1. Molecular and Cellular Neuroscience BMP-218 Benjamin M. Ellingson, Ph.D. Dept. of Radiological Sciences David Geffen School of Medicine at UCLA 10/11/2011

2. Divisions of the Nervous System The nervous system is composed of two primary divisions: 1. CNS - Central Nervous System (Brain + Spinal Cord) 2. PNS - Peripheral Nervous System (Nerves from CNS to other cells/organs)

3. Cells of the Nervous System The nervous system is composed of two primary types of cells: 1. Neurons - transmit information 2. Glia - largely supporting cells

4. Neurons Occur in a wide variety of sizes and shapes, but all share the feature of “cell-to-cell” communication

5. Neuronal Cytoarchitecture Dendrites Receives signals from other cells (Input) Cell Body (Soma/Perikaryon) Contains cell nucleus Initial Segment/Axon Hillock Integrates information Fires an “action potential” (explained later) Axon Projects to other cells for communication Other neurons, muscles, organs Axon Terminal / Synapses Release of neurotransmitters

6. Myelin Multilayered lipid and protein covering axons at certain areas Electrically insulates axons and increases speed of conduction Nodes of Ranvier separate myelinated areas and are important in saltatory conduction Produced by Oligodendrocytes in the CNS and Schwann Cells in the PNS Oligodendrocytes myelinate multiple axons Schwann cells myelinate a single axon Oligodendrocyte Schwann Cell

7. Myelin Myelin sheath is formed from multiple tight layers This restricted molecular mobility gives rise to unique characteristics on MRI

8. Gray and White Matter Gray Matter Does not contain myelin Contains neurons, dendrites, axons without myelin, soma Cerebral Cortex (surface of the brain) Deep parts of the brain (nuclei) containing neuron cell bodies Central regions of the spinal cord White Matter Contains myelin Parallel axons surrounded by myelin that traverse from one part of the nervous system to another Peripheral regions of the spinal cord

9. Myelin stained tissue section of Human Brain Myelin (White Matter) (Stained Dark) Gray Matter (No Stain)

10. Types of Neurons

11. Classifications of Neurons Afferent Neurons Transmits information into the CNS from receptors Cell body and long peripheral process of the axon are in the PNS; only the short central process enters the CNS Have no dendrites (do not receive inputs from other neurons) Efferent Neurons Transmit information out of CNS to effector cells (muscles, glands, other neurons) Cell body, dendrites, and a small segment of the axon are in the CNS; most of the aon is in the PNS Interneurons Function as integrators and signal changers Integrate groups of afferent and efferent neurons into reflex circuits Entirely in the CNS; 99% of all neurons CNS PNS

12. Glia Subtypes include: Astrocytes Oligodendrocytes Microglia Ependymal Cells Choroidal Cells Glia Provide Physical (structural) support for surrounding neurons Metabolic support for surrounding neurons Immune function Myelin (Oligodendrocytes in CNS; Schwann Cells in PNS) Communication? (Calcium channel communication between astrocytes)

13. Astrocytes In development, guide neurons as they migrate to their destinations Stimulate neuronal growth by secreting growth factors Forms the Blood-Brain Barrier (BBB), connecting neurons to blood vessels

14. Astrocytes In development, guide neurons as they migrate to their destinations Stimulate neuronal growth by secreting growth factors Forms the Blood-Brain Barrier (BBB), connecting neurons to blood vessels Most common type of primary brain tumor (astrocytoma) Hayden EC, Nature. 2010; 463(7278):154-6.

