Introduction to CNS 1

Introduction to CNS 1

Types of ion channels 1- voltage-gated 2-legends-gated Voltage-gated channel A voltage Sensor component of the protein controls the gating (broken arrow) of the channel. Voltage-gated channels respond to changes in the membrane potential of the cell. In nerve cells, these channels are responsible for the fast action potential, which transmits the signal from cell body to nerve terminal. 2

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Neurotransmitters exert their effects on neurons by binding to two distinct classes of receptors: 1- A ligand-gated channel The binding of the neurotransmitter to the ionotropic channel receptor controls the gating of the channel. The receptor consists of subunits, and binding of ligand directly opens the channel. Activation of these channels typically results in a brief opening of the channel. Ligand-gated channels are responsible for fast synaptic transmission typical of hierarchical pathways in the CNS. 4

2- metabotropic receptors. A G protein-coupled (metabotropic) receptor, which, when bound, activates a G protein that interacts directly to modulate an ion channel. These interactions can occur entirely with the plane of the membrane and are referred to as membrane-delimited pathways 5

Metabotropic receptors can also modulate voltagegated channels less directly by the generation of diffusible second messengers. A G protein-coupled receptor, which, when bound, activates a G protein that then activates an enzyme. The activated enzyme generates a diffusible second messenger, e.g., camp, which interacts to modulate an ion channel. Metabotropic receptors predominate in the diffuse neuronal systems in the CNS. 6

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SYNAPSE & SYNAPTIC POTENTIALS Steps in synaptic transmission include: a) action potential generation b) opening of Ca channel c) fusion of synaptic vesicles & exocytosis of neurotransmitter d) its binding with post synaptic membrane causes brief increase of membrane conductance resulting in EPSP e) if sufficient EPSPs generated threshold is achieved AP is generated 8

When an inhibitory pathway is stimulated, the postsynaptic membrane is hyperpolarized owing to the selective opening of chloride channels, producing an inhibitory postsynaptic potential (IPSP). As a result, an excitatory postsynaptic potential that evoked an action potential fails to evoke an action potential during the inhibitory postsynaptic potential presynaptic inhibition. Presynaptic inhibitory receptors are present on almost all presynaptic terminals in the brain. In the brain, transmitter spills over to neighboring synapses & activate presynaptic receptors. 9

Cellular Organization of the Brain 1- Hierarchical Systems large myelinated fibers, AP more than 50 m/s. phasic, occurs in bursts of action potentials. In sensory systems, the information is processed sequentially by successive integrations at each relay nucleus on its way to the cortex. A lesion at any link incapacitates the system. Within each nucleus there are two types of cells: relay or projection neurons local circuit neurons. The projection neurons: Excitatory, ionotropic receptors, very short-lived. The excitatory transmitter released is glutamate. 10

Local circuit neurons : Smaller, axons branch repeatedly in the immediate vicinity of the cell body. Release GABA or glycine. Have 2 types of pathways recurrent feedback feed-forward. local circuit neurons in the spinal cord forms axoaxonic synapses on the terminals of sensory axons. 11

2- Nonspecific or Diffuse Neuronal Systems Contain NE, DA or serotonin. Act on metabotropic receptors & initiate long-lasting synaptic effects. axons are fine, unmyelinated, conduct very slowly, at about 0.5 m/s. Branches from the same neuron innervate several functionally different parts of the CNS. The pattern of innervations is diffuse, and the axons with periodic enlargements called varicosities, which contain large numbers of vesicles. implicated in sleeping and waking, attention, appetite, and emotional states. 12

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Amino Acids Glutamate Excitatory transmitter, released by exocytosis & cleared by glutamate transporters present on surrounding glia. Acts on: Ionotropic receptors 1-NMDA. permeable to Na+ & Ca2+ 2-Kainate & 3-AMPA permeable to Na+ & K+ 4- Metabotropic Glutamate receptors (mglurs), divided into 3 groups (I, II, & III). Group I postsynaptic, activating a nonselective cation channel. Also activate phospholipase C, leading to inositol 14 trisphosphate - mediated intracellular Ca2+ release.

Group II & III, presynaptic inhibitory autoreceptors. NMDA cause an increase in synaptic efficiency known as LTP (Long-Term Potentiation), crucial to learning & