spontaneous periodic firing.
EXCITATORY AND INHIBITORY SYNAPSES HAVE DIFFERENT MORPHOLOGIES
Axo-axonic synapses
do not directly
generate postsynaptic
currents
These synapses mediate
short- and long-term
signaling events
that modulate how much
neurotransmitter is
released by an
action potential
reaching its terminus.
MOST EXCITATORY SYNAPSES ELICIT EPSP WITH REVERSAL POTENTIAL OF 0 mV
NEUROTRANSMITTE
R
IONOTROPIC
RECEPTOR
ION
PERMEABILITY
GLUTAMATE
GLUTAMATE
AMPA GluR
Kainate GluR
Na+, K+
Na+, K+
GLUTAMATE
NMDA GluR
Na+, K+, Ca++
ACETYLCHOLINE
Nicotinic AChR
Na+, K+
ATP
SEROTONIN
ATP Receptor
5-HT3 Receptor
Na+, K+, Ca++
Na+, K+
Excitatory reversal potential,
EEPSP,
is near 0 mV,
due to permeability of
receptor to both
sodium and potassium
NMDA AND NON-NMDA RECEPTORS FUNCTION DIFFERENTLY
NMDA receptors open only when depolarization precedes glutamate binding.
Depolarization releases Mg+2 blocking particle from ligand-binding site.
NMDA receptors only open with prolonged presynaptic activity.
Calcium entry through NMDARs induces signaling processes that can
modify synaptic behavior both short- and long-term
NMDA RECEPTORS CONDUCT LATE CURRENT AFTER DEPOLARIZATION
Single Channel Recordings in V-Clamp
Whole Cell Recordings in V-Clamp
NMDA receptors open only when depolarization precedes glutamate binding.
Depolarization release Mg+2 blocking particle from ligand-binding site.
NMDA receptors only open with prolonged presynaptic activity.
Calcium entry through NMDARs induces signaling processes that can
modify synaptic behavior both short- and long-term
MOST INHIBITORY SYNAPSES ELICIT IPSP WITH REVERSAL POTENTIAL OF -60 mV
NEUROTRANSMITTE
R
GABA
Glycine
IONOTROPIC
RECEPTOR
GABAA Receptor
Glycine Receptor
ION
PERMEABILITY
ClCl-
IPSP ACTS TO SHORT-CIRCUIT EPSP CURRENT AND BLOCK DEPOLARIZATION
TWO WAYS TO THINK OF HOW IPSP CURRENTS INHIBIT EXCITATION
I.
Goldman’s equation shows that membrane potential is driven to a level
determined by the weighted sum of each ionic Nernst potential weight
by the relative permeability of each ion.
Increasing Cl- or K+ permeability
PK EK + PNa ENa + PCl
reduces the effect of
Vm =
excitatory Na+ current
P +P +P
K
II.
Na
Inhibitory channels gate ions (usually Cl-) with Nernst (reversal) potential
of -60 to -70 mV. Since this is about the same potential as that of leak
channels, we can consider inhibitor channels as increasing the leak
conductance. Since at the peak of an EPSP, IEPSP(in) = Ileak(out),
Ohm’s law says DVEPSP = IEPSP(in) / gleak. The larger the leak conductance
the smaller the depolarization induced by excitatory inward currents.
Cl
ECl
INTEGRATION OF MULTIPLE SYNAPTIC INPUTS DETERMINED BY
CELL ARCHITECTURE, ACTIVE DENDRITIC CURRENTS, AND LEAK CURRENTS
Time constant of an EPSP determined by
leak conductance.
If leak conductance is low, EPSP persists
well after IEPSP current ends
(long time constant).
A second IEPSP can induce further
depolarization than did the first.
This is called TEMPORAL SUMMATION
If leak conductance is high, EPSP
is finished before a second
IEPSP , so there is no
temporal summation
INTEGRATION OF MULTIPLE SYNAPTIC INPUTS DETERMINED BY
CELL ARCHITECTURE, ACTIVE DENDRITIC CURRENTS, AND LEAK CURRENTS
Length constant of an EPSP determined by
ratio of axial conductance
to leak conductance; I.e.,
by the cable properties of the dendrite
The greater the ratio of gdendrite to
gleak, the less an EPSP diminishes
over distance; I.e.,
the bigger the length constant
EPSP with bigger length constant
can more readily undergo
spatial summation with the EPSP
at another synapse
INTEGRATION OF MULTIPLE SYNAPTIC INPUTS DETERMINED BY
CELL ARCHITECTURE, ACTIVE DENDRITIC CURRENTS, AND LEAK CURRENTS
Axosomatic inhibitory synapse exerts a more powerful inhibitory effect
on excitation than does an axodendritic inhibitory synapse.
Axosomatic inhibitory currents are shunts preventing dendritic EPSPs
from propagating past to reach the trigger zone.
INTEGRATION OF MULTIPLE SYNAPTIC INPUTS DETERMINED BY
CELL ARCHITECTURE, ACTIVE DENDRITIC CURRENTS, AND LEAK CURRENTS
In large neurons with long, extensively arborized dendrites,
currents from dendritic voltage-gated calcium channels (VGCCs)
can boost distant dendritic EPSPs towards the soma.
The density of VGCCs in proximal dendritic trunk and soma are much lower,
so active propagation does not proceed across soma to
sodium channel trigger zone.
Temporal and spatial summation of excitatory inputs are still
required to induce the axonal action potential.
EPSP in
DISTAL
DENDRITE
CALCIUM
ACTION POTENTIAL
DOWN DENDRITE
SUBTHRESHOLD
DEPOLARIZATION in
PROXIMAL DENDRITE
SUBUNIT STRUCTURES OF LIGAND GATED IONOTROPIC RECEPTORS
IMPERMEABILITY OF AMPA RECEPTORS TO CALCIUM GENERATED
BY RNA EDITING
NEXT LECTURE: Metabotropic Receptors
READING: KANDEL text, Chapter 13