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 determinewhether 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 synapsesdo not directly

generate postsynapticcurrents

These synapses mediateshort- and long-term

signaling eventsthat modulate how much

neurotransmitter isreleased by an action potential

reaching its terminus.

MOST EXCITATORY SYNAPSES ELICIT EPSP WITH REVERSAL POTENTIAL OF 0 mV

NEUROTRANSMITTER

IONOTROPIC

RECEPTOR

IONPERMEABILIT

YGLUTAMATE AMPA GluR Na+, K+

GLUTAMATE Kainate GluR Na+, K+

GLUTAMATE NMDA GluR Na+, K+, Ca++

ACETYLCHOLINE Nicotinic AChR Na+, K+

ATP ATP Receptor Na+, K+, Ca++

SEROTONIN 5-HT3 Receptor Na+, K+

Excitatory reversal potential,

EEPSP,

is near 0 mV,due to permeability of

receptor to bothsodium 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 canmodify synaptic behavior both short- and long-term

NMDA RECEPTORS CONDUCT LATE CURRENT AFTER DEPOLARIZATION

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 canmodify synaptic behavior both short- and long-term

Single Channel Recordings in V-Clamp Whole Cell Recordings in V-Clamp

MOST INHIBITORY SYNAPSES ELICIT IPSP WITH REVERSAL POTENTIAL OF -60 mV

NEUROTRANSMITTER

IONOTROPIC

RECEPTOR

IONPERMEABILIT

YGABA GABAA Receptor Cl-

Glycine Glycine Receptor Cl-

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 reduces the effect of excitatory Na+ current

II. 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 VEPSP = IEPSP(in) / gleak. The larger the leak conductance the smaller the depolarization induced by excitatory inward currents.

PK EK + PNa ENa + PCl

ECl PK + PNa + PCl

Vm =

INTEGRATION OF MULTIPLE SYNAPTIC INPUTS DETERMINED BYCELL ARCHITECTURE, ACTIVE DENDRITIC CURRENTS, AND LEAK CURRENTS

Time constant of an EPSP determined by leak conductance.

If leak conductance is low, EPSP persistswell after IEPSP current ends

(long time constant).

A second IEPSP can induce furtherdepolarization than did the first.

This is called TEMPORAL SUMMATION

If leak conductance is high, EPSPis finished before a second

IEPSP , so there is notemporal summation

INTEGRATION OF MULTIPLE SYNAPTIC INPUTS DETERMINED BYCELL ARCHITECTURE, ACTIVE DENDRITIC CURRENTS, AND LEAK CURRENTS

Length constant of an EPSP determined by ratio of axial conductanceto 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 EPSPat another synapse

INTEGRATION OF MULTIPLE SYNAPTIC INPUTS DETERMINED BYCELL ARCHITECTURE, ACTIVE DENDRITIC CURRENTS, AND LEAK CURRENTS

Axosomatic inhibitory synapse exerts a more powerful inhibitory effecton excitation than does an axodendritic inhibitory synapse.

Axosomatic inhibitory currents are shunts preventing dendritic EPSPsfrom propagating past to reach the trigger zone.

INTEGRATION OF MULTIPLE SYNAPTIC INPUTS DETERMINED BYCELL 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 stillrequired to induce the axonal action potential.

EPSP inDISTAL

DENDRITE

CALCIUMACTION POTENTIALDOWN DENDRITE

SUBTHRESHOLDDEPOLARIZATION inPROXIMAL DENDRITE

SUBUNIT STRUCTURES OF LIGAND GATED IONOTROPIC RECEPTORS

IMPERMEABILITY OF AMPA RECEPTORS TO CALCIUM GENERATEDBY RNA EDITING

NEXT LECTURE: Metabotropic Receptors

READING: KANDEL text, Chapter 13