BIO2305

Neuron Physiology

The Neuron The functional and structural unit of the nervous system There are many, many different types of neurons but most have certain structural and functional characteristics in common Neurons are excitable cells (responsive to stimuli) specialized to conduct information (communicate) from one part of the body to another via electrical impulses (Action Potentials) conducted along the length of axons - Electricity: flow of electrons through conductor - Nerve impulse: flow of ions across membrane - Electrical signals are used at synapses - Electrical signals are temporary alterations in the membrane potential Basic Concepts Ions charged particles Anions Negatively charged particles Cations Positively charged particles Electrostatic forces Opposite charges attract, same charges repel Ions flow along their electrical gradient when they move toward an area of opposite charge Concentration forces Diffusion movement of ions through semipermeable membrane Ions flow along their chemical gradient when they move from an area of high concentration to an area of low concentration Together, the electrical and chemical gradients constitute the Electrochemical gradient

Active Membrane Transport (Pump). The carrier protein splits ATP into ADP and a Phosphate which attaches to the carrier (phosphorylation) the membrane binding site now has greater affinity for its passenger on the low [C]. Phosphorylation and binding of the passenger causes the carrier protein to flip its conformation so that the passenger is now exposed the high [C] side of the membrane. The change in shape results in the detachment of the phosphate (dephosphorylation) which reduces the affinity and the passenger is released into the high [C] side. Na+ - K+ pump The plasma membrane of all cells contains an active transport carrier, the Na+ - K+ ATPase pump, which uses energy to sequentially transport Na+ out of the cell and K+ into the cell against their [C] gradients. The pump moves three Na+ out of the cell for every two K+ pumped in. Importance: establishes ion [C] gradients (membrane potentials) necessary for muscle and nerve cells to generate electrical signals Role of Na+ -K+ pump - 20% of the membrane potential due to the pump - 3 Na+ pumped out for every 2 K+ pumped in - leads to accumulation of + charges in the ECF - large anions cannot escape from the ICF to balance the electrical charges Role of passive diffusion - There are more K+ than Na+ channels in the membrane - Membrane is 50-100 times more permeable to K+ than to Na+ - Concentration gradients are established by the pump - More K+ diffuses through the membrane than Na+ - The Na+ -K+ pump maintains the difference Membrane potential Separation of charges across the membrane/difference in the relative number of cations & anions in the ICF and ECF Energy used to separate the charges to put them on opposite sides of the membrane

 Na+ and Cl- outside the cell K+ and organic anions inside the cell - Cell membranes are electrically polarized (negative inside/positive outside) - Opposite charges attract each other and the force of that attraction can be used to do work - A membrane potential is a form of potential energy - Potentials in cells are measured in millivolts (mV), typical resting membrane potential is -70 mV Resting Membrane Potential - The resting potential (when the cell is not firing) is a 70mV difference between the inside and the outside - the membrane is polarized -When gated ion channels open, ions diffuse across the membrane following their electrochemical gradients. - This movement of charge is an electrical current and can create voltage (measure of potential) energy change across the membrane. -This electrical charge across the membrane is the membrane potential. There are two types of ion channels; leaky (non-gated) channels which are always open and gated channels which open and close in response to a stimulus Ion gated channels are classified by the type of stimulus 1. Voltage - open and close in response to a direct change in the membrane potential, proteins are sensitive to voltage changes, structure is altered by changes in ion distribution 2. Chemical - response to a variety of chemical ligands - neurotransmitters, hormones and ions. 3. Mechanical - response to pressure or vibration Summary Simultaneously movement of 3 Na+ ions outside the membrane and 2 K+ ions inside the cell. However the membranes permeability to K+ is 50 to 100 times greater than that of Na+ and there are also many more K+ leakage channels in the plasma membrane, so K+ ions quickly diffuse back outside the cell, therefore producing a net negative charge on the inside of the membrane. The net negative charge is caused by the fact that the negative ions inside the cell are on proteins and other large organic molecules that cant cross the membrane. The positive-negative or voltage difference is called the resting membrane potential (RMP) and measures about -70mV (millivolts), the cell is said to be polarized. Membrane Potential Signals -Neurons use changes in membrane potential to receive, integrate, and send information -Two types of signals are produced by a change in membrane potential: Graded potentials (short-distance)

Action potentials (long-distance)

Graded Potentials Short-lived, local changes in membrane potential Currents decrease in magnitude with distance Their magnitude varies directly with the strength of the stimulus the stronger the stimulus the more the voltage changes and the farther the current goes Sufficiently strong graded potentials can initiate action potentials Types of graded potentials include: 1) postsynaptic potentials (EPSPs and IPSPs) 2) receptor potentials 3) end plate potentials 4) pacemaker potentials 5) slow wave potentials Action Potentials -Supra-threshold stimuli cause voltage-gated Na+ channels to open -Na+ to enters the cell down its electrochemical gradient to produce depolarizing currents that are translated into action potentials -Threshold Voltage membrane is depolarized by ~ 20 mV stimulus -The AP is a brief reversal of membrane potential with a total amplitude of 100 mV (from -70mV to +30mV -APs do not decrease in strength with distance

