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The nervous system: 1. The Functions of Neurons and Glia Anatomy & Physiology Spring 2016 Stan Misler <[email protected]> Table of contents • Introduction: what the nervous system is composed of and what it does • Structure of neurons • Function of neurons: How neurons spread electrical impulses by conduction and talk to one another by synaptic transmission • The Reflex arc • Glial cells • Introduction to neuron dysfunction caused by toxins and genetic lesions Neuron composed of dendrites, cell body and axons conduct electrical impulses Is partially wrapped in glia cells for insulation (like plastic surrounding a copper wire) The central nervous system (Brain + spinal cord): Weighs Weighs 3 lb with consistency of soft jello; contains 100 billion neurons in chains + helper glial cells and blood vessels; cerebral cortex accounts for 80 % of mass; metabolically very active getting 20% of body’s blood flow for 2% of body mass Schematic representation of the nervous system Afferent fibers in bundles carry impulses from peripheral or internal sensory receptor organs to the CNS. Efferent fibers carry impulses from CNS to peripheral effector organs (muscles of various types and glands) Enteric nervous system is in gut Nervous system is basis for: (a) sensation: vision, hearing, touch, smell, taste, pain and heat receptors at periphery and internal receptors sensing stretch and nutrients all projecting to the brain (b) body movement ( + gait, station, balance): reflex or fixed movement in response to stimuli of pain, touch or stretch vs. voluntary movement formulated by brain (c) modulation of involuntary (vegetative) functions: changes in contraction of gut or heart muscle and stimulation or inhibition of fluid and hormone secretion by glands (d) memory and learning: due to strengthening or proliferation of synapses (e) behavior: integration of complex movement by sensory input or by activation of multisystem intrinsic neural circuitry (fixed action pattern) (f) Cognition : comprised of wakefulness; selective attention; language use; memory / forgetting; sensory perception; problem solving; thinking / creativity; and decision making Structure of neuron Dendritic branches (resembling branches of a tree) carry small electrical signals generated at periphery of neuron to cell body. In the cell body these signals add. If the sum of these signals is large enough it will trigger a nerve impulse which can travel down the axon and end in a synaptic terminal or knob near the next neuron in the chain. In response to the nerve impulse these knobs release chemicals which can excite the next neuron in the chain. The cell body contains a nucleus and all of the apparatus for protein and membrane (lipid bilayer) synthesis needed by the axon and dendrites Types of neuronal structure: variation on pattern of input region (dendrites), integrative region (start of axon where action potential is triggered), conductive region (axon) and output or synaptic region (nerve terminal) (i) (ii) (iii) (iv) All neurons are derived from common neuroepithelial cells of embryo All neurons have morphological and functional asymmetry (dendrites vs. axon) All neurons are made excitable by electrical and chemical stimuli All neurons inherit same complement of genes but only express a restrictive set to code for enzymes needed to make neurotransmitters, structural proteins to determine structure of neurons, ion channels to give ride to action potentials of different waveforms, receptors for different transmitters and other secretory products How neurons generate their electrical signals and transmit them down the axon All cells separate concentrations of ions, especially Na and K, across their cell membranes. The outside fluid, which bathes the cell, is rich in Na (130 mM) but poor in K (5 mM), while the inside fluid, or cytoplasm, of the cell is rich in K (130 mM) but poor in Na (10 mM). These differences in ion concentrations are known as ion concentration gradients. The fact that membrane is permeable to K but barely permeable to Na produces a voltage across the membrane called a resting membrane potential ( = RMP). This is usually 1/14 of a volt inside negative (or -70mV) and is measured by poking the cell with a glass microelectrode filled with a high KCl solution. Nerve cells are special because they are excitable. In response to a stimulus (chemical, voltage pulse or stretch) which charges the membrane potential to a threshold voltage of -50 mv, a nerve cell