1DAWN V TOMY M.Pharm., Asst. Professor, Dept. of Pharmacology, ST.JOSEPHS COLLEGE OF PHARMACY, CHERTHALA.THE NERVOUS SYSTEMIt is a highly organized network of billions of neurons and numerous neuroglia.Structure of nervous system:It consists of the brain, cranial nerves and their branches, the spinal cord, the spinal nerves, ganglia, enteric plexuses and sensory receptors.Histology of nervous tissue:Nervous tissue is made up of two types of cells. They are1. Neurons and2. Neuroglia.1. Neurons: They have the property of electrical excitability (the ability to produce action potentials or impulses in response to stimuli). Its functions are:a. Sensingb. Thinkingc. Rememberingd. Controlling muscle activity ande. Regulating glandular secretions.2. Neuroglia: They support, nourish and protect the neurons. It also maintains homeostasis of the fluid nourishing neurons.Parts of a neuron:The typical neuron has 3 main parts. They are:1. A cell body.2. Dendrites and 3. An axon.1. Cell body contains nucleus and cytoplasm with cell organelles like lysosomes, mitochondria, Golgi complex, Nissl bodies (clusters of rough endoplasmic reticulum which are sites of protein synthesis used for replacement, growth and regeneration). The cytoskeleton (provide support and shape) contains neurofibrils and microtubules. The 2 processes/extensions arising from the cell body of a neuron are the multiple dendrites and axons.2. Dendrites (tree like): It is the receiving/input portion of a neuron; they are mainly connected to receptors for receiving stimuli. Its cytoplasm contains Nissl bodies, mitochondria and other organelles.

3. Axon: It propagates nerve impulses to another neuron/a muscle fiber/a gland cell. An axon contains mitochondria, microtubules, and neurofibrils. It has no rough endoplasmic reticulum and hence no protein synthesis. Its structure includes:a) Axon hillock: It is a cone shaped elevation at which axon connects to the cell body.b) Initial segment: It is the first segment of the axon arising from cell body.c) Trigger zone: It is the junction between axon hillock and initial segment.d) Axoplasm: It is the cytoplasm of an axon.e) Axolemma (sheath/husk): It is the plasma membrane covering axoplasm.f) Neurolemma: It is the outer cytoplasmic layer of the Schwann cell, which encloses the myelin sheath. It aids regeneration of injured axon. g) Nodes of Ranvier: It is the gap in the myelin sheath which appears at intervals along the axon.h) Axon collaterals: It is the branches of the axon arising at right angles to the axon.i) Axon terminals: Axon and axon collaterals divides into fine process called axon terminals.j) Synaptic end bulbs: The axon terminals swell into bulb shaped structures known as synaptic end bulbs.k) Varicosities: Some axon terminals have strings of swollen bumbs called varicosities.l) Synaptic vesicles: They are tiny membrane bound sacs which stores neurotransmitter (chemicals).m) Synapse: It is the site of communication between two neurons/between a neuron and an effector cell.n) Neurotransmitters: They are chemicals/hormones released throughout the body from synaptic vesicles of neuron for communication, when released into synaptic cleft they excite/inhibit other neurons/muscle fibers/gland cells. E.g. Acetylcholine, amino acids: glutamate and aspartate have powerful excitatory action in CNS, Gamma aminobutric acid (GABA) and glycine have important inhibitory action in CNS. Biogenic amines: Norepinepherine, epinephrine, dopamine, serotonin or 5-Hydroxytryptamine (5-HT), ATP and other purins: Adenosine, ATP, ADP and AMP have excitatory action in both CNS and PNS, nitric acid have vasodilator effect on blood vessels. Neuropeptides: Substance P, enkephalins, endorphins, dynorphins, hypothalamic releasing and inhibitory hormones, angiotensin II, cholecystokinin.o) Synaptic cleft: The space between neurons at a nerve synapse across which a nerve impulse is transmitted by a neurotransmitter called also synaptic gap.p) Ganglia: ___________Different types of neurons:1. Multiple neurons: They have several dendrites and one axon. E.g. neurons in the brain and spinal cord.2. Bipolar neurons: They have one main dendrite and one axon. E.g. Neurons in retina of eye, in the inner ear and in olfactory area of the brain.3. Unipolar neurons: The dendrites and axon fused into a single process that divides into 2 branches a short distance from the cell body. E.g. sensory neurons of touch/stretch.Neuroglia (Glue): They are smaller (than neurons), more numerous than neurons. They mature, divide and fill the spaces occupied by neurons which may be damaged or injured. Brain tumors derived from glia are known as gliomas (highly malignant).There are 6 types of neuroglia. Four are found only in the Central Nervous System (CNS).1. Astrocytes,2. Oligogendrocytes,3. Micorglia and4. Ependymal cells.The remaining 2 types:1. Schwann cells2. Satellite cells are present in the Peripheral Nervous System (PNS).