-All APs are alike to the brain, so the intensity of a stimulus or response is coded in the and number of neurons that generate AP and the frequency of APs. -The AP travels along the nerve fiber because the flow of ions that depolarize and repolarize the neurons membrane act as stimuli for neighboring patches of membrane along the nerve, this mode of travel is called propagation or conduction. All-or-None phenomenon action potentials either happen completely, or not at all The AP travels along the nerve fiber because the flow of ions that depolarize and repolarize the neurons membrane act as stimuli for neighboring patches of membrane along the nerve, this mode of travel is called propagation or conduction. Depolarization Phase Na+ activation gates open quickly and Na+ enters causing local depolarization which opens more activation gates and cell interior becomes progressively less negative. Threshold a critical level of membrane potential (~ -50 mV) where depolarization becomes self-generating Repolarization Phase Positive intracellular charge reduces the driving force of Na+ to zero. Sodium inactivation gates of Na+ channels close. After depolarization, the slower voltage-gated K+ channels open and K+ rapidly leaves the cell following its electrochemical gradient restoring resting membrane potential Hyperpolarization The slow K+ gates remain open longer than needed to restore the resting state. This excessive efflux causes hyperpolarization of the membrane. The neuron is insensitive to stimulus and depolarization during this time. SUMMARY At rest all voltage-gated Na+ channels are closed and RMP is -70 mV, a stimulus (triggering event) opens some voltage-gated Na+ channels. Na+ diffuses into cell down its concentration gradient and entry decreases membrane potential, causing more Na+ channels to be activated. If depolarization reaches the threshold potential, Na+ permeability becomes 600x that of K+. So much Na+ enters the cell that the inside of the membrane becomes positive (+30 mV) the inactivation gates slowly block the channels Na+ stops entering the cell. During repolarization, the Na+ inactivation gate is replaced by the Na+ activation gate. K+ channels open at peak of AP (+30mV), K+ diffuses out of cell down its concentration gradient, loss of K+ from cell increases membrane potential and causes cell to become more negative inside as membrane returns to RMP (-70 mV) the voltage-gated K+ channels close (the K+ leak channels stay open). Slow closure of K+ channels causes a momentary hyper-polarization. During repolarization the neuron enters a refractory period which may last for 0.4ms to 4ms. The cell has to rest for long enough to have its ionic balance restored and the Na+ and K+ concentration gradients re-established. During the absolute refractory period the neuron cannot generate an AP at all, during relative refractory period an AP can be generated only by a suprathreshold stimulus. Nerve Physiology Part II: Propagation, Synapse and Neurotransmitters -The action potential is self-propagating and moves away from the stimulus (point of origin) Refractory Period Absolute refractory period is the time from the opening of the Na+ activation gates until the closing of inactivation gates, the neuron cannot respond to another stimulus Relative refractory period follows the absolute refractory period. Na+ gates are closed, K+ gates are open and repolarization is occurring. Only a strong stimulus can generate an AP Axon Conduction Velocity -Conduction velocities vary widely among neurons, determined mainly by: -Axon Diameter the larger the diameter, the faster the impulse (less resistance) - Presence of a Myelin Sheath myelination increases impulse speed (Continuous vs. Saltatory Conduction) -Neurofibers with large diameters conduct impulses faster that those with smaller diameters and myelinated fibers conduct impulses faster that unmyelinated fibers. -Nerve impulse conduction in which the impulse jumps form neurofibral node to node is called saltatory conductions Myelin Sheath -A Schwann cell envelopes and encloses the axon with its plasma membrane. -The concentric layers of membrane wrapped around the axon are the myelin sheath -Neurilemma cytoplasm and exposed membrane of a Schwann cell