rapidly changes its membrane’s relative permeabilities to Na and K (PNa and PK). The membrane becomes very permeable to Na which can move down its concentration gradient into the cell (high Na out to low Na in). This changes the amplitude and polarity of the membrane potential (MP) from -70 mV to +20 or + 30mV (depolarization). However, over 1 ms the membrane loses its permeability (P) to Na and increases its permeability K resulting in the recovery of the membrane potential back to the RMP or slightly negative to RMP. This spike of voltage change (from -70 to +20 or +30 and back again to -70 mV) propagates as an electrical wave (or spike impulse) called the membrane action potential (AP). The AP travels down the neuron’s long cable-like axon at velocities up to 10s of meters per seconds particularly when the axon is myelinated PNa increases PNa decreases & PK increases PK returns to baseline Ion Channel gating and excitability Underlying the resting potential and AP are the opening and closing of ionic channels = pores, of angstrom diameter, which run through specialized multimeric proteins spanning the plasma membrane, a lipid bilayer (1) These channels are selectively permeable to one or more ionic species (among these are K, Na, Ca, Cl). Ions traverse channels down an electrochemical gradient (2) Channels flicker open and closed spontaneously but are gated to open/close in a more concerted fashion by (i) external ligands or transmitters (including acetylcholine); (ii) DVm; (iii) membrane stretch; or (iv) cytoplasmic messengers (including Ca, cGMP) Each channel opening gives rise to a flow of thousands of ions per millisecond making the channel opening detectable as a step jump of current (3) Over time channel activity is modulated by phosphorylation at specific internal sites and/or by insertion into/retrieval from the plasma membrane. (4) Channels identified by their ionic selectivity, gating and pharmacology (drugs that open or close them) Details of voltage gating of ion channels The model of gating of a channel in the AP is that on changing MP from -70 mV inside to -40 mV inside there is movement of charged voltage sensor wings of the channel within the membrane thereby opening the criss-crossed tail of channel and allowing ions into the vestibule of the channel where ions are stripped of water. If the ion is of the right size and charge it can move through a selectivity filter and out of the channel (top two cartoons) In some types of channels this followed by slower movement of ball-on-chain into channel to occlude pore from its cytoplasmic side. However on return to -70 mV inside the ball on chain is swept out of the channel before the channel pore closes. The channel is then ready to reopen when the membrane voltage is returned to -40 mV (bottom cartoon) Ion Pumps, channel inactivation; refractory period between spikes; one way saltatory conduction of AP 1. After a train of APs the nerve has gained some Na and lost some K. To make sure the ion concentrations recover to their original quantities, a Na/K pump within the membrane moves Na out and K in. Because the pump is moving ions against their concentration gradients requires energy (breakdown of stored ATP. 2. Recall that after Na channels have been activated and open a few times they close down and are not available to open until they have sat at the RMP for at least several milliseconds (channel inactivation). Inactivation lengthens the smallest interval between spikes (refractory period) and the maximum frequency with which the axon can conduct APs (at most a few hundred per second). At any higher frequency the AP is aborted and does not propagate (all or none feature). Na channel inactivation also makes conduction possible only in one direction, that is from a region that has just been excited to a neighboring region closer to the nerve terminal that has been at its RMP for several ms. 3. In a myelinated axon the ion channels are clustered at the nodes of Ranvier, The impulse jumps from one node to the next one down the line without losing its shape. This is called saltatory conduction Summary of features of AP 1. Initiation threshold 2. Refractory period 3. All or none 4. Conduction without decrement if axon is myelinated The synapse Neurons contact each other or muscle cells at synapses. These are closely apposed areas of chemical transmitter release, from knoblike ending of a presynaptic neuron, and transmitter reception by the dendrite of next neuron in the chain or by a muscle membrane. The knob-like ending