Fundamentals of the Nervous System and Nervous Tissue 11 P A R T B Fundamentals of the Nervous System and Nervous Tissue

Synaptic Transmission

Typically composed of two cells and the space between them: Synapses A junction that mediates information transfer from one neuron to another neuron or to an effector cell Specialized for the release and reception of neurotransmitters (chemical communication) Typically composed of two cells and the space between them: Axonal terminal of the presynaptic neuron, which contains synaptic vesicles Receptor region on the dendrite(s) or soma of the postsynaptic neuron

Fluid-filled space separating the presynaptic and postsynaptic neurons Synaptic Cleft Fluid-filled space separating the presynaptic and postsynaptic neurons Prevents nerve impulses from directly passing from one neuron to the next Transmission across the synaptic cleft: Is a chemical event (as opposed to an electrical one) Ensures unidirectional communication between neurons

Steps in Synaptic Transmission Action potential reaches the axon terminal of the presynaptic neuron and opens Ca2+ channels (voltage gates) Ca2+ enters axon terminal and causes vesicles to fuse with pre-synaptic membrane Neurotransmitter is released from the vesicle into the synaptic cleft via exocytosis Neurotransmitter diffuses across the synaptic cleft Neurotransmitter binds to receptors on the postsynaptic neuron Receptors open chemical gates, causing an excitatory or inhibitory effect which may cause the postsynaptic cell to fire an AP or block it Neurotransmitter is inactivated, ending the chemical signal. Inactivation could be caused by enzymatic degradation or by reuptake of neurotransmitter into pre-synaptic cell.

Termination of Neurotransmitter Effects Neurotransmitter bound to a postsynaptic neuron: Produces a continuous postsynaptic effect Blocks reception of additional “messages” Must be removed from its receptor to end signals Removal of neurotransmitters occurs when they: Are degraded by enzymes Are reabsorbed by astrocytes or the presynaptic terminals (known as reuptake) Diffuse away from the synaptic cleft

Synaptic Delay Neurotransmitter must be released, diffuse across the synapse, and bind to receptors Synaptic delay – time needed to do this (0.3-5.0 ms) Synaptic delay is the rate-limiting step of neural transmission

Synaptic Transmission Neurotransmitter Ca2+ Na+ Axon terminal of presynaptic neuron Action potential Receptor 1 Postsynaptic membrane Mitochondrion Postsynaptic membrane Axon of presynaptic neuron Ion channel open Synaptic vesicles containing neurotransmitter molecules 5 Degraded neurotransmitter 2 Synaptic cleft 3 4 Ion channel closed Ion channel (closed) Ion channel (open) Figure 11.18

Neurochemistry The study of chemical interactions in the nervous system; primarily focused on neurotransmitter molecules, their receptor molecules, and the influences they have on the voltage potentials of neurons.

Neurotransmitter Molecules Location Functions Other Info Set up a chart like this to organize your notes from the next series of slides….

Neurochemistry: Neurotransmitters Chemicals used for neuronal communication with the body and the brain At least 50 different neurotransmitters have been identified Classified chemically and functionally Any single neuron only makes and releases ONE kind of neurotransmitter from ALL of its axon terminals Any single neuron may have receptors for many kinds of neurotransmitters on its dendrites and soma

Types of Chemical Neurotransmitters Acetylcholine (ACh) Biogenic amines (Adrenaline, Dopamine, Serotonin, and others) Certain Amino acids & Peptides (glycine, endorphins, GABA (Gamma  -AminoButyric Acid) and others Novel messengers: ATP and dissolved gases such as NO and CO  = Greek letter Gamma

First neurotransmitter identified, and best understood Acetylcholine First neurotransmitter identified, and best understood Synthesized and enclosed in synaptic vesicles Degraded by the enzyme acetylcholinesterase (AChE) Released by: All neurons that stimulate skeletal muscle (NMJ) Some neurons in the autonomic nervous system Some CNS neurons Causes muscle contraction and autonomic activity

Broadly distributed in the brain Biogenic Amines Include: Catecholamines – dopamine, norepinephrine (NE), and epinephrine Indolamines – serotonin and histamine Broadly distributed in the brain Play roles in emotional behaviors, our biological clock, and more

