Cell Biology of the Nervous System

Transcription

1 Cell Biology of the Nervous System 1. Functions of a Nervous System receive information from environment outside and inside the body; process, integrate and interpret this information to organize motor responses appropriate for survival; provide the ability to change (learning/plasticity) these responses (behavior) based on specific demands of the environment the CNS contains nerve cells (~100 billion) and glial cells (~1 trillion) ; the PNS contains nerve cells, glial cells, fibroblasts, and macrophages. 2. The Neuron The functional unit of the nervous system is the nerve cell or neuron Its function is to receive and integrate information, to conduct this information to other regions of the nervous system, and then to transmit this information to other neurons and cells. General structure of neurons: Cell body Dendrites Axon Synaptic terminals Neurons in different regions of the nervous system process information differently and therefore differ in their morphological and physiological properties, affecting number and length of dendrites, size of cell body, axon length and diameter, complexity of synaptic terminal, types of neurotransmitters and their receptors. 1

2 3. Dendrites (95% of neuron s total volume!) specialized to receive information from other nerve cells contains receptors for neurotransmitters released by other neurons The diversity of neuron shape is due to the complexity of dendrites. Number of dendrites and their degree of branching depend on the type of nerve cell and its task in integrating signals from other neurons. The more complicated the dendritic tree, the greater the ability to integrate information from a larger number of inputs. Truex and Carpenter, Human Neuroanatomy, Williams and Wilkins, 1969 Dendrites of many neurons contain small extensions known as spines. They are the sites for synapses on these dendrites. They increase the surface area for synapses Because they are separated from the main dendrite, they compartmentalize synaptic activity (ie each synapse can change independently of others). Dendrites contain ribosomes, allowing local control of proteins involved in the structure and physiology of synapses. Dendrites and spines expand and retract based on synaptic activity. These changes in the density and morphology of dendrites alter the strength of synaptic inputs, providing a way for neurons and ultimately the brain to change their function. Pathological processes induce swelling and atrophy. Truex and Carpenter, Human Neuroanatomy, Williams and Wilkins,

3 4. Cell Body (similar to other cells!) contains the nucleus; surrounding cytoplasm contains ribosomes, endoplasmic reticulum, Golgi, mitochondria, Nissl Substance lysosomes, etc found in other cells. may contain pigment - lipofuscin granules; melanin nucleus usually large and centrally positioned has major role in protein synthesis for sustaining the dendrites, axon, and terminals. Rough ER/ribosomes are extensive and appear as clumps (Nissl Substance) when stained. Related to abundant synthesis from Wagner and Hossler, of proteins destined for membrane insertion or export (ion channels, receptors, protein neurotransmitters). An important pathological feature is dispersion of Nissl substance (chromatolysis) indicating injury. Other pathological changes: inclusions and storage of lipids and misfolded proteins. 5. Axon conducts action potentials single axon emerges from cell body at region known as axon hillock. Action potentials are initiated there due to presence of Na+ channels. Axons may have branches. Vary in length from 10 microns to greater than 1 meter. Large axons are covered by a myelin sheath Formed by the extensive wrapping of glial cell membrane (lots of it!!) around the axon. Myelin is made by Schwann cells in the PNS and oligodendrocytes in the CNS. From Conn, Neuroscience in Medicine, Lippincott, Phila. Many glial cells are needed to cover the entire length of an axon. The myelin sheath is interrupted at regular intervals where one glial cell ends and another begins - known as Nodes of Ranvier. Ion channels are concentrated at the nodes where action potentials occur. Myelin is an electrical insulator along axon. It increases the conduction speed for action potentials and supports axons nutritionally. Myelin is crucial for propagation of action potentials along the axon. myelinated axons myelin Schwann nucleus and cytoplasm axon Cross-section of peripheral nerve. The thick membrane around axons is myelin. Also note the different diameters of axons and that smaller axons have less myelin. Wrabitz et al. J Cell Biology 3

