ü The Electrical and Chemical Responses of Neurons

ü Neuron’s Cell Membrane

ü Double layer of lipid (fat) molecules with large proteins stuck in it

ü Only certain things (water, oxygen, carbon dioxide, or fat soluble substances) can freely pass thru the membrane (“selectively permeable” or “semi-permeable”). Must be special transport mechanisms (protein channels) for other materials to pass through the membrane.

ü Neuron’s Ion Balance

ü Sodium (Na+) and Chloride (Cl) outside and Potassium (K+) inside.

ü Polarization

ü Neuron at rest is “polarized” - difference in charge of inside vs. outside is like the - and + poles of a battery. There is “potential” for current flow between them.

ü The Sodium/Potassium Pump

ü The ion difference between the inside & outside is also maintained by “pumps” built into cell membrane, which actively pump Na+ out and K+ in.

ü The Result: Resting Potential

ü inside of neuron at rest is -70 millivolts more negative than outside of neuron

ü this is known as the resting potential

ü this difference in charge depends on

ü 1. the Semi-permeable membrane and

ü 2. the Na+/K+ pumps

ü Changes in the Neuron’s Charge

ü For a neuron to send an impulse down its axon its charge must get more + .

ü This is called “depolarization”.

ü Depolarization is what excites neurons.

ü If neuron instead gets more negative charged (“hyperpolarization”), firing is inhibited.

ü Axon Hillock = Beginning of Axon

ü Changes in the Potential

ü lots of ion channels in axon

ü these channels usually closed when the neuron is at rest

ü depolarization can open channels

ü Example: axon contains “voltage-activated” Na+ channels which open when soma is “excited”(depolarized) to the critical threshold level (getting about 15 millivolts more positive)

ü

ü Diagram of a Na+ Channel

ü Can be open or closed

ü Axon’s Na+ channels are “voltage activated”

ü Diagram of a neuron with many, many, many ion channels in the length of its axon’s membrane.

ü Pictures of everyday devices that are opened by a change in voltage (electric doors, curtains, faucets)

ü Imagine I have my electrode in a neuron and I am recording its voltage and displaying changes in its voltage across time (picture of microelectrode in a neuron)

ü Graph of what a depolarization (getting more positive) vs hyperpolarization (getting more negative) would look like.

ü The Action Potential

ü If sufficient exciting input is coming into the neuron’s dendrites and soma to reach threshold mentioned above, the voltage-gated Na+ channels at axon hillock open, & so much Na+ enters that that spot becomes positively charged! (e.g. instead of being -70 it now becomes +30mV)

ü This is enough + voltage to trigger the opening of the next Na+ channel so the next segment of axon becomes positively charged, and this again triggers the opening of the next Na+ channel, etc. etc. etc.

ü This process is repeated all the way down the axon.

ü This “action potential” thus is self-perpetuating & stays the same size (always reaching the same positive voltage at each spot along the axon) as it travels down the axon.

ü Naked Neuron – the example we have been working through – where one Na+ channel after another is triggered to open in the axon’s membrane – describes the situation in a “naked” neuron (one that naturally does not have a myelin sheath on its axon).

ü The Action Potential or Nerve Impulse – graphic representation of the voltage changes of an axon potential

ü The nerve impulse of a neuron is “all or none”- it either happens (“fires”) or it does not, like a gun either fires or it doesn’t. Within a particular neuron nerve impulses are always the same “size” or voltage. Stronger stimuli produce more impulses not bigger impulses (e.g. neuron fires several times in succession if it is strongly stimulated).

ü What About a Myelinated Neuron?

ü “Saltatory Conduction”

ü Neurons that naturally have a myelin sheath do NOT have Na+ channels lined up all the way down their axon’s cell membrane like the picture we saw earlier. Those parts of the axon normally covered by the myelin have no channels. Instead the channels are concentrated at the bare spots (the “nodes of Ranvier”). When such a neuron receives sufficient exciting input to its dendrites and soma to trigger the opening of the first Na+ channels at the axon hillock, we can think of all those incoming Na+ ions as heading for the next node of Ranvier (about 1 mm. away), where the next set of Na+ channels are located in a myelinated neuron. The positive charge will trigger the opening of those channels and once again, the incoming positive charges head towards the next node of Ranvier. So, unlike the naked neuron, where the entire length of the axon’s membrane must undergo the gradual opening of channel after channel, in a myelinated axon this happens just every mm. or so – the positive charge or “message” jumping from node to node to node much, much faster than it travels in a naked neuron. “Saltatory” means jumping, so salutatory conduction describes the travel of the action potential in a myelinated neuron.

ü Neurons can’t send electrical messages normally if the ion channels don’t work

ü Local anesthetics like Novacaine prevent Na+ channels from opening (no positive charge, no message)

ü General anesthetic gases open K+ channels too much

ü Scorpion venom holds Na+ channels open and K+ channels closed

ü Diseases like MS, where some of the myelin deteriorates, leaves lengths of axon (without Na+ channels) unable to generate the positive charge of the message.

ü A different kind of ion channel is involved in neurotransmitter release: voltage gated calcium Ca++ channels

ü Chemical Transmission

ü Arrival of action potential voltage at presynaptic or axon terminals opens Ca++ channels.

