Outline Neuroanatomy

• Neuroanatomy Overview of the basics needed for this course • To know about drug action, have to know what a neuron is, where it is, and how neurons interact with each other • Digital Anatomist Program (will place link on website) • Neuroanatomy and Nomenclature University of Washington

• Principles of Chemical Transmission • Hierarchical Approach to navigating around brain • E.g., • Neurotransmitters and Neuropeptides • GTA • Neighborhoods • Principal Streets • Smaller Streets

Navigating Neuroanatomy: Cardinal Terms Sagittal

• Anterior / Rostral Toward Front • Posterior / Caudal Toward Back Horizontal • Medial Middle (Axial) Coronal • Lateral Side • Dorsal Toward Back Side • Ventral Toward Front Side • Superior Upper • Inferior Lower • Proximal Near Center • Distal Toward Periphery

Navigating Neuroanatomy Neuroanatomical Axes

• Sagittal Plane LEFT & RIGHT or LATERAL & MEDIAL

• Coronal Plane ANTERIOR & POSTERIOR or ROSTRAL & CAUDAL

• Axial / Horizontal Plane SUPERIOR & INFERIOR or DORSAL & VENTRAL

1 Nomenclature

• Cytoplasm • Contents of a cell Nomenclature • All contents outside of the nucleus of a membrane bound cell • Includes organelles and the cytosol

• Cytosol • The semi-fluid component of a cell’s cytoplasm

Nomenclature Nomenclature

• Polymer • Organelle • A large compound of a number of subunits, • A specialized part of a cell monomers • Membrane-bound body found in cytoplasm of the cell that performs specific functions • Amino Acid • Nucleus • A class of organic chemical compounds that combine to build proteins • Most prominent organelle in the cell • A membrane bound structure that contains the cell’s • The monomer of proteins hereditary information and controls the cell’s growth and reproduction

Nomenclature Nomenclature

• Protein • Polymer composed of amino acids • Mitochondria • Bodies found in the cytoplasm where aerobic • Enzyme processes takes place • Protein catalyst that accelerates certain chemical reactions • Endoplasmic reticulum (ER) • Any of several complex proteins that are produced • An organelle responsible for protein synthesis by cells and act as catalysts in specific biochemical reactions • Ribosome • Site of protein synthesis • Found in cytoplasm, ER, and mitochondria

2 Nomenclature Nomenclature

• Nucleotide • Deoxyribonucleic Acid (DNA) • The monomer of nucleic acids • The king of molecules • Associated with the transmission of genetic information • Nucleic Acid • A nucleic acid found in the nucleus • A polymer of nucleotides • Ribonucleic Acid (RNA) • Plays an important role in protein synthesis • A nucleic acid found in the nucleus and cytoplasm

Nomenclature Nomenclature

• Gene • Polymerase • In DNA, a sequence of nucelotides that contain • Enzyme that catalyzes the synthesis of nucleic acids information necessary for the metabolism and from an existing strand of DNA or RNA structure of an organism • i.e., assembling RNA from ribonucleotides or DNA from deoxyribonucleotides • Chromosome • Threadlike body in nucleus that carries the genes in a • Adenylate cyclase linear order • An enzyme that catalyses cAMP from ATP • Growth Factor • A protein involved in cell differentiation and growth

Nomenclature Nomenclature

• Transcription Factor • Active Transport • Any factor that controls the process of transcription (making of an RNA copy of a DNA segment). • The forced pumping of molecules from one side of a membrane to other • Usually it is some sort of enzyme or other protein, or some other sort of organic molecule. • Molecule located in membrane

• Gene expression • Ion channel • Conversion (transcription) of information encoded in • A protein imbedded in a cell membrane that serves a gene first into messenger RNA and then as a crossing point for the regulated transfer of a (translated) into a protein specific ion or group of ions across the membrane.