Epinephrine & Norepinephrine Epinephrine is the proper name for adrenaline Used in the sympathetic nervous system (fight or flight) and in the CNS Adrenal glands release epinephrine

Dopamine Used in the CNS (basal ganglia) Involved in integrating (combining) sensory inputs with motor outputs; also involved with the reward center and addictive behaviors Low dopamine levels occur in patients with Parkinson’s disease – dopamine replacement therapy relieves their symptoms but does not cure the disease – stem cell transplants may allow a cure in the future

Synthesis of Catecholamines Enzyme The catecholamines are formed by converting one neurotransmitter into the next The presence or absence of enzymes in the cell determine which neurotransmitter is formed Figure 11.21

Serotonin Used in CNS Often plays an inhibitory role, helping to filter out excess stimuli

Dopamine & Serotonin Pathways

Peptides Include: GABA: inhibitory neurotransmitter Substance P – mediator of pain signals Endorphins and enkephalins: Act as natural opiates; reduce pain perception

Neurotransmitters: Novel Messengers ATP Is found in both the CNS and PNS Provokes pain sensation Nitric oxide (NO) Is involved in learning and memory

Functional Classification of Neurotransmitters Two classifications: excitatory and inhibitory Excitatory neurotransmitters (e.g., glutamate) cause depolarizations by opening chemical gates for Na+ Inhibitory neurotransmitters (e.g., GABA and glycine) cause hyperpolarizations by opening chemical gates for Cl-

Functional Classification of Neurotransmitters Some neurotransmitters have both excitatory and inhibitory effects Different receptors for the same neurotransmitter result in either excitation or inhibition Example: acetylcholine has 2 receptors called nicotinic and muscarinic Excitatory at neuromuscular junctions with skeletal muscle (nicotinic receptor) Inhibitory in cardiac muscle (muscarinic receptor – part of parasympathetic system)

Neurotransmitter Receptor Mechanisms Direct: neurotransmitters that open ion channels Promote rapid responses that quickly fade Examples: ACh and amino acids Indirect: neurotransmitters that act through second messengers such as cyclic AMP Promote long-lasting but slower effects Examples: biogenic amines, peptides, and dissolved gases PLAY InterActive Physiology ®: Nervous System II: Synaptic Transmission

Neuropharmacology: Drug Interactions with Neurons Drugs are chemicals that influence the physiology of the body Psychoactive drugs are chemicals that influence the physiology of the brain Psychoactive drugs may send false messages by enhancing the action of a neurotransmitter (these drugs are called agonists) or they may block true messages by preventing the action of a neurotransmitter (these drugs are known as antagonists)

Agonists may function in several ways: Agonists (mimics) Drugs that enhance the action of a specific neurotransmitter are called agonists Regardless of HOW they function, they send false signals to the post-synaptic cell Agonists may function in several ways: Release extra neurotransmitter from vesicles Block degradation or reuptake of neurotransmitter Bind to the receptor and activate it, mimicking the neurotransmitter

Antagonists (blockers) Drugs that block the action of a specific neurotransmitter are called antagonists Regardless of HOW they function, they block true signals to the post-synaptic cell Antagonists often function by binding to the receptor without activating it, blocking the neurotransmitter from sending its signal Other possibilities include preventing NT release from vesicles, or blocking action potentials by keeping Na+ gates closed, etc.

Copy this chart in your notes and fill it out as you study each of the following slides. Notice that extra space is left for “Action” and “Comments.” Just copy the first row for now, since each row will be a different size. Category Drug Neurotrans-mitter Action Comments Etc.