Saltatory Conduction -Gaps in the myelin sheath between adjacent Schwann cells are called nodes of Ranvier (neurofibral nodes) -Voltage-gated Na+ channels are concentrated at these nodes -Action potentials are triggered only at the nodes and jump from one node to the next -Much faster than conduction along unmyelinated axons - Saltatory condction is more rapid because fewer Na+ and K+ channels have to open and close than in continuous conduction Synapse -As the impulse reaches the axon terminals the signal is relayed to target cells at specialized junctions known as synapses - is a junction that mediates information transfer from one neuron to another neuron or to an effector cell - The synapse is composed of presynaptic membrane -synaptic end bulb / knob, the postsynaptic membrane - a dendrite (axodendritic) cell body (axosomatic), or axon (axoaxonic) -The presynaptic neuron causes changes in the membrane potential of postsynaptic neuron, the flow of communication is one-way. Synaptic Cleft: Information Transfer Nerve impulses reach the axon terminal of the presynaptic neuron and open Ca2+ channels Neurotransmitter is released into the synaptic cleft via exocytosis Neurotransmitter crosses the synaptic cleft and binds to receptors on the postsynaptic neuron Postsynaptic membrane permeability changes due to opening of ion channels, causing an excitatory or inhibitory effect Effects of the Neurotransmitter Different neurons can contain different NTs. Different postsynaptic cells may contain different receptors. -Thus, the effects of an NT can vary. Some NTs cause cation channels to open, which results in a graded depolarization. Some NTs cause anion channels to open, which results in a graded hyperpolarization. Synaptic Transmission An AP reaches the axon terminal of the presynaptic cell and causes V-gated Ca2+ channels to open. Ca2+ rushes in, binds to regulatory proteins & initiates NT exocytosis. NTs diffuse across the synaptic cleft and then bind to receptors on the postsynaptic membrane and initiate some sort of response on the postsynaptic cell. Synaptic delay = time required for impulse to cross one synapse, approximately 0.5 to 1.0 msec, the more synapses in a pathway, the longer the delay EPSPs and IPSPs Typically, a single synaptic interaction will not create a graded depolarization strong enough to migrate to the axon hillock and induce the firing of an AP. However, a graded depolarization will bring the neuronal membrane potential closer to threshold. Thus, its often referred to as an excitatory postsynaptic potential or EPSP. Graded hyperpolarizations bring the neuronal membrane potential farther away from threshold and thus are referred to as inhibitory postsynaptic potentials or IPSPs. Excititatory and Inhibitory Neurotransmitters If a transmitter depolarizes the post-synaptic neuron, it is said to be excitatory If a transmitter hyperpolarizes the post-synaptic neuron, it is said to be inhibitory Whether a transmitter is excitatory or inhibitory depends on its receptor Example Acetylcholine is excitatory because its receptor is a ligand-gated Na+ channel

GABA is inhibitory because its receptor is a ligand-gated Cl- channel Other transmitters (e.g. vasopressin, dopamine) have G-protein-linked receptors

Effects depend on the signal transduction pathway and cell type Summation One EPSP is usually not strong enough to cause an AP. However, EPSPs may be summed. Temporal summation -The same presynaptic neuron stimulates the postsynaptic neuron multiple times in a brief period. The depolarization resulting from the combination of all the EPSPs may be able to cause an AP. 4

Spatial summation -Multiple neurons all stimulate a postsynaptic neuron resulting in a combination of EPSPs which may yield an AP

Convergence and Divergence Convergence - any neuron may have many other neurons synapsing on it the neuron converts several incoming signals to a single outgoing signal this increases sensitivity in the pathway, but it decreases precision Divergence - the axon terminals of each neuron branch out and synapse with many postsynaptic cells the neuron converts one incoming signal to many simultaneous outgoing signals this spreads out a signal and amplifies it Communication between neurons is not typically a one-to-one event. Sometimes a single neuron branches and its collaterals synapse on multiple target neurons. This is known as divergence. A single postsynaptic neuron may have synapses with as many as 10,000 postsynaptic neurons. This is convergence. Can you think of an advantage to having convergent and divergent circuits? Neurotransmitters - Each synapse uses a specific neurotransmitter - Each postsynaptic cell may respond to many different neurotransmitters Common neurotransmitters: Acetylcholine - most common, used in all neuromuscular junctions and 5-10% of brain synapses GABA (gamma aminobutyric acid) - most prevalent in brain, primarily an inhibitor, keeps excitatory impulses in check. Dopamine - plays a role in motor coordination Norepinephrine - released in sympathetic synapses controlling smooth and cardiac muscle, and glands. Serotonin - involved in temperature regulation, sensory perception, and emotion, induces sleep. Neurtotransmitters must be removed from the synaptic cleft for normal synaptic function. They are rapidly inactivated after they have stimulated the postsynaptic cell by: - Enzymatic degradation in the postsynaptic membrane - Uptake into axon terminal (recycled or destroyed) - Diffusion Neuromodulators are neuropeptides that may be released simultaneously with neurotransmitters to enhance or depress synaptic function Long-term effects on either pre- or post-synaptic cell - Change level of enzyme for neurotransmitter synthesis - Change level of neurotransmitter receptors Drugs may alter synaptic function by - Changing neurotransmitter synthesis or release - Modifying the ability of the neurotransmitter to bind with its receptor - Altering neurotransmitter inactivation - Substituting for defective or absent neurotransmitter Diseases may be caused by - Lack of neurotransmitter - Abnormal or absent receptors