molecular and cellular neuroscience

Molecular and Cellular

NeuroscienceBMP-218

Benjamin M. Ellingson, Ph.D.Dept. of Radiological Sciences

David Geffen School of Medicine at UCLA

10/11/2011

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)

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

Neurons• Occur in a wide variety of sizes and shapes, but all share

the feature of “cell-to-cell” communication

Neuronal CytoarchitectureDendrites

• 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

MyelinMultilayered 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 axonOligodendrocyte

Schwann Cell

MyelinMyelin sheath is formed from multiple tight layers

This restricted molecular mobility gives rise to unique characteristics on MRI

Gray and White MatterGray 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

Myelin stained tissue section of Human Brain

Myelin (White Matter) (Stained Dark)

Gray Matter(No Stain)

Types of Neurons

Classifications of NeuronsAfferent 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

GliaSubtypes 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)

AstrocytesIn 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

AstrocytesIn 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.

OligodendrocytesForms the myelin covering of CNS axons

MicrogliaThe main phagocytic cell and antigen-presenting cells in the CNS

Smallest cell bodies among the neuroglia

Immune response / injury

Ependymal and Choroidal CellsConsidered “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

Neurophysiology

NeurophysiologySignaling 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

Transmembrane protein ion channels (in neurons)

• Transmission of signal along surface of the cell

• Controlled (gated permeability) to both K+ and Na+

• Projections to other neurons and synapses

• Between cell signal propagation via a chemical intermediate

Na +/K + ATPase

Na +/K + ATPaseUses 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

Na +/K + ATPase

Gated Ion Channels Allow Na+ and K+ to flow down their concentration gradientsFormation of transmembrane electric current(Partial) collapse of RMP when gates are openGates are controlled by transmembrane voltage (transistor-like properties)

(Gated) Ion Channels

The Action Potential(electrical transmission of signals

along the neuron)

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)

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 openRepolarization: Na + channels close and K + openHyperpolarization: K + channels still open

ConductionA

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 membraneDepolarization occurs at Nodes of RanvierCurrent “jumps” from node to nodeFaster and more energy efficient

Neurotransmission(synapse function)

Presynaptic neuron

Postsynaptic neuron

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

Presynaptic events:-depolarization opens Na+ and Ca2 + channels.-influx of Ca2 + 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

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

Neurotransmitters

– Agonists – accentuate neurotransmission– Antagonists – suppress neurotransmission– Neurotransmitter analogs are used as

nuclear medicine tracers (i.e. 2-deoxy-glucose)

Drugs can influence neurotransmitter action

Drugs affecting neurotransmission

Nicotine and cancer(www.wikipedia.com)

Drug effects on action potential