of the pre-synaptic cell contains small 40 nm diameter vesicles filled with neurotransmitter and large mitochondria to provide it with local ATP. The post-synaptic membrane is filled with neurotransmitter receptor channels. The two membranes are separated by a 150 nm gap across which the released transmitter must diffuse. Chemical Neurotransmission at simplest synapse (between motor nerve terminal and skeletal muscle) : Depolarization-secretion coupling at presynaptic terminal (Ca entry during AP -> transmitter release) and reception-depolarization coupling at post-synaptic muscle cell (opening of acetylcholine receptor channel allowing Na entry -> post-synaptic potential Opening of Voltage activated Ca channels near vesicle attachment sites raises local [Ca]; vesicles containing thousands of transmitter molecules fuse with plasma membrane and release their contents, here acetylcholine (Ach), into synaptic cleft by a process known as expcytosis Ach binds to Ach receptor channels (combination of ach receptor and cation selective channel -> Na entry into muscle cell giving rise to postsynaptic (or endplate) potential. If 50 vesicles fuse within 1 ms after the presynaptic AP the amount of Ach released brings MP to threshold for activating an AP in the muscle cell Details of synaptic transmission (i) Voltage activated Ca channels, which contribute to the nerve terminal AP, are located very near vesicle attachment sites so entry of several thousand Ca molecules over 1 ms can raise the local effective internal [Ca] from 100 nM to 10s of uM and trigger the fusion of the vesicle with the presynaptic membrane (exocytosis) (ii) Each 40 um diameter vesicle stores and synchronously releases a packet of many thousands of acetylcholine molecules. Each packet produces ~0.5 mV change in RMP in the positive direction. At least 50 quanta must be released over 1 ms by Ca entry during the nerve terminal AP to produce a post-synaptic or endplate potential (epp) of 25 mV from rest. This change in MP is enough to bring the muscle membrane to threshold for firing trigger its own AP. This rate of “evoked” quantal release is > 1000 fold higher than spontaneous (or resting) rate of exocytosis (at most 1 vesicle /s). (iii) After exocytotic release of transmitter the fused vesicle membrane gets coated by clathrin and is then retrieved from the nerve terminal membrane by a process known as endocytosis. The retrieved vesicle fills with transmitter and is attracted to the nerve terminal membrane where the intertwinement of vesicle SNAREs with plasma membrane SNARES pulls the vesicle close to the plasma membrane and primes it for for another bout of exocytosis. (iv) Even small nerve terminal contains hundreds of vesicles in different states of readiness for release including those moving in the cytoplasm and those tethered or hooked onto the presynaptic membrane by SNAREs (v) A Ca pump rids the presynaptic terminal of excess cytosolic Ca to insure that vesicles do not clump together or fire off randomly The central miracle of exocytosis: how granules get to, dock at, get “primed” and then fuse with the plasma membrane (an “exocyst complex”) for fusion pore formation Diffusion of vesicles from microtubule to membrane; vesicles then become ensnared to plasma membrane by intertwinement of vesicle and plasma membrane SNARE proteins Protein components of vesicle membrane a. Attachment devices for vesicle transport b. Vesicle or v-SNAREs to intertwine with plasma membrane target or T-SNARES (docking and priming c. Ca sensors (synaptotagmins) Ach response and vesicle and Ach metabolism at skeletal NMJ (i) Acetylcholine binding to transmitter receptors sites within channel (top left) -> conformational change of receptor complex and opening of constriction in pore (top right) (ii) Rapid disposal of released Ach in the synaptic cleft: diffusion of Ach out of cleft to be disposed of by glia and degraded to choline + acetylCoA by acetyl cholinesterase in synaptic cleft (bottom lft. Free choline is taken back up into the presynaptic terminal by plasma membrane. These reactions limit the active time of Ach in synaptic cleft to several millisec. If this were not so the channel bound to Ach would go into a desensitized state and be unavailable to open for many seconds (bottom left) •(iv) Retrieval and Recycling of vesicle membrane fused with pre-synaptic membrane (ATP dependent). Capture of vesicle membrane (endocytosis) for recycling: kiss and run vs. more complete kiss and stay fusion into membrane the latter with