4 MYELIN Numerous diseases (viral, genetic, autoimmune, metabolic, inflammatory; eg peripheral neuropathy, multiple sclerosis ) involve degradation of myelin and consequently impair propagation of action potentials (slow or completely block them) and thereby impair function. Several aspects of the structure of myelin contribute to its involvement in disease : Myelin = glial cell membrane. Lipid bilayer has higher proportions of sphingomyelin and glycosphingolipids compared to other cell membranes. Sphingomyelin is ceramide sphingomyelinase FattyAcid sphingosine P choline Glycosphingolipids include the cerebrosides, gangliosides, sulfatides hydrolases ceramide saccharide These specialized lipids as well as other specialized proteins of myelin contribute to its unique property of tightly compacted membrane layers. axon Implications of myelin biochemistry for disease: 1. Degradation of sphingomyelin and glycosphingolipids require specific enzymes. Genetic defects in these enzymes cause developmental storage diseases (sphingolipidoses). 2. Myelin proteins are susceptible to viral, inflammatory, immunologic disorders that cause demyelination. 3. Saccharide components of glycosphingolipids make them antigenic! They are involved in autoimmune responses that cause peripheral demyelination. 6. Synaptic Terminal The synapse is a specialized structure that transmits signals from one neuron (presynaptic) to another (postsynaptic). 4

5 Two types of synapses exist, differing in structure and physiology: Electrical Synapse (gap junction) Chemical Synapse Cell 2 membrane Cell 1 membrane Presynaptic terminal Postsynaptic terminal Receptors Synaptic vesicles Voltage gated calcium channels Transporters From Malcolm Slaughter, Ph.D. Information flow 1. Electrical Synapse (Gap Junction) two neurons are physically connected through membrane channels (gap junctions) formed by proteins called connexins; allows electrical current to flow quickly between two neurons bidirectionally. Useful for synchronizing acivity in a network of connected neurons. 2. Chemical Synapse two neurons are separated by a 20 nm cleft; presynaptic terminal releases neurotransmitter contained in vesicles that binds to receptors on postsynaptic neuron. More opportunity for modulation! Neurotransmitters excite or inhibit postsynaptic neurons depending on the properties of the receptors. Chemical synapses are the most common type of synapse. However, electrical synapses are expressed throughout the CNS (cortex, cerebellum, retina, and between glia). Postsynaptic locations for synapses are usually on dendrites, but they also can occur on cell bodies and axons. Dendrites are usually densely populated with synapses from other neurons. Each neuron typically receives 100s-1000s of synapses. Chemical synapses have a complex structure containing mitochondria, smooth ER, vesicles, pre- and post- synaptic densities, synaptic cleft, etc. Hundreds of proteins are involved presynaptically in transmitter release! Why so complex?? The complex structure and large number of proteins provide many possibilities for modulating the process of synaptic transmission. However, this also allows many opportunities for mutations, autoimmune diseases, and toxins to impair synaptic transmission (eg some forms of myasthenia gravis, snake/spider/marine toxins). An estimated 1400 proteins comprise the postsynaptic surface/density alone. Mutations there are associated with 133 neuronal and psychiatric disorders. At some synapses, the postsynaptic membrane can release molecules (neurotransmitters and neuropeptides) that affect transmitter release from the presynaptic terminal. Why do synapses exist? Why not connect one neuron directly to another? Synapses have the remarkable property of changeability (plasticity) the amount of transmitter released or the properties of postsynaptic receptors can change depending upon previous activity. This alters the strength of a synapse, ie how strongly one neuron affects another, which is the basis for changes in behavior such as learning and memory. 5

