Physiology of a Neuron From Dendrite to synaptic transmission 1

Outline Dendrites A. Graded potentials i. EPSP ii. IPSP B. Summation- temporal and spatial Axon A. Action potentials B. Refractory periods C. Myelination Synapse A. Voltage gated calcium channels B. Neurotransmitters IV. Functional classification of receptors A. Ionotropic B. Metabotropic i. Second messengers V. Drugs that induce spastic or flaccid paralysis

Neuron anatomy Draw and label a neuron Dendrite - projections from the soma the sensory portion of the neuron Soma - main body of the neuron Axon hillock- trigger zone Axon - extends from soma to the terminal the effector part of the neuron Terminal bouton/ axonal terminus/synaptic terminal Synaptic vesicles Synaptic cleft 3

Function of Dendrites in Stimulating Neurons Dendrites spaced in all directions from neuronal soma. allows signal reception from a large spatial area providing the opportunity for summation of signals from many presynaptic neurons Dendrites transmit signals by graded local potentials from opening of LGC’s LGC (Ligand-gated channels): are not dependent on membrane potential but binding of ligands (e.g. neurotransmitters)‏ Neurotransmitter receptors Located on dendrites and cell body Intensity of potential diffuses away from stimulus Axon hillock VGC’s LGC’s Act as receptor for neurotransmitter open and allow ligand in or out of cell 4 4

Types of Ligand Gated Channels (LGC’s)‏ Pore loop- amino acids here control ion selectivity, what passes Gene Families- many different channel genes and have different structures, functions and expression patterns Importance is found in diversity- many human diseases are associated with dysfunction of individual classes of ion channels Na+ LGC K+ LGC Cl- LGC Vm -74 mV What would happen to the resting membrane potential if these channels opened?

-45mV axon dendrite 14 mEq/L K+ : 4.5 mEq/L 120 mEq/L Cl- : 107 mEq/L The Excitatory Postsynaptic Potential (EPSP)‏ Na+ ions rush to inside of membrane through ionophores opened by transmitter. The increase in voltage above the normal resting potential (to a less negative value is the excitatory postsynaptic potential. A single EPSP can be 0.5-1.0 mV (how many mV difference do we need to reach threshold? axon dendrite Na+: 142 mEq/L 14 mEq/L K+ : 4.5 mEq/L 120 mEq/L Cl- : 107 mEq/L 8 mEq/L -45mV Membrane is depolarized, more likely to reach threshold 6 6

-90mV The Inhibitory Postsynaptic Potential (IPSP) K+ : 4.5 mEq/L axon Inhibitory synapses open K+ or Cl- channels and causes hyperpolarization of the neuron. Making neuron less likely to reach threshold Positively charged K+ ions moving to exterior make membrane potential more negative than normal (hyperpolarizing). Negatively charged Cl- ions moving to interior make membrane potential more negative than usual (hyperpolarizing). axon Na+: 142 mEq/L 14 mEq/L K+ : 4.5 mEq/L 120 mEq/L Cl- : 107 mEq/L 8 mEq/L -90mV 7 7

Whether a neuron “responds” or not, depends on temporal and spatial summation of EPSPs and IPSPs These channels open and close rapidly providing a means for rapid activation or rapid inhibition of postsynaptic neurons. 1msec is needed for an action potential, but a graded potential can last ~15msec. This means we can “add” excitatory and inhibitory potentials Temporal summation: same presynaptic neuron fires repeatedly 8 8

Spatial summation- stimuli from two different presynaptic neurons (different locations) 9 9

Disturbing an Excitable Cell Electrical stimulation (or even mechanical stimulation) can result in changes in voltage. Depolarizing currents change the voltage on the membrane, bringing it toward threshold: If stimuli are sub-threshold, the result is a local potential If stimuli are threshold or above threshold stimuli, the result is an action potential 10