ü Ca++ entering the terminal triggers chemical release (“exocytosis”)by synaptic vesicles

ü Neurotransmitter molecules bind to post-synaptic receptors, triggering a change in the next cell

ü Okay – we have followed the electrical message of the axon from the axon hillock to the axon terminal, triggering neurotransmitter release. Now it is time to talk about what happens in dendrites receiving those neurotransmitter messages.

ü The Electrical Responses of Dendrites: The Simplest Case

ü Ionotropic Receptors (means ion-changing or ion-stimulating)

ü Some neurotransmitter receptors are located on ion channel proteins. When the transmitter binds to the receptor, the ion channel opens. These are chemically-activated channels (NOT voltage activated)

ü Diagram of an Ionotropic Receptor

ü Imagine now that I have a microelectrode in a dendrite.

ü Post-Synaptic Potentials

ü If transmitter opened a Na+ channel, the dendrite will depolarize. Remember depolarization is exciting to a neuron, so we call this an excitatory post-synaptic potential or “EPSP”.

ü If the transmitter binding to a receptor opened Cl- or K+ channel however, negative chlorides would enter the dendrite or positive potassiums would leave the dendrite. In either case the dendrite will get more negative or hyperpolarize. This turns off the neuron so is called an inhibitory post-synapatic potential or “IPSP”.

ü These electrical changes are NOT “all or none” like the action potential.

ü Instead they are called “graded” potentials which means they come in different gradations or sizes depending on just how many molecules of neurotransmitter bound to the dendrite. These electrical changes are also NOT self-perpetuating like the action potential. They are more like ripples of charge that dissipate as they travel from the dendrite towards the soma, much like the ripples caused by throwing a stone in water get smaller and smaller as the ripples move away from the original location.

ü Depending on the strength and number of electrical ripples being triggered in a neuron’s dendrites, some of them reach the soma. All those positive and negative “ripples” add together (in an algebraic fashion) in the soma (e.g. +3 ripple -2 ripple +5 ripple = +6, not quite enough to reach +15 threshold)

ü Sum total of all of the EPSPs and the IPSPs reaching the soma must reach the neuron’s threshold to begin the opening of the voltage gated Na+ channels of the AXON and start the process of an action potential in the axon.

ü Adding Together the Effects of Incoming Messages: Summation

ü The electrical effects of chemical transmissions occurring close together in time can add together.

ü Temporal summation – additive effects of transmissions occurring at the same synapse several times close together

ü Spatial summation – effects of different synapses on a neuron’s dendrites & soma add together

ü Diagram representing summation of inputs

ü If we could see charges adding together…

ü Ionotropic receptors
are right on the ion channel protein and trigger its opening

ü But: neurotransmitter receptors are not all located on ion channels.

ü Some instead are located on a different membrane protein called a G-protein.

ü When neurotransmitter molecules bind to G-proteins, they may trigger a variety of “metabolic” changes in the neuron.

ü “Metabotropic Receptors”

ü Receptors which, when activated, trigger a sequence of metabolic reactions

ü Reactions are slower, more lasting & more varied than ionotropic effects

ü Receptor protein is attached to a “G-protein” rather than an ion channel

ü When activated by the neurotransmitter, the G-protein triggers reactions via a “second messenger” which alters the functioning of postsynaptic cell in one of several ways.

ü Diagram of a G-Protein Linked Receptor

ü Otto Loewi’s Classic Experiment

ü Transmitter removed by:

ü 1. Reuptake back into the presynaptic ending and/or

ü 2. enzymatic breakdown

ü Reuptake

ü Breakdown of Transmitter

ü Best Known Transmitter Groups

ü Acetylcholine (ACh)

ü Monoamines

ü Norepinephrine (NE)

ü Dopamine (DA) These 3 are “catecholamines”

ü Epinephrine (E)

ü Serotonin (5HT)

ü Amino Acids

ü Glutamate

ü GABA

ü More Transmitters

ü Peptides

ü Endorphins

ü Substance P

ü Many others

ü Gases

ü Nitric oxide (NO)

ü The Action of Neurotransmitters

ü The effect produced at the synapse depends not only on the type of neurotransmitter but also the type of receptor.

ü We now know each neurotransmitter fits multiple types of receptors – e.g. at least 5 types of DA receptors and 6 types of 5HT receptors have been discovered.

ü Parkinson’s Disease

ü About 1/100 of those over 50 have PD (about 1,000,000 total in US)

ü Progressive loss of DA cells in substantia nigra which normally send messages to basal ganglia

ü We all gradually lose neurons but those with PD may have accelerated loss (70% or more gone)

ü Symptoms: Difficulty initiating movements, slow movements, muscle rigidity & tremors-at-rest

ü Also cognitive slowing & depression in many

ü Possible Causes

ü Early Parkinson’s disease – strong genetic link, but not the common late-life form of PD

ü Environmental toxin of some sort (herbicides, pesticides) . IA, MN, ND, SD, & NEB have highest rates in US!

ü Brain trauma may increase your risk

ü Treatments

ü Increase DA production with l-dopa

ü Problems: l-dopa induced side effects & loss of effectiveness over time

ü Use DA substitute (bromocriptine/Parlodel or pergolide/Permax) to activate receptors

ü Surgical approaches

ü Implant new cells to produce DA

ü Lesions in other parts of brain (thalamus, GP)

ü Implant stimulating electrodes (thalamus, GP)