6 7. Cytoskeletal components support neuronal structure The highly complex structure of dendrites and length of axons requires cytoskeletal support and integrity. Actin, microtubules, intermediate filaments are the basic structural proteins that give neurons their shape. Diseases that impair cytoskeletal proteins result in neurological disorders. They are polymers formed by assembly of individual monomer subunits. They lengthen and shorten dynamically to allow changes in cell shape. Actin filaments anchor transmembrane molecules; keep ion channels/receptors in place. actin Microtubules Support the tubular structure of axons and dendrites and mediate axonal transport. Assembly and stability of microtubules is promoted by microtubule associated proteins (MAPs; eg tau). Defects in tau are associated with dementias known as tauopathies. Due to the length of the axon and distance of the terminal from the cell body, axons and synapses cannot rely on diffusion of proteins and organelles. Microtubules provide a pathway for moving components more quickly to these locations in an energy-requiring process known as axonal transport. Axonal transport of proteins and organelles occurs along microtubules at rates up to 400 mm/day. (Calculate how long it would take to move a protein synthesized in the cell body in the cortex down an axon to its terminal in the spinal cord 1 meter away!) Axonal transport depends upon motor proteins (kinesin, dynein) that bind to and walk along microtubules while cargo is bound MT to their other end. It is bidirectional, transporting cargo from cell body to terminal and terminal to cell body, depending on the particular motor protein. An important aspect of axonal transport is that it can sort proteins to specific locations, eg sending neurotransmitter receptors to dendrites, but proteins involved in neurotransmitter release to terminals. Axonal transport requires energy to move cargo. When neurons are metabolically impaired (eg diabetes), cargo is not moved efficiently to replace proteins that turn-over. This tends to be worst for neurons with the longest axons, a condition that underlies peripheral neuropathy. Intermediate filaments (neurofilaments)- regulate axon diameter GFAP (glial fibrillary acidic protein) is a component of intermediate filaments that occurs specifically in astrocytes. It is an immunological marker for those cells. Cytoskeletal defects associated with neurological disorders. Microtubule defects affect nuclear migration in cortical development (lissencephaly) Defects in the microtubule associated protein tau are associated neurodegenerative diseases such as Alzheimer s and other dementias. 6

7 Many neurodegenerative diseases involve defects in axonal transport, resulting in accumulation of organelles in axons that cause swellings and spheroids. Toxins depolymerize microtubules (vincristin, colchicines), intermediate filaments (acrylamide) and actin filaments (cytochalasin), impairing or killing neurons. 8. Types of neurons why don t all neurons look alike: the morphology of a neuron is specialized for its role in receiving, conducting, and transmitting information e.g. receive info from one or many cells, conduct action potentials short or long distances. unipolar - one process connected to cell body; not present in vertebrates pseudounipolar one process connected to cell body; called pseudo because initially 2 processes that fuse into one. MOST peripheral sensory neurons are pseudounipolar. bipolar two processes connected to cell body - one axon and one dendrite. multipolar one axon but multiple dendrites; most CNS neurons are multipolar. multiple dendrites give this neuron the greatest ability to integrate information. pseudounipolar sensory bipolar sensory multipolar motor neuron, interneuron signal Functionally, neurons are classified as sensory, motor, interneurons, or projection neurons. Neurons are arranged in pathways to transmit information. The simplest vertebrate pathways contain a chain of 2 neuron a sensory neuron connected to a motor neuron. Most pathways contain a chain of 3 or more neurons, which interposes a neuron (interneuron) between the other neurons. This provides the opportunity for increased integration of information and interaction between neurons. It provides the capacity for more complex responses and detection of finer features of stimuli. Excitation and inhibition can be combined in many ways to control activity. e.g.: Glial Cells The OTHER cells of the nervous system. Support neuronal structure, metabolism, growth/repair, and respond to injury. They actively communicate with neurons and participate in nerve cell function. PNS Glia (Schwann cells, satellite cells) Peripheral nerves are supported by connective tissue (fibroblasts, collagen, macrophages) Schwann (satellite) cells surround cell bodies in ganglia. 7

