LECTURE 9: INTEGRATION OF SYNAPTIC INPUTS (Ionotropic Receptors)

LECTURE 9: INTEGRATION OF SYNAPTIC INPUTS (Ionotropic Receptors)

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 I EPSP 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 NEUROTRANSMITT

ER IONOTROPI C RECEPTOR ION PERMEABILIT Y GLUTAMATE AMPA GluR Na+, K+

GLUTAMATE Kainate GluR Na+, K+ GLUTAMATE NMDA GluR Na+, K+, Ca++ ACETYLCHOLINE ATP

SEROTONIN Excitatory reversal potential, EEPSP, is near 0 mV, due to permeability of receptor to both sodium and potassium Nicotinic AChR ATP Receptor 5-HT3 Receptor Na+, K+ Na+, K+, Ca++

Na+, K+ 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 NEUROTRANSMITT ER IONOTROPI C RECEPTOR

GABA GABAA Receptor Glycine Glycine Receptor ION PERMEABILIT Y Cl- Cl-

IPSP ACTS TO SHORT-CIRCUIT EPSP CURRENT AND BLOCK DEPOLARIZATION TWO WAYS TO THINK OF HOW IPSP CURRENTS INHIBIT EXCITATION I. II. Goldmans 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 Vm = PK EK + PNa ENa excitatory Na+ current PK + PNa +

ECl 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, I EPSP(in) = Ileak(out), + PCl PCl Ohms law says VEPSP = IEPSP(in) / gleak. The larger the leak conductance the smaller the depolarization induced by excitatory inward currents. 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

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