3 Nomenclature Nomenclature

• Adenosine triphosphate (ATP) G-Protein • • A cofactor that contributes either energy or a • A protein embedded in the cytoplasmic membrane of phosphate group or both to a reaction the cell that transmits signals from outside the cell to • as it does so, it loses either one or two of three the inside of the cell phosphate groups, becoming either ADP or AMP • Causes biochemical reaction within the cell, e.g., gene expression • Guanosine triphosphate (GTP) • serves as an energy source for many biochemical • Second Messenger reactions • An effector molecule that is synthesized in a cell in • during translation and is required for ribonucleic response to a signaling first messenger acid synthesis since it is a direct precursor

Nomenclature Nomenclature

• Phosphorylation • Neuropeptide • The addition of a phosphate group to a compound • A member of a class of protein-like molecules made • This is usually achieved by transferring a phosphate in the brain group from ATP • short chains of amino acids, with some functioning as neurotransmitters and some functioning as • Protein Kinase hormones. • An enzyme that adds phosphate groups to a protein molecule

Cells in the Central Nervous System Anatomy of the Neuron

• Glial cells • Mechanical and metabolic support for neurons • Cell Body (Soma) • Dendrites (Branchlike Extensions) • Neurons (nerve cells) • Dendritic Spines • Basic units of structure and function in the nervous • Axon Hillock (Signal begins) system • Synaptic terminals (Boutons) • Brain cell, and hence with DNA, nucleus, • Myelin Sheath (Glia) mitochondria (energy generating components of the • Synapse (Gap between dendrite/axon) cell), etc.

4 The Basic Structure of the Neuron The Resting Membrane Potential

• Boundary of the neuron is known as the cell membrane • Voltage difference between inside and outside of the membrane (-70 mV relative to outside) • High [Na+] outside • High [K+] inside • Na+/K+ pump — active maintenance of gradient • Permeability at rest: • K+ YES • Na+ NO

The Action Potential Phases of the Action Potential

• Na+ & K+ flow through ion channels • If ‘threshold’ is reached….. • Ion channel opening • AP is ‘all or none’ response • all or none • Self Propogating • -70 mV to +50 mV transient • Phases • Electrical charge is redistributed across membrane • Rising to threshold • Membrane becomes ‘depolarized’ • Depolarization • Repolarization • Hyperpolarization

Importance of action potential to NT Electrical versus Chemical Synapses neurotransmission Electrical Synapses Chemical Synapses

• Impulse from AP opens ion channels for Ca2+ Rapid bidirectional transmission Slow unidirectional transmission • The increased Ca2+ concentration in the axon terminal initiates the release of the neurotransmitter (NT) Gap junctions Presynaptic vesicles, active zones, • NT is released from its vesicle and crosses the “gap” or postsynaptic receptors synaptic cleft and attaches to a protein receptor on the dendrite Ion current Chemical neurotransmitters • Interaction of NT and protein receptor open post- synaptic membrane ion channel for Na+ • After transmission the NT is either degraded by an Electrotonic transmission Complex amplifying enzyme or taken back into the pre-synaptic membrane excitatory/inhibitory signals by a transporter or reuptake pump Cytoplasmic continuity Synaptic cleft

5 Principles of Chemical Neurotransmission Chemical Transmission

• Understanding of synaptic transmission is necessary to understand the causes of mental disorders and the actions of psychoactive drugs

• Piggy-back on preexisting infrastructure because NTs are endogenous signaling molecules that alter the behaviour of neurons or effector cells

• The properties of the NTs do NOT determine its effects on the the postsynaptic cell, but rather the receptor determines whether a NT is excitatory or inhibitory

Chemical Synapses Chemical Transmission • Specialized junction that transfers nerve impulse information from a presynaptic membrane to a postsynaptic membrane using neurotransmitters and • Slower than electrical and generally unidirectional enzymes • Integrative

• Amplifies and regenerates the signal

Principle of the Synapse Anatomy of the Synapse

• The Synapse • Organized to send synaptic information to other • Point where two cells meet to transfer signal from neurons one neuron to another neuron or effector • AXON • Chemical event • Primarily unidirectional communication between neurons • Organized to receive synaptic information from other neurons • Synaptic Cleft • DENDRITE • 20-50 nm wide • CELL BODY • Prevent impulses from directly passing from one • AXON neuron to another

6 Anatomy of the Synapse Anatomy of the Synapse

• Synaptic Bouton (Presynaptic Terminal) • Membrane Differentiations • Contains synaptic vesicles (~50 nm in diameter) • accumulations of proteins on either side of the synaptic cleft • Contains synaptic granules (~100 nm in diameter) called large dense core vesicles • Active Zones • presynaptic side of neurotransmitter (NT) release • Postsynaptic Density • contains receptors to translate NT into intracellular signal

ELECTRON MICROGRAPHS OF A SYNAPSE

The Synapse Function of the Synapse

• Receive information in the form of action potentials • Axon from the presynaptic neuron joins the • Electrical impulses traveling down the axon postsynpatic neuron at either a dendrite or a cell body • Can be multiple neurons interacting at the synapse