endoctyosis consisting of complex recycling of clathrin -coated membrane recovery (bottom right) Membrane recycling Transmitter synthesis and degradation What are the major energy (ATP) requiring processes of the brain? Stringing together neurons: the reflex arc How MDs Check Simple Spinal Reflex the Knee Jerk Response a 1A Reflex arc = stretch of muscle -> activation of stretch receptor fibers in muscle -> activation of 1A afferent nerve to spinal cord -> synaptic transmission (release and reception of glutamate) -> activation of a motor neuron to muscle -> release of Ach at neuromuscular junction -> muscle contraction to restore length Glia (50 times number of neurons) and their accessory, homeostatic function Oligodendrocytes = myelination of axon by wrapping -> 50 fold increase in conduction velocity of AP Radial glia cells = scaffold for neuronal migration and axonal outgrowth Astrocytes = Uptake and metabolism of released neurotransmitters + buffering of ions in extracellular environment (take up of excess K) + source of blood brain barrier (encasement of capillary by end-feet of astrocytes produces selectively permeable to barrier to substrates Microglia = Scavengers to remove debris produced by dying neurons oligodendrocyte radial glia astrocyte microglia Defects in neuron function 1. Toxins affecting peripheral nerve Tetrodotoxin (TTX) from ovaries of puffer fish fits in and blocks pore of voltage activated Na channels at nodes of Ranvier and blocks AP conduction -> paralysis of diaphragm and block of lung ventilation aLatrotoxin (aLTx) from venom glands of black widow spider makes Ca permeable channels in presynaptic terminal -> massive quantal release (left)-> depletion of vesicle pool (right, A -> B) from phrenic nerve terminal -> paralysis of diaphragm -> KO breathing 2. Genetic Diseases of Nerves: Autoimmune Multiple sclerosis = patch demyelination of central neurons -> slowed conduction velocity or even block of propagation of AP. Two or more sporatic often resolving defects separated in time and neural location including numbness and tingling, monocular visual loss (optic neuritis), reduced balance and uncoordinated gait, and slurred speech. Warmth worsen symptoms as it desynchronizes AP volleys in trunks of neurons. Inflammation around small veins -> leakiness to immune T cells and production of antibodies to oligodendrocytes -> stripping myelin off the axon. Inflammation may recede with time -> partial remyelination or else formation of scar by astrocytes Normal MS Myasthenia gravis = antibodies and immune cells targeting acetylcholine receptor channels of muscle endplate -> reduced number of functional Ach receptor channels and insufficient depolarization of muscle to give consistent muscle AP in response to firing of motor neuron -> muscle weakness (especially drooping eyelids). Weakness is treated with a cholinesterase inhibitor Enrichment topics The Stereotypic Neuron: Anatomy and Physiology (1) Dendritic tree = Sensory pole for signal detection: Reception of transmitter inputs from other neurons at spines -> post-synaptic potential (psp = a & b) while sensory transduction of light or membrane vibration (stretch) -> generator potential (GP = c) (2) & (2a) Soma (cell body) & initial segment of axon = sites of integration and conversion where the amplitude and duration of small psps are summed and encoded as trains of action potentials (APs) (3) Axon = impulse propagator cable for APs. Axons are often wrapped in a myelin sheath made of glial membrane for insulation with interval electrical boosting along length at nodes (*) to maintain fidelity (4) Presynaptic terminal = secretory pole: depolarization-dependent release of neurotransmitter from synaptic vesicles by exocytosis (or pore formation between vesicle and plasma membranes), onto sensory pole of follower cell. Overview of biochemistry of neuron 11 2 (1) (1) Dendritic tree: local organization of receptor apparatus; Microfilament (actin)-based scaffold to maintain shape and growth. (2) Soma + initial segment of axon: Protein synthesis beginning with DNA transcription to nuclear transcriptional RNA and then to messenger RNA -> translation on free ribosomes or rough endoplasmic reticulum Synthesis of organelles (vesicles and mitochondria and microfilaments for transport along dendrites and axons) microfilament (3) Axon: transport of organelles to and from presynaptic terminals along microtubules by stepping motors on surface of organelles 3 4 (4) Presynaptic terminal: (a) release of amino acid or peptide