Central Nervous System:1. Astrocytes: They are star shaped with many processes.Functions: It maintains appropriate chemical environment for generation of nerve impulses. Provide nutrients to the neurons. Takes up extra/excess neurotransmitters released. Helps in the migration of neurons during brain development. Helps in the formation of Blood Brain Barrier (BBB).2. Oligogendrocytes (tree like): They are smaller than astrocytes with fewer processes with round or oval cell body.Functions: It forms supporting network around CNS neurons. It produces myelin sheath around adjacent axons of CNS neurons.3. Micorglia (small): Small cells with few processes derived from mesodermal cells that also give rise to monocytes and macrophages.Functions: It protects CNS cells from diseases by engulfing invading microbes. Migrate to areas of injured nerve tissue where they clear away debris of dead cells (may also kill healthy cells)4. Ependymal cells (epen above, dym - garment): Epithelial cells arranged in a single layer, range in shape from cuboidal to columnar, and may be ciliated/nonciliated.Functions: It lines the ventricles of the brain and central canal of the spinal cord (spaces filled with CSF). It helps in the formation of Cerebrospinal Fluid (CSF) and assists in its circulation.Peripheral Nervous System (PNS):1. Schwann cells: They are flattened cells that encircle PNS axons.Functions: Each cell surrounds multiple unmyelinated axons with a single layer of its plasma membrane or produces part of the myelin sheath around a single axon of a PNS neuron. Participate in regeneration of PNS axons.2. Satellite cells: Flattened cells arranged around the cell bodies of neurons in ganglia.Functions: Support neurons in PNS ganglia.Myelination: Multilayered lipid and protein covering produced by neuroglia called myelin sheath electrically insulates the axon of a neuron and increases the speed of nerve impulse conduction. Neurons which have myelination are called myelinated neurons and without myelination are called unmyelinated neurons. The amount of myelin increases from birth to maturity. It increases the speed of nerve impulse conduction.Two types of neuroglia produce myelin sheath, i.e. Schwann cells in the PNS and Oligodendrocytes in the CNS.Gray and white matter:White matter: It is due aggregations of myelinated and unmyelinated axons of many neurons.Gray matter: It contains cell bodies, dendrites, unmyelinated axons, axon terminals and neuroglia. It looks grayish because of Nissl bodies and absence of myelin.Functions of nervous system:1. Sensory function: Detection of internal (blood acidity) and external (touch/smell etc.) stimuli. The sensory/afferent neurons carry information from cranial and spinal nerves into the brain and spinal cord.2. Integrative: It process the information received, analyze and store the information for giving appropriate responses. The interneurons process the information. They have short axons and contact nearby neurons in the brain, spinal cord/a ganglion. Most of the neurons in the body are interneurons.3. Motor function: It is the response to the processed information. The motor neuron/efferent neuron carries the response information from the brain towards the spinal cord/out of the brain and spinal cord to the cranial/spinal nerves known as effectors.Functional classification (based on direction of nerve impulse)1. Sensory or afferent neurons: They have sensory receptors in the dendrites of sensory neurons forms action potential which is conveyed into the CNS through cranial/spinal nerves. They are mostly unipolar in structure.2. Motor or efferent neurons: They convey action potential away from the CNS to effectors (muscles and glands) in the PNS through cranial and spinal nerves. They are mostly multipolar in structure.3. Interneuron or association neurons: They are found in the CNS in between sensory and motor neurons. It integrates (process) incoming sensory information from sensory neurons and then triggers a motor response by activating the neurons. They are mostly multipolar in structure.Organization of the nervous systemI. Central Nervous System (CNS): It consists of the brain and spinal cord. It controls all the activities of the body and also the source for thoughts, emotions and memories.II. Peripheral Nervous System (PNS): It consists of all the nerves outside the CNS and includes cranial nerves and their branches, spinal nerves and their branches, ganglia and sensory receptors. It is classified into 1. Somatic Nervous System (SNS, somat-=body): It consists of (a) sensory neurons that convey information from somatic receptors in the sense organs, head, body wall and limbs to the CNS and (b) motor neurons that conduct impulses from CNS to skeletal muscles and is voluntary.2. Autonomic Nervous System (ANS, auto-=self, -nomic=law): It consists of (a) sensory neurons that convey information from autonomic sensory receptors in the visceral organs (internal organs) to the CNS and (b) motor neurons that conduct nerve impulses from CNS to smooth muscles, cardiac muscles and glands and is involuntary. The motor part of the ANS consists of 2 branches: (i) The sympathetic nervous system and (ii) The parasympathetic nervous system. The 2 divisions have opposing action e.g. sympathetic neurons increase heart rate and parasympathetic neurons decreases heart rate.3. Enteric Nervous System (ENS, enter-=intestine): It supplies to the GI (Gastrointestinal tract) tract and is involuntary. It consists of (a) sensory neurons of the ENS monitor changes within the GI tract and stretching of its walls and convey the information to the CNS and (b) motor neurons contracts GI tract smooth muscle to propel food through the tract and helps in the secretions of GI tract organs such as acid in the stomach, enzymes and hormones from the exocrine and endocrine glands.