• Presynaptic Neuron conducts impulses toward the • Simply pass on the same information received onto the synapse next neuron • SIGNAL

• Block transmission from one neuron to the next • Postsynaptic Neuron transmits impulses away from the synapse • RECEIVER & COMMUNICATOR • Integrate signals from other neurons

Input to the Neuron Flow of Information

• Synapses can be excitatory or inhibitory • An axon that flows to and innervates a structure is AFFERENT • Signals arriving at an excitatory synapse tend to cause the receiving neuron to fire • An axon that flows from a structure is EFFERENT

• Signals arriving at an inhibitory synapse tend to inhibit the receiving neuron from firing

7 Flow of Information Flow of Information

• Neuron receives electrical impulses / signals at its • Each neuron has many synapses on its dendrites and dendrites soma (e.g., a pyramidal cell has 10,000s) • These signals are transmitted along axons • Long axons are wrapped with myelin sheath to make • When the NT released by the axon at the synapse signal travel faster diffuse across the cleft they open or close molecular • Dendrites INPUT signals to the soma gates at the receptors that allow ions to flow in or out, thus inhibiting or exciting the receiving neuron • Axons OUTPUT signal from the soma (postsynaptic neuron) • If enough excitatory signals arrive at same time at the soma it will fire and send an electrical signal down its axon

Flow of Information Flow of Information

• Signals flow in through the dendrites and/or cell body, • When signal from the axon reaches the bouton, it accumulate at the axon hillock, and out the axon to the prompts vesicles (small storage compartments full of synaptic terminal (boutons) NT ) to fuse to the end of the bouton • Once fused, the vesicle releases the NT into the synaptic • Signal arrives at the axon/dendrite connection point cleft (synapse) and the packets of neurotransmitter • These NTs cross the cleft to reach the postsynaptic molecules (NT) diffuse across the gap, and attach to the neuron receptors receptors of the receiving neuron • Sufficient stimulation of these receptors prompts the postsynaptic neuron to start its own action potential

Convergence, Integration & Divergence Neuronal Integration

What neurons do with thousands of excitatory (EPSP’s) and A single neuron receives thousands of inputs inhibitory (IPSP’s) inputs from other neurons = CONVERGENCE

Activation of more excitatory Activation of more inhibitory inputs than inhibitory inputs inputs than excitatory inputs

A single neuron ‘INTEGRATES’ all these inputs Membrane potential will Membrane potential moves approach threshold away from threshold

A single neuron synapses with thousands of other neurons = (if threshold reached) DIVERGENCE Action Potential No Action potential

8 Neuronal Integration What’s needed for Chemical Transmission

• Spatial Summation • Mechanism for synthesizing and packing NT into • Numerous postsynaptic potentials converge on a vesicles single postsynaptic neuron • Vesicular transporter • A space (distance) dependent process • Mechanism for causing vesicle to release NT into • Temporal Summation synaptic cleft in response to action potential (electrical signal) • Successive waves of NT release (time) Biosynthetic enzymes • A time dependent process •

What’s needed for Chemical Transmission Synaptic Transmission

• Mechanism for producing an electrical or biochemical • AP in presynaptic cell response to NT in postsynaptic neuron • Depolarizes presynaptic membrane • Opens voltage-gated Ca2+ channels • Ca2+ ions flow into cell • Mechanism for removing NT from synaptic cleft • NT/NP stored in vesicles • Uptake transporters in the plasma membrane • Ca2+ triggers vesicle docking at active zones (NP at release sites) • Mechanism for degradation for the NT • Vesicles and membrane fuse (activated proteins) • Ca2+ activates calmodulin, which activates protein kinase • Protein kinase phosphorylates synapsins • Synapsins aid in the fusion of synaptic vesicles

Synaptic Transmission continued… Chemical Synapses

• By exocytosis, NT/NP released into synaptic cleft • Neurotransmitter (NP requires higher frequency APs) • Endogenous chemical (signaling molecule) released from one neuron and influences another NTs released and diffuse across synaptic cleft • • Synaptic Cleft • NT (ligands) bind to specific receptor proteins in postsynaptic cell • A small gap between the presynaptic (sender) and the membrane postsynaptic (receiver) neurons Chemically-regulated gated ion channels open • • Synaptic Vesicles (clear NT vs. dense NP) Resultant EPSPs (depolarization) or IPSPs (hyperpolarization) • • Small spherical organelles that contain quanta (~5000 • NT inactivated to end transmission molecules) of chemical used in transmission • Polarization • Communication generally occurs in only one direction from presynaptic site to postsynaptic site