derived transmitters and reuptake and degradation amino acid-derived transmitters (e.g., glutamate, acetylcholine) and (b) endocytic uptake vesicle membrane More precise Definitions and origins of key electrical signals in neurons (1) Baseline voltage or resting membrane potential, is roughly stable, inside negative transmembrane voltage, Vm, ~-70 mV (A) largely due to high permeability to K and operation of the Na/K pump to maintain ionic gradients (2) Non-propagating analog impulse = postsynaptic potential (psp) or generator potential (GP) = local, slow onset signal corresponding to the passage of inward ionic current bringing Vm closer to 0 mV (depolarization, B) or the passage of outward ionic current, bringing more negative to Vm,rest (hyperpolarization, C). These signals sum with each other but all decrement with distance from sites of initiation. (3) Propagating digital impulse = action potential (AP) = rapidly depolarizing signal brings Vm to (or positive to) 0 mV (the overshoot) and then rapidly returns it to Vm,rest. (see D). Set off by sum of psps and GP that results depolarization exceeding an all-or-none threshold. Neuronal signals and their ionic origins Action potential Generator or post-synaptic potential: Depolarizing Equation for how Na entry depolarizes cell and K exit repolarizes cell given on last slide below. This will be presented in more detail in IB Physics Electricity Unit Hyperpolarizing Key evidence for Ca, quantal and vesicle hypotheses Epp varies by defined steps from AP to AP suggesting packet-like release of transmitter (upper) Electron microscopic view of of presynaptic ending containing thousands of vesicles (Lower) Effect of Spritz of 10K molecules of Ach on endplate -> 0.5 mV depolarization = effect of single packet or “quantum” of release Evidence that aLT makes Ca conducting channels (bottom) that promote Ca entry into cytoplasm (middle) and support fusion of synaptic vesicles with plasma membrane (exocytosis) measured as increase in nerve terminal surface (membrane capacitance Cm) 2. Specific loci for synaptic modulation a. b. c. d. e. f. Changes in pre-synaptic Ca entry: # Ca channels opening Change in available (release – ready) pool of vesicles = delivery towards membrane; docking; priming; refilling at high release rates; Change in size of quantum: either pre-synaptic kinetics of fusion pore; or blockade of post-synaptic receptor channels Changes in density of post-synaptic receptor channels Change in time that transmitter remains in synaptic cleft before it is broken down or taken up by pressynaptic cells Modification of structure or sprouting of new terminals (pre) or dendrites (post) 3. Cell surface receptors, second messengers, and the post-synaptic reception of transmitters Direct response: ion channel is transmitter receptor -> nearly instantaneous response Indirect response: transmitter receptor coupled at a distance to ion channel via G-protein cascade; response after 100s of msec delay Details of Ach response (nicotinic, nAch) at skeletal NMJ (ii) Acetylcholine binding to transmitter receptors sites within channel -> conformational change of receptor complex and opening of constriction near pore Ripped off piece of post-synaptic response as well to ACH as patch of membrane attached to cell 4. Modes of Synaptic Plasticity or Remodeling to change synaptic efficiency constitute bases for memory: “neurons that fire together wire together” Homosynaptic potentiation: increased frequency of synaptic transmission -> post-synaptic remodeling (increased number of high current carrying postsynaptic receptors and “awakens a quiet or silent dendrite” Heterosynaptic potentiation : high frequency stimulation of a nerve synapsing onto the test presynaptic terminal -> pre-synaptic remodeling (increases number of active zones (regions of coupling of Ca channels and vesicle\ release zones) and nerve terminal extension and sprouting Brain programmed to pay special attention to acquisition of novel information. Also the more you learn the easier it is to learn Nature vs. nurture: Dialogue between genes and synapses Putting synaptic inhibition into the picture = synaptic potential produced by the interneuron excited by sensory afferent opens chloride channels and brings MP of flexor motor neuron to RMP thus transiently abolishing any AP activity that may be occurring in flexor motor neuron and relaxing flexor muscle Spinal cord Quadriceps femoris Hamstrings inhibitory Central excitatory transmitter = glutamate; Central inhibitory transmitter = GABA