ION CHANNELS:They are channel proteins present in the plasma membrane; when open it allows the movement of specific ions across the plasma membrane based on their electrochemical gradient (charge and concentration). The movement of ions creates a flow of electrical current which changes the membrane potential. The channels will open or close due to the presence of gates.Types of ion channels in the plasma membraneThere are 4 types of ion channelsa. Leakage channels: There are 2 types of leakage channels in the plasma membrane. The sodium leakage channels are less than potassium leakage channels and hence the membrane permeability to potassium ion is higher than sodium ion permeability. The gates of leakage channels randomly alternate between open and closed positions.

b. Ligand gated channels: The gates of the ion channels opens or closes in response to specific chemicals. The chemical ligands include neurotransmitters, hormones and ions e.g. Neurotransmitter acetylcholine opens cation channels and allow sodium and calcium influx and potassium out flux.

c. Mechanically gated channels: The gates of the ion channels opens or closes in response to mechanical stimulation in the form of vibrations (sound), touch, pressure or tissue stretching etc. e.g. the auditory receptors in the ear monitor stretching of diaphragm and opens or closes the ion channels.

d. Voltage gated channels: The gates of the ion channels opens or closes in response to change in membrane potential (voltage). Voltage gated channels participate in the generation and conduction of action potential.

Resting membrane potential:The resting membrane potential is the charge exhibited by the membrane of the excitable cell at rest. It exists because the inside of the cell is negative due to the charge of the phosphates and amino acids in proteins. The potential varies from -40 to -90 according to the cells. Usually it will be -70 mV. The minus sign denotes that the inside of the cell is negative to outside the cell. The cell exhibiting membrane potential is polarized.Factors contributing to resting membrane potential:1. Unequal distribution of ions in the Extracellular Fluid (ECF) and cytosol: Extracellular fluid rich in sodium and chloride ions and the cytosol is rich in potassium ions.2. Inability of most anions to leave the cell: The anions inside the cell are attached to non-diffusible molecules such as ATP and large proteins.3. Electrogenic nature of the Na+ /k+ ATPases: These pumps help to maintain resting membrane potential by pumping out Na+ and pumps in k+. The pumps expel 3 Na+ in exchange of 2 k+ and this contribute to the negativity of the resting membrane potential.Graded potential generation:The graded potential is a small change in the membrane potential making it either more polarized (inside of the cell more negative) known as hyperpolarizing graded potential or less polarized (inside of the cell less negative) known as depolarizing graded potential.