Stimulants Stimulants such as amphetamines and cocaine act primarily as catecholamine agonists They increase release of norepinephrine and dopamine and also block their reuptake Stimulants such as nicotine act as ACh agonists by binding to and activating receptors Activates sympathetic nervous system quickly (direct action via chemical gates) and parasympathetic nervous system slowly (indirect action via second messengers) Caffeine’s effects largely result from increasing blood flow to the brain

Depressants Tranquilizers like valium act as agonists of GABA, an inhibitory neurotransmitter They increase the binding of GABA to its receptor This results in greater inhibition of APs in the CNS Alcohol acts on multiple types of neurons, but does not act on the synapse It reduces the flow of Na+ across membranes, interfering with action potentials Neurons respond more slowly or not at all

Narcotics Opium, morphine, and heroin are agonists of endorphins Bind to and activate endorphin receptors Block pain, induce euphoria Endorphins were discovered by scientists trying to determine how opiates influenced the brain Endorphin levels increase in women about to give birth, and they increase slightly during exercise (resulting in the “runner’s high”)

Hallucinogens Widespread effects by drugs such as LSD, mescaline, and psilocybin One aspect of their action is acting as antagonists to serotonin Bind to and block serotonin receptors Serotonin’s role in filtering excess stimuli is thereby reduced – the extra stimulation could be perceived as a hallucination

Hallucinogens Marijuana is sometimes classified as a hallucinogen – its active ingredient is THC (tetra hydra cannibanol) Its mechanism of action is unclear – it seems to influence multiple types of neurons More research is needed Like tobacco, inhaling any form of smoke is harmful to the lungs – marijuana may be worse since it is usually smoked without a filter and each inhalation may leave more deposits than a cigarette. However, the amount of marijuana smoked is usually less than for tobacco.

Neurotoxins 1 – Poisonous Drugs These drugs may be used for experimental purposes, because they can isolate the action of different neurotransmitter systems. Some of them also have uses beyond research. Curare & Tetrodotoxin – ACh antagonist at NMJ, binding irreversibly to receptors, causes paralysis and suffocation – once collected from frogs and used on poison arrows by South American natives – useful for frogs by protecting them from predators (tetrodo.is from pufferfish) Botox (botullism toxin, produced by bacteria) – Blocks release of ACh from vesicles at NMJ, causes paralysis

Neurotoxins 2 – Poisonous Drugs Nicotine – large doses result in complete tetanus due to activating ACh receptors at the NMJ – commonly used as an insecticide and probably evolved for this purpose in the tobacco plant Convulsants – block the enzyme that synthesizes GABA. Since GABA is an inhibitory neurotransmitter, the lack of inhibition allows neurons to have more APs than normal, resulting in convulsions.

Antipsychotics and Antidepressants These drugs are used to treat psychological conditions, but are not used recreationally Antipsychotics reduce symptoms of schizophrenia; they act by blocking dopamine receptors Antidepressants reduce symptoms of clinical depression; there are different types, but one acts by blocking the action of the enzyme that breaks down dopamine, epinephrine, and norepinephrine (“MAO inhibitors” – monoamine oxidase)

Fundamentals of the Nervous System and Nervous Tissue 11 P A R T C Fundamentals of the Nervous System and Nervous Tissue

Nerve Fiber Classification Nerve fibers are classified according to: Diameter Degree of myelination Speed of conduction

Synapses Figure 11.17

Other types of synapses include: Axodendritic – synapses between the axon of one neuron and the dendrite of another Axosomatic – synapses between the axon of one neuron and the soma of another Other types of synapses include: Axoaxonic (axon to axon) Dendrodendritic (dendrite to dendrite) Dendrosomatic (dendrites to soma) PLAY InterActive Physiology ®: Nervous System II: Anatomy Review, page 5

Electrical Synapses Electrical synapses: Are less common than chemical synapses Correspond to gap junctions found in other cell types Are important in the CNS in: Arousal from sleep Mental attention Emotions and memory Ion and water homeostasis PLAY InterActive Physiology ®: Nervous System II: Anatomy Review, page 6

Synaptic Cleft: Information Transfer Ca2+ Axon terminal of presynaptic neuron Action potential 1 Axon of presynaptic neuron Figure 11.18

Synaptic Cleft: Information Transfer Ca2+ Axon terminal of presynaptic neuron Action potential 1 Mitochondrion Axon of presynaptic neuron Synaptic vesicles containing neurotransmitter molecules 2 Figure 11.18

Synaptic Cleft: Information Transfer Ca2+ Axon terminal of presynaptic neuron Action potential 1 Postsynaptic membrane Mitochondrion Axon of presynaptic neuron Synaptic vesicles containing neurotransmitter molecules 2 Synaptic cleft 3 Ion channel (closed) Ion channel (open) Figure 11.18