15. Oligodendrocytes Forms the myelin covering of CNS axons

16. Microglia The main phagocytic cell and antigen-presenting cells in the CNS Smallest cell bodies among the neuroglia Immune response / injury

17. Ependymal and Choroidal Cells Considered “glial like” cells Ependymal Cells Line the ventricular system in CNS Regulate the production and flow of cerebrospinal fluid (CSF) Choroidal Cells Form the inner layer of the choroid plexus which abuts the ventricular system in specific locations Secretes CSF into the ventricles

18. Neurophysiology

19. Signaling within groups of neurons depends on three (3) basic properties of these cells: 1. The reseting membrane potential (most cells) Negative charge on the inside of the cell Positive charge on the outside of the cell RMP ranges from -30mV to -90mV (typically -70mV) [Na + ] high on the outside and [K + ] high on the inside 2. Transmembrane protein ion channels (in neurons) Transmission of signal along surface of the cell Controlled (gated permeability) to both K+ and Na+ 3. Projections to other neurons and synapses Between cell signal propagation via a chemical intermediate

20. Na + /K + ATPase Uses energy stored in ATP (which is formed mostly by mitochondial oxidative glucose metabolism) to maintain transmembrane gradients of K+ and Na+ Transports 3 Na + out while bringing in 2 K + (Gated) Ion Channels

21. Na + /K + ATPase Gated Ion Channels Allow Na + and K + to flow down their concentration gradients Formation of transmembrane electric current (Partial) collapse of RMP when gates are open Gates are controlled by transmembrane voltage (transistor-like properties) (Gated) Ion Channels

22. The Action Potential (electrical transmission of signals along the neuron)

23. Action Potential The action potential is a wave of transient depolarization that travels along the neuron and particularly the axon Depolarization causes voltage sensitive ion channels to open to propagate depolarization – Na + flows inward (sodium current) – K + flows outward (potassium current) Myelin and Nodes of Ranvier speed the conduction Pharmacology of voltage sensitive channels – Site of action of neurotoxic drugs (snake venom, scorpion toxins, plant alkaloids etc) – Site of action of local anesthetics (lidocaine)

24. Action Potential Hodgkin- Huxley model – Developed in 1950’s through voltage recordings with intracellular and extracellular electrodes in squid giant axons depolarization repolarization hyperpolarization Depolarization: Na + and K + channels open Repolarization: Na + channels close and K + open Hyperpolarization: K + channels still open

25. Conduction A B A. Conduction in an unmyelinated fiber. Na + flows in depolarizing adjacent sections of membrane. Self propagating B. Saltatoty conduction in myelinated fibers. Myelin insulates and blocks current across membrane Depolarization occurs at Nodes of Ranvier Current “jumps” from node to node Faster and more energy efficient

26. Neurotransmission (synapse function)

27. Presynaptic neuron Postsynaptic neuron

28. Intracellular Communication: Synaptic Function & Neurotransmission Signal conveyed by neurotransmitter diffusion across synaptic cleft – Presynaptic electrical signal converted to a chemical signal that is reconverted to an electrical signal in the postsynaptic cell – Slow compared to action potential propagation Specific networks of nerve cells tend to use specific neurotransmitters – Anatomically based networks use specific neurotransmitters – Inhibitory neurons frequently use dopamine and GABA – Excitatory neurons frequently use glutamate and acetylcholine

29. Presynaptic events: - depolarization opens Na + and Ca 2 + channels. - influx of Ca 2 + causes docking and exocytotsis of neurotransmitters (NT) vesicles into the synaptic cleft Postsynaptic events: - NT binds to receptors and opens ion channels that depolarize the membrane (excitatory postsynaptic potential (EPSP)) or hyperpolarize the postsynaptic membrane (inhibitory postsynaptic membrane (IPSP). Synaptic transmission Glial cells remove neurotransmitter from the synaptic cleft

30. Summation A single impulse doesn’t initiate an impulse/action potential in the post-synaptic neuron - partially depolarize neuron and bring it closer to threshold or - hyperpolarize the postsynaptic neuron and make it harder to depolarize

31. Neurotransmitters

33. – Agonists – accentuate neurotransmission – Antagonists – suppress neurotransmission – Neurotransmitter analogs are used as nuclear medicine tracers (i.e. 2-deoxy-glucose) Drugs can influence neurotransmitter action

34. Drugs affecting neurotransmission

37. Nicotine and cancer (www.wikipedia.com)

38. Drug effects on action potential