It occurs when stimulus opens or closes mechanically gated or ligand-gated channels present in the dendrites of sensory neurons. It occurs mainly in the dendrites and cell body of a neuron. They are called graded because they vary in their amplitude depending on the strength of the stimulus. They die out by decremental conduction as they spread along the membrane. They are useful for short distance communication only. Graded potential add together by summation.Action potential generation:The action potential (AP) is a big and rapid change in the membrane potential that which can produce an action. An action potential occurs in the membrane of the axon of a neuron when the depolarization reaches threshold (-55mV). A sub-threshold stimulus cannot produce an action potential.

It has 2 main phases: 1. Depolarizing phase: An impulse on reaching the pre-synaptic nerve ending opens the voltage-gated Ca2+ channels and triggers the release of neurotransmitter from the synaptic vesicles by exocytosis. The released neurotransmitter binds to the ligand-gated ion channel receptors and opens the Na+ channels producing depolarizing graded potential. When it reaches threshold voltage-gated Na+ channels open rapidly facilitating the influx of Na+ by the electrical and chemical gradient. This sudden influx of Na+ changes the membrane potential from -55 mV to +30 mV. At peak potential the inside of the membrane is 30 mV more positive than the outside.Voltage-gated Na+ channel has 2 gates, the activation gate and inactivation gate. At resting state the inactivation gate is open but activation gate is closed and Na+ ions cannot move inside. At threshold voltage-gated Na+ channels are activated and both activation and inactivation gates are opened and influx of Na+ ions begins. As a result the membrane depolarizes further resulting in opening of more and more voltage-gated Na+ channels by positive feedback mechanism to reach +30 mV.2. Repolarizing Phase: After depolarizing phase the activation gates in the voltage-gated Na+ channel opens and closes the inactivation gates rendering the channel in an inactivated state. The threshold depolarization also opens the voltage-gated K+ channels but they open more slowly and happen about the same time the voltage-gated Na+ channels are closing. The slower opening of voltage-gated K+ channels and closing of the Na+ channels produce the repolarization phase of the action potential. Na+ channels are inactivated and the voltage-gated K+ channels opens accelerating the outflow of K+ ions. This leads to change in membrane potential from +30 mV to -70 mV. Repolarization allows inactivated Na+ channels to come to resting state.After-hyperpolarizing phase: At repolarization phase outflow of K+ ions may be large to cause an after-hyperpolarizing phase of the action potential. The voltage-gated K+ channels remain open and the membrane potential becomes more negative (-90 mV). Voltage-gated K+ channels will close and the membrane potential returns to resting membrane potential (-70 mV).Refractory period: The period of time after an action potential begins during which an excitable cell cannot generate another action potential in response to a normal threshold stimulus is called the refractory period.Absolute refractory period: During Na+ channel activation and inactivation even a very strong stimulus cannot initiate a second action potential and this period is defined as absolute refractory period.Relative refractory period: It is the period at which a second action potential could be initiated with a larger stimulus. It is the period at which voltage-gated K+ channels are still open after inactivated Na+ channels have returned to their resting state.All-or-none principle: An action potential is generated when there is a threshold stimulus and does not form when there is a sub-threshold stimulus. When an action potential is generated it completely occurs after threshold stimulus. If it is sub-threshold stimulus an action potential is not at all generated. This characteristic of an action potential is known as the all-or-none principle.Propagation of action potentials:In order to communicate information from one part of the body to another, the action potential has to travel from the trigger zone to the axon terminal; which is known as propagation of action potential. There are 2 types of propagation:1. Continuous conduction: It involves step-by-step depolarization and repolarization of each adjacent segment of the plasma membrane, as the ions flows through