What happens at threshold? A temporary, short-lived membrane permeability change. Membrane becomes 40 x more permeable to Na+ than to K+, then quickly returns to previous state How? Opening and closing of voltage-gated channels. VGC (Voltage-gated channels): Open/close depending on the voltage across the membrane Na+ VGC, K+ VGC, Ca++VGC Located on the axon, at hillock and beyond Can allow ions to move at high rates Allow ions to move down their EC gradients Conductances are voltage dependent Threshold is the “trigger” that starts a “dance of the gates” 11

The action potential, dance of the gates Upstroke Na+ permeability increases Membrane potential approaches E Na+ Downstroke Potassium permeability increases Hyperpolarization occurs due to increased K+ conductance from late K+VGC closure Membrane potential approaches E K+ 12

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but it also causes inactivation Ion channels – Activation, Inactivation, deactivation Depolarization causes: Na channels to activate (open)‏ but it also causes inactivation inactivated channels do not pass any ions (non-conducting state)‏ By contrast, most K channels show activation and deactivation but not inactivation The fall in current at the end is deactivation (opposite of activation)‏ open inactivation inactivated closed depolarization repolarization 14 Copyright © 2006 by Elsevier, Inc. 14

Refractory Periods ARP - due to voltage inactivation of Na channels mV -40 -80 Threshold 0 1 2 3 4 5 msec Maximum frequency is several hundred APs per second. Absolute Relative ARP - due to voltage inactivation of Na channels Refractory periods limit maximum frequency of APs 15 15

Functions of action potentials Information delivery to CNS Transfers all sensory input to CNS. The frequency of APs encodes information (recall amplitude cannot change). Rapid transmission over distance (nerve cell APs)‏ Note: speed depends on fiber size and whether it is myelinated. In non-nervous tissue APs are the initiators of a range of cellular responses. Muscle contraction 16 Figure 5-16; Guyton & Hall 16

A “wave of depolarization” occurs along the neighboring areas. http://www.blackwellpublishing.com/ matthews/actionp.html http://faculty.washington.edu/chudler/ap.html Figure 5-17; Guyton & Hall Saltatory Conduction The AP is a passive event: ions diffuse down their EC gradients when gated channels open. A “wave of depolarization” occurs along the neighboring areas. Occurs in one direction along the axon; actually, AP regenerates over and over, at each point by diffusion of incoming Na+ ….WHY? Refractory period (Na+ channels become inactivated). AP’s only occur at the nodes (Na channels concentrated here!)‏ increased velocity energy conservation 17 17

- non-myelinated vs myelinated - Conduction velocity - non-myelinated vs myelinated - non-myelinated myelinated 18 18

Multiple Sclerosis - MS is an immune-mediated inflammatory demyelinating disease of the CNS - Patients have a difficult time describing their symptoms. Patients may present with paresthesias of a hand that resolves, followed in a couple of months by weakness in a leg or visual disturbances. Patients frequently do not bring these complaints to their doctors because they resolve. Eventually, the resolution of the neurologic deficits is incomplete or their occurrence is too frequent, and the diagnostic dilemma begins. - About 1 person per 1000 in US is thought to have the disease - The female-to-male ratio is 2:1 - whites of northern European descent have the highest incidence 19 http://www.emedicine.com/pmr/topic82.htm Copyright © 2006 by Elsevier, Inc. 19

The Synapse Structures important to the function of the synapse: presynaptic vesicles contain neurotransmitter substances to excite or inhibit postsynaptic neuron mitochondria provide energy to synthesize neurotransmitter Membrane depolarization by an action potential causes emptying of a small number of vesicles into the synaptic cleft Presynaptic membranes contain voltage - gated calcium channels. depolarization of the presynaptic membrane by an action potential opens Ca2+ channels influx of Ca2+ induces the release of the neurotransmitter substance The Synapse VOCC Ca+2 Postsynaptic membrane contains receptor proteins for the transmitter released from the presynaptic terminal. 20 20

Synaptic Events-watch animation NTS release NTS diffuses across cleft Binds to receptors (LGC’s) reversible binding Opens LGC (LGC’s are ion selective) and diffusion of ions: Influx or efflux Allowing depolarization or hyperpolarization of cell body Result in graded voltage changes, local potentials in postsynaptic cell body If depolarizing, called EPSP If hyperpolarizing, called IPSP 21