9 Synaptic Transmission Model Summary

• Precursor Transport • Chemically synthesized presynaptically • NT synthesis / Synthesis of Signal • Electrical signal flow along axon to synaptic terminal • Storage • Electrical stimulation releases chemical • Release • Chemical produces physiological effect • Activation / Detection • Postsynaptically • Termination / Removal of Signal • Interacting with receptors Diffusion • • Fast versus slow neurotransmission • Enzymatic Degradation • Excitatory versus inhibitory neurotransmission • Reuptake • Autoreceptors — on presynaptic terminal, decreases NT release and synthesis

Neurotransmitters

• There are dozens of different neurotransmitters (NT) in the neurons of the body. Neurotransmitters • NTs can be either excitatory or inhibitory based on interaction with the post-synaptic receptor • Each neuron generally synthesizes and releases a single type of neurotransmitter (deal with complexity of cotransmission later) • The major neurotransmitters are indicated in Table 3-1

Drugs Interfere with Neurotransmission Definition of Neurotransmitter

• Chemical that exists in the presynaptic terminal • Drugs can affect synapses at a variety of sites and in a variety of ways, including: • Enzyme for synthesizing the chemical must exist in the presynaptic terminal or in cell body (peptides) • Increasing number of impulses • Release NT from vesicles with or without • Chemical released when electrical signal reaches the presynaptic terminals and in sufficient quantities to produce changes in impulses postsynaptic neurons • Block reuptake or block receptors • Produce more or less NT • Specific receptors for the chemical exist on the postsynaptic • Prevent vesicles from releasing NT membrane

• Blocking release of the chemical prevents the presynaptic signals from altering postsynpatic neurons

10 Classes of Neurotransmitters

• Amine • Acetylcholine • Monoamines • Catecholamines, e.g., Dopamine Neuropeptides • Indoleamines, e.g., Serotonin • Amino Acids • E.g., Glutamate, GABA (γ-aminobutyric acid) • Peptides • E.g., Opioid peptides, pituitary hormones

Neuropeptide Profile Biosynthesis of Neuropeptides

• While only ~10 classical NT, there are over 100 • Gene transcription in nucleus neuropetides • mRNA constructed and travels to ribosome • mRNA eventually translated into NP • Neuropeptides • Processesed in ER • Are made from protein precursors encoded by genes • Packaged into vesicles in Golgi Apparatus • Are usually co-transmitters • Transported to synaptic terminal • Use slow neurotransmission • Wait for enough of excitatory signal to be released • Are released from dense core vesicles • May be important in genetic differences in behavior

Biosynthesis of Neuropeptides Biosynthesis of Neuropeptides

• Difference in synthesis leads to storage of peptides in • Translationally inserted into ER followed by signal different vesicles than classic NTs sequence cleavage • Signal sequence to obtain entry to the endoplasmic reticulum • Encoded by genes, transcribed into mRNA and translated into proteins • Transported through Golgi Apparatus and then sorted into transport vesicles and then cleaved from their precursors • Precursors with cleavage sites to release active peptide

11 Regulation of Neuropeptides

• Regulation at the level of gene expression predominant • Cells can express new neuropeptide through gene expression NT vs. NP

• Not released at active zones, must diffuse to receptors

• Not released with every action potential • Require high rates of stimulation

• Multiple mechanisms of Degradation

Classical NT vs. Neuropeptide Classical NT vs. Neuropeptide

• Major difference is how they are synthesized • Some difference in release site and action

• Classical NTs • Classical NTs Synthesized in cytoplasm • • Released at the active zone • Packaged into synaptic vesicles by transporters • Can mediate both fast and slow neurotransmission

• Neuropeptides Neuropeptides • Synthesized by the translation of mRNA • • Processed through the Golgi Apparatus, where they • Released from outside the active zone are packaged and into dense core vesicles • Only mediate slow neurotransmission

What common between Super Summary Classical NT and Neuropeptide?

• Use of a precursor molecule • Synthesis • Synthesis within cell • Storage in vesicles • Localization in presynaptic terminal (Storage) • Release into synaptic gap (NP not at active zones) • Ca2+ dependent (NP less required) • Release • Binding to receptor sites on postsynaptic membrane • Message transmitted • Activation (Binding & Recognition) • Breakdown/Inactivation of NT or NP • Inactivation

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