their voltage-gated channels in each adjacent segment of the membrane. This occurs in unmyelinated axons in muscle fibers.2. Salutatory conduction: It occurs in the myelinated axons due to the uneven distribution of voltage-gated channels. There are only few voltage-gated channels at the place where the myelin sheath covers the axolemma, and at the node of Ranvier the axolemma has many voltage-gated channels. Hence current flows across the membrane mainly at the nodes. Current flows through the extracellular fluid surrounding the myelin sheath and through the cytosol from one node to next. The flow of current across the membrane occurs only at the node of Ranvier.Factors affecting the speed of propagation:The factors are:1. Amount of myelination: Action potentials propagate more rapidly along myelinated axons than along unmyelinated axons.2. Axon diameter: larger diameter axon propagates action potentials faster than smaller ones due to their larger surface areas.3. Temperature: The speed of action potential propagation lowers when cooled.Presynaptic neuron, postsynaptic neuron, presynaptic potential and postsynaptic potential.The neurons sending signals (impulses) are called the presynaptic neuron and the potential is known as presynaptic potential. The neurons receiving the signals (impulses) are called postsynaptic neuron and the potential generated in the postsynaptic neuron is known as postsynaptic potentials. The post synaptic potentials are of 2 types:a. EPSP: It facilitates the release of excitatory neurotransmitters if it reaches threshold and greater than the inhibitory effects.b. IPSP: It facilitates the release of inhibitory neurotransmitters if it reaches threshold and greater than the excitatory effects.Removal of neurotransmitter:The removal of neurotransmitter from the synaptic cleft after action potential generation is necessary for normal synaptic function. The removal of neurotransmitter from synaptic cleft by three ways:1. Diffusion: The neurotransmitter molecules diffuse away from the synaptic cleft and taken back to synaptic vesicles.2. Enzymatic degradation: The neurotransmitters are inactivated through enzymatic degradation. E.g. enzyme acetyl cholinesterase breaks down acetylcholine in the synaptic cleft into acetate and choline which are reused.3. Uptake by cells: the neurotransmitters are actively transported back into the neuron that released them (reuptake). Some are transported into the neighboring neuroglia (uptake). The membrane proteins that facilitate uptake are called neurotransmitter transporters. E.g. neurotransmitter norepinephrine is up taken by the cells.Synapses1. Electrical synapse: Action potential (impulses) conduct directly between adjacent cells through structures called gap junctions containing tubular connexons acting like tunnels to connect the cytosol of the 2 cells directly. The movement of ions from one cell to next results in the spreading of the action potential from cell to cell. E.g. Synapses found in the visceral smooth muscle, cardiac muscle and CNS.Advantages of electrical synapses:a. Faster communication Electrical synapses are faster than chemical synapses.b. Synchronization Electrical synapses can synchronize (coordinate) the activity of a group of neurons or muscle fibers. E.g. Cardiac muscle in heart beat and visceral smooth muscle move food through the gastrointestinal tract.2. Chemical synapse: The plasma membranes of the presynaptic and postsynaptic neurons in the chemical synapse are close but they dont touch. It leaves a gap of 20-50 nm called synaptic cleft which is filled with interstitial fluid. As the impulse arrives at the presynaptic nerve ending it opens the voltage gated Ca2+ channels resulting in Ca2+ influx. It in-turn results in the exocytosis of the synaptic vesicles releasing neurotransmitters into the synaptic cleft. The neurotransmitter molecule diffuses across the synaptic cleft and bind to the neurotransmitter receptors in the postsynaptic neurons plasma membrane. Binding of the neurotransmitter to their receptors on ligand-gated channels opens the channels and allows influx of the particular ions. Influx of ions changes membrane voltage and postsynaptic potential resulting in depolarization or hyperpolarization based on the ion channels activated. E.g. opening of Na+ channels allows influx of Na+ which results in depolarization and opening of Cl- channels allows inflow of Cl- ions resulting in hyperpolarization.Comparison of graded potentials and action potentials in neuron