Synaptic Cleft: Information Transfer Neurotransmitter Ca2+ Na+ Axon terminal of presynaptic neuron Action potential Receptor 1 Postsynaptic membrane Mitochondrion Postsynaptic membrane Axon of presynaptic neuron Ion channel open Synaptic vesicles containing neurotransmitter molecules 2 Synaptic cleft 3 4 Ion channel (closed) Ion channel (open) Figure 11.18

Synaptic Cleft: Information Transfer Neurotransmitter Ca2+ Na+ Axon terminal of presynaptic neuron Action potential Receptor 1 Postsynaptic membrane Mitochondrion Postsynaptic membrane Axon of presynaptic neuron Ion channel open Synaptic vesicles containing neurotransmitter molecules 5 Degraded neurotransmitter 2 Synaptic cleft 3 4 Ion channel closed Ion channel (closed) Ion channel (open) Figure 11.18

Postsynaptic Potentials Neurotransmitter receptors mediate changes in membrane potential according to: The amount of neurotransmitter released The amount of time the neurotransmitter is bound to receptors The two types of postsynaptic potentials are: EPSP – excitatory postsynaptic potentials IPSP – inhibitory postsynaptic potentials PLAY InterActive Physiology ®: Nervous System II: Synaptic Transmission, pages 7–12

Excitatory Postsynaptic Potentials EPSPs are graded potentials that can initiate an action potential in an axon Use only chemically gated channels Na+ and K+ flow in opposite directions at the same time Postsynaptic membranes do not generate action potentials

Excitatory Postsynaptic Potential (EPSP) Figure 11.19a

Inhibitory Synapses and IPSPs Neurotransmitter binding to a receptor at inhibitory synapses: Causes the membrane to become more permeable to potassium and chloride ions Leaves the charge on the inner surface negative Reduces the postsynaptic neuron’s ability to produce an action potential

Inhibitory Postsynaptic (IPSP) Figure 11.19b

Summation A single EPSP cannot induce an action potential EPSPs must summate temporally or spatially to induce an action potential Temporal summation – presynaptic neurons transmit impulses in rapid-fire order

IPSPs can also summate with EPSPs, canceling each other out Summation Spatial summation – postsynaptic neuron is stimulated by a large number of terminals at the same time IPSPs can also summate with EPSPs, canceling each other out PLAY InterActive Physiology ®: Nervous System II: Synaptic Potentials

Summation Figure 11.20

Neurotransmitters: Acetylcholine Degraded by the enzyme acetylcholinesterase (AChE) Released by: All neurons that stimulate skeletal muscle Some neurons in the autonomic nervous system

Channel-Linked Receptors Composed of integral membrane protein Mediate direct neurotransmitter action Action is immediate, brief, simple, and highly localized Ligand binds the receptor, and ions enter the cells Excitatory receptors depolarize membranes Inhibitory receptors hyperpolarize membranes

Channel-Linked Receptors Figure 11.22a

G Protein-Linked Receptors Responses are indirect, slow, complex, prolonged, and often diffuse These receptors are transmembrane protein complexes Examples: muscarinic ACh receptors, neuropeptides, and those that bind biogenic amines

G Protein-Linked Receptors: Mechanism Neurotransmitter binds to G protein-linked receptor G protein is activated and GTP is hydrolyzed to GDP The activated G protein complex activates adenylate cyclase

G Protein-Linked Receptors: Mechanism Adenylate cyclase catalyzes the formation of cAMP from ATP cAMP, a second messenger, brings about various cellular responses

Neurotransmitter Receptor Mechanism Ions flow Blocked ion flow Ion channel Adenylate cyclase Channel closed Channel open (a) Neurotransmitter (ligand) released from axon terminal of presynaptic neuron PPi GTP 4 5 Changes in membrane permeability and potential 3 1 cAMP ATP 5 3 GTP Enzyme activation Protein synthesis 2 GDP GTP Receptor Activation of specific genes G protein (b) Nucleus Figure 11.22b

Neurotransmitter Receptor Mechanism Ions flow Blocked ion flow Channel closed Channel open (a) Neurotransmitter (ligand) released from axon terminal of presynaptic neuron 1 Receptor G protein (b) Figure 11.22b

Neurotransmitter Receptor Mechanism Ions flow Blocked ion flow Adenylate cyclase Channel closed Channel open (a) Neurotransmitter (ligand) released from axon terminal of presynaptic neuron 1 GTP 2 GDP GTP Receptor G protein (b) Figure 11.22b

Neurotransmitter Receptor Mechanism Ions flow Blocked ion flow Adenylate cyclase Channel closed Channel open (a) Neurotransmitter (ligand) released from axon terminal of presynaptic neuron GTP 3 1 3 GTP 2 GDP GTP Receptor G protein (b) Figure 11.22b

Neurotransmitter Receptor Mechanism Ions flow Blocked ion flow Adenylate cyclase Channel closed Channel open (a) Neurotransmitter (ligand) released from axon terminal of presynaptic neuron PPi GTP 4 3 1 cAMP ATP 3 GTP 2 GDP GTP Receptor G protein (b) Figure 11.22b

Neurotransmitter Receptor Mechanism Ions flow Blocked ion flow Adenylate cyclase Channel closed Channel open (a) Neurotransmitter (ligand) released from axon terminal of presynaptic neuron PPi GTP 4 5 Changes in membrane permeability and potential 3 1 cAMP ATP 5 3 GTP Enzyme activation Protein synthesis 2 GDP GTP Receptor Activation of specific genes G protein (b) Nucleus Figure 11.22b

Neurotransmitter Receptor Mechanism Ions flow Blocked ion flow Ion channel Adenylate cyclase Channel closed Channel open (a) Neurotransmitter (ligand) released from axon terminal of presynaptic neuron PPi GTP 4 5 Changes in membrane permeability and potential 3 1 cAMP ATP 5 3 GTP Enzyme activation Protein synthesis 2 GDP GTP Receptor Activation of specific genes G protein (b) Nucleus Figure 11.22b

G Protein-Linked Receptors: Effects G protein-linked receptors activate intracellular second messengers including Ca2+, cGMP, diacylglycerol, as well as cAMP Second messengers: Open or close ion channels Activate kinase enzymes Phosphorylate channel proteins Activate genes and induce protein synthesis

Neural Integration: Neuronal Pools Functional groups of neurons that: Integrate incoming information Forward the processed information to its appropriate destination

Neural Integration: Neuronal Pools Simple neuronal pool Input fiber – presynaptic fiber Discharge zone – neurons most closely associated with the incoming fiber Facilitated zone – neurons farther away from incoming fiber

Simple Neuronal Pool Figure 11.23

Types of Circuits in Neuronal Pools Divergent – one incoming fiber stimulates ever increasing number of fibers, often amplifying circuits Figure 11.24a, b

Types of Circuits in Neuronal Pools Convergent – opposite of divergent circuits, resulting in either strong stimulation or inhibition Figure 11.24c, d

Types of Circuits in Neuronal Pools Reverberating – chain of neurons containing collateral synapses with previous neurons in the chain Figure 11.24e

Types of Circuits in Neuronal Pools Parallel after-discharge – incoming neurons stimulate several neurons in parallel arrays Figure 11.24f

Patterns of Neural Processing Serial Processing Input travels along one pathway to a specific destination Works in an all-or-none manner Example: spinal reflexes

Patterns of Neural Processing Parallel Processing Input travels along several pathways Pathways are integrated in different CNS systems One stimulus promotes numerous responses Example: a smell may remind one of the odor and associated experiences

Development of Neurons The nervous system originates from the neural tube and neural crest The neural tube becomes the CNS There is a three-phase process of differentiation: Proliferation of cells needed for development Migration – cells become amitotic and move externally Differentiation into neuroblasts

Axonal Growth Guided by: Scaffold laid down by older neurons Orienting glial fibers Release of nerve growth factor by astrocytes Neurotropins released by other neurons Repulsion guiding molecules Attractants released by target cells

N-CAMs N-CAM – nerve cell adhesion molecule Important in establishing neural pathways Without N-CAM, neural function is impaired Found in the membrane of the growth cone