8 Schwann cells surrounding larger axons are myelinating (form myelin around axon); around small axons they are nonmyelinating (surround axon but do not form myelin). Schwann cells release growth factors that influence recovery from injury. CNS Glia (oligodendrocytes, astrocytes, microglia, ependyma) The CNS lacks fibroblasts and connective tissue Astrocytes protoplasmic - found in gray matter; fibrous - found in white matter; radial glia guide neuron migration during development have long processes that give the cell the appearance of a star (hence the name astro-cyte) some processes terminate as end feet on capillaries, nodes of Ranvier, and synapses regulate the ionic environment. contain an intermediate filament protein known as Glial Fibrillary Acidic Protein (GFAP), which is used to identify astrocytes in pathological conditions. Functions: end-feet provide communication route between extracellular space and blood. remove excess K + (consequence of action potentials) from the extracellular space. ensheath CNS synapses and remove neurotransmitters from extracellular space. proliferate in response to injury (reactive gliosis) secrete growth factors and extracellular matrix guide neuronal migration in embryo; may provide neuronal stem cells in adult participate in neuronal metabolism they metabolize glucose to lactate and provide it to neurons as an energy source. Blood Brain Barrier What is it: Many blood-derived molecules including small ions, water soluble molecules, charged molecules, many proteins, most nonessential amino acids and nonessential fatty acids cannot enter the CNS (brain and spinal cord) from blood vessels. Why: The CNS is a protected environment. Many neurotrnsmitters are also common components of blood. Entry into the CNS would interfere with synaptic communication. Also, other components of blood are toxic to the CNS environment. What causes it: The basis for their exclusion is a sophisticated barrier formed by brain capillaries, pericyes, and astrocytes that block diffusion of most molecules regardless of size. Endothelial cells that comprise all capillaries are held together by adhesive junctions (adherens junctions and tight occludens junctions). Body capillaries have a partial barrier to large molecules (> 66,000 mol weight), but allow smaller molecules to diffuse into tissues. However, brain capillaries block diffusion of almost all molecules. The difference is due to the properties of the tight junctions between endothelial cells, which are leaky in body capillaries, but almost Pericyte impermeable in brain capillaries. Astrocyte end feet that contact brain capillaries, pericytes, and neurons all participate in inducing these impermeable tight junctions. Basal lamina Capillary Astrocyte end feet 8

9 Additional structural, physiological, and biochemical properties strengthen the BBB: No fenestrated endothelium in brain capillaries: Fenestrated endothelial cells in liver, kidney, endocrine glands contain pores in their membranes, which free passage of plasma molecules into interstitial space. What substances CAN enter the brain from blood: lipid-soluble molecules such as alcohol that can pass through lipid bilayers; molecules such as glucose and amino acids for which carrier-mediated transporters are present. Choroid plexus** has a Blood-CSF Barrier created by ependymal cells, only small molecules can pass from blood to CSF. However, most of the ependymal lining of the ventricles has no barrier, so molecules can exchange freely between extracellular space and CSF. Pathological conditions (inflammation, infection, autoimmune diseases, tumors, ischemia, acidic blood ph, lead, hyperosmolarity, etc) alter the properties of endothelial tight junctions and cause the BBB to be leaky. BBB results in a much decreased immune response due to few white cells, little complement, decreased immunoglobulins that are prevented from entering the CNS. Breakdown of the BBB results in leakage of neurotoxic bloodderived proteins into the CNS. This causes microvascular and cerebral blood flow changes that can lead to neurodegeneration. Circumventricular Organs are regions in the CNS that have NO BBB. These are located near the midline adjacent to the 3 rd and 4 th ventricles. They are important sites of communication between the brain and blood, eg posterior pituitary and median eminence of hypothalamus for release of hormones, vagal area in medulla monitors blood toxins and controls vomiting, areas around 3 rd ventricle monitor blood osmolarity and gut hormones. No fenestrated endothelium ** What is choroid plexus at specific locations along the ventricular system, capillaries invaginated into the ventricular space during development. As they invaginated, they were covered first by pia and then by ependymal cells. Ependymal cells covering the choroid plexus are secretory, but they are interconnected by tight junctions that limit permeability to small molecules, creating a blood-csf barrier. 9

10 Be amazed by the numbers. The nervous system contains: 100 billion neurons 1 trillion glial cells Axons/dendrites produce 300 million feet of wiring packed into a 1.5 qt space Each neuron receives 1,000 10,000 synapses, creating 100 trillion connections These connections are the basis for how brain circuits function. How can such a large number of connections that result in very specific functions be created/specified? REFERENCES for Histological pictures of nerve and glial cells: