Neurobiology Cells of the nervous system Anthony Heape 2010 1
The nervous system Central nervous system (CNS) Peripheral nervous system (PNS) 2
Enteric nervous system (digestive tract, gall bladder and pancreas) Functional sub-divisions of the nervous system Afferent = carry towards Efferent = carry away from 3
Cells of the nervous system Neurons Neuroglia Functional classification Sensory or afferent: Action potentials toward CNS Motor or efferent: Action potentials away from CNS Interneurons or association neurons: Within CNS from one neuron to another Structural classification Multipolar Bipolar (pseudo-) unipolar Astrocytes Ependymal Cells Microglia Oligodendrocytes Schwann cells Satellite cells Radial glia (embryonic) Polarity is defined as the number of a neuron s own processes (extensions) that are directly associated with the cell body (soma) 4
Cells of the nervous system Neurons The excitable cells of the nervous system that transmit electrochemical signals from one cell to another 5
Neurons Morphology 6
Neuronal morphology Bipolar: most rare, associated with some sense organs; retina, olfactory mucosa and inner ear. Pseudounipolar: these are always sensory neurons, but not all sensory neurons are pseudounipolar. Multipolar: most neurons (e.g. motor neurons, interneurons/association neurons) Examples of Multipolar cells Pyramidal cells in the cerebral cortex Purkinje cells, stellate cells, granular cells and basket cells in the cerebellum 7
Cells of the Cerebellum 8
Cerebellum Granule Cells 100X Golgi stain Purkinje cells 400X 400X silver stain Granular layer Molecular layer Molecular layer H & E stain Granular layer 9
Purkinje cells fluorescently labelled with GFP Santiago Ramón y Cajal (1905) In images acquired by normal light microscopy, it is rare to see more than a few (if any) processes of a given cell, but, even without GFP, Ramón y Cajal didn t miss much detail in his drawings. 10
Cerebral cortex Cerebellum Molecular layer Cerebral cortex Molecular layer Pyramidal Cells Stellate Cells 11
Spinal cord anterior horn motor neurons (multipolar) Dorsal root ganglion sensory neurons (pseudounipolar) SILVER STAIN (BIELSCHOWSKY) 400X 800X 12
Retina (bipolar neurons) Bipolar neurons 13
Neurons Structure A typical neuron has: Cell body (or soma) with nucleus & organelles Dendrites to receive information (from another neuron). Axon to carry information to another cell (another neuron, muscle, gland), with which it communicates via a synapse. In histological sections, it is often difficult to distinguish between dendrites and axons. They are thus often referred to as processes 14
Typical neurons Myelin sheath 15
The neuronal soma The soma (or perikaryon) contains: a single nucleus, with a prominent nucleolus (site of ribosome synthesis) Most normal cellular organelles are also present: Mitochondria Golgi apparatus Endoplasmic reticulum, etc. Karyon = nucleus (literally, nut ) 16
Special features of the neuronal soma Nissl bodies (pink) Lipofuscin granules (blue/yellow) The soma contains a very active and highly developed rough endoplasmic reticulum (responsible for the synthesis of proteins) that has a granular appearance. These granules are referred to as Nissl bodies. Nissl bodies can be demonstrated by a method of selective staining developed by Nissl, to label extranuclear RNA granules. This staining method is useful to localize the perikaryon, as it can be seen in the soma and dendrites of neurons, though not in the axon, nor in the axon hillock. Neurofibrils Abundant network of protein filament bundles, which help maintain the shape, structure, and integrity of the cell. Lipofuscin granules accumulate with age around the nucleus and represent lipid-containing degradation products, often referred to as wear-and-tear pigments. 17
The neuronal processes Axon (only 1) Dendrites 18
Dendrites dendrites axon collateral axon dendrites axon (sensory input) axo-dendritic synapses axo-somatic synapse axon (motor output) A dendrite is a neuronal process (usually short, with multiple branches) emerging from the soma, and through which the soma of a neuron receives signals from other neurons, and transmits it to the rest of the neuron via (short-range) graded potentials ( action potentials). Note: dendrites do not have a myelin sheath and contain no neurofibrils. Myelin = insulating multilamellar membrane sheath around axons of CNS & PNS neurons. It allows a faster transmission of action potentials along the nerve fibre. Synapse = specialized junction between a neuronal axon and another cell, across which a (bio)chemical signal is transmitted. 19
Dendrites and Dendritic spines Each dendrite presents many small membranous protrusions, called dendritic spines, along its whole length. There can be as many as 10 3 10 5 (e.g. in Purkinje cells) dendritic spines/neuron. Each dendritic spine typically receives (inhibitory or excitatory) input from a single axon, but sometimes two (one inhibitory and one excitatory). Low power LM High power LM 3D reconstruction Confocal microscopy with GFP EM The spine apparatus Specialization of the smooth endoplasmic reticulum responsible for the release of calcium in response to receptor activity 3D reconstructions of a dendrite (above) and dendritic spines (above and left). Excitatory (red) and/or inhibitory (blue) synapse regions are located on the head of the spine. The spine apparatus (brown) is located in the head and neck of the spine. 20
Axons? Axons An axon is a neuronal process (often long, with few collateral branches) emerging from the soma, and through which the neuron transmits signals towards another cell (neuron, muscle, gland,...), by means of action potentials. A neuron always has one axon that, typically, transmits signals away from the neuronal soma. The peripheral axons of (pseudo-unipolar) sensory neurons are exceptions: are they in fact dendrites? 21
Special features of axons the axon hillock Axon hillock The axon hillock has no Nissl bodies. Multiple signals generated at the dendritic spines, and transmitted by the soma, all converge at the axon hillock. The axon hillock has a very high concentration of voltage-activated Na + channels. The axon hillock is generally considered to be the spike initiation zone for action potentials. 22
Special features of axons The axon starts from the axon hillock. Branches (axon collaterals) along length are infrequent. Multiple terminal branches (telodendria) at end of axon end in knobs, called axon terminals (also end bulbs, or boutons ). The axon can be short, or as long as 1 metre, or more. Neurofilaments, actin microfilaments, and microtubules provide structural support and aid in the transport of substances to and from the soma (axonal transport). Axons contain numerous mitochondria, as well as voltagesensitive sodium ion (Na+) channels along the whole length of their plasma membrane (axolemma). telodendria 1 mm (1000 nsec) The Na + channels are either distributed uniformly over the whole axolemma, or clustered in bands spaced at (±) regular intervals along the axon, at the nodes of Ranvier. These ion channels are responsible for the propagation of the action potentials from the hillock to the axon terminals. 23
Neuronal signalling Plasma membranes of neurons conduct electrical signals Resting neuron membrane is polarized Inner, cytoplasmic side (axoplasm) is negatively charged (~ 70 mv, normal range of -60 to -90 mv) Voltage-sensitive (-gated) ion channels allow depolarization Excitatory signal Signals occur as changes in membrane potential Stimulation: depolarisation Inhibition: hyperpolarisation Inhibitory signal 24
Neuronal signalling potentials Local (graded) potentials Local potentials result from Ligands binding to receptors Changes in charge across membrane Mechanical stimulation Temperature changes Spontaneous change in membrane permeability Local potentials are graded membrane depolarisations Magnitude varies from small to large depending on stimulus strength or frequency Local potentials can summate (= add onto) each other, eventually creating an action potential. Action potentials A series of self-propagating permeability changes occurring when a local potential causes depolarization of membrane that exceeds the threshhold for opening the axonal voltage-gated Na + channels. Phases of the action potential include Depolarization: the axoplasm becomes more positive due to massive influx of Na + ions. Repolarization: the axoplasm becomes more negative due to exit of K + ions from the axoplasm. Action potentials follow the all-or-nothing principle. 25
Propagation of the nervous impulse 1 2 3 4 5 1. Resting potential (-70 mv): High Na + and low K + outside, low Na +, high K + inside. 2. Arrival of Na + (positive charge) depolarisation wave from upstream in axoplasm Opens voltage-gated Na + channels and some K + channels. Allows massive influx of Na + ions from outside, and exit of K + ions from inside, Resulting in depolarisation (activates channels further downstream). 3. Depolarisation causes voltage-gated Na + channels to close, and remaining K + channels to open. K + ions continue to leave Resulting in repolarisation. 4. And hyperpolarisation (over-shoot) 5. K + channels close. K + is outside and Na + is inside The membrane is now refractory (non-responsive) to further stimulation. Active (ATP-dependant) Na + (outward) and K + (inward) pumps return the membrane to an excitable state. 26
Special features of axons the axon terminals and synapses The axon terminals transform the action potentials arriving along the axon into a chemical signal, which is transmitted across a synapse to another cell via substances called neurotransmitters. Neurotransmitters are synthesized in the axon terminal, where they are accumulated (to high concentrations) and stored in synaptic vesicles. When the action potential arrives at the axon terminal, the synaptic vesicles fuse with the presynaptic membrane, releasing the neurotransmitter into the synaptic cleft. Receptors on ion channels of the postsynaptic (plasma) membrane of the target cell bind the neurotransmitter and generate a cell-specific response by the target cell (e.g. generation of a graded potential in neurons, muscle fibre contraction,...). 27
Neuromuscular Junction 100x 400x Axon telodendria NMJ NMJ skeletal muscle fiber Axon terminal Synapse 28
Excitatory and inhibitory signaling across synapses: The neuro-muscular junction 29
Excitatory and inhibitory signaling across synapses Excitatory neurotransmitters open channels in the postsynaptic membrane and leads to an increase in the concentration of Na + ions within the postsynaptic cell, leading to a depolarisation of the postsynaptic cell, and an active response. Inhibitory neurotransmitters encourage the hyperpolarization of the postsynaptic cell, making it less likely to respond. Neurotransmitters, and their effects, may be specific to particular target organs and have multiple roles around the body. E.g. Acetylcholine can be either excitatory to skeletal muscle cells, or inhibitory to both smooth muscle and cardiac muscle. Examples of neurotransmitters Acetylcholine voluntary movement of the skeletal muscles and movement of the viscera Glutamate the most abundant excitatory neurotransmitter in the central nervous system. GABA the most abundant inhibitory neurotransmitter in the central nervous system. 30
Cells of the nervous system Neuroglia (or glial cells) The non-excitable cells of the nervous system that provide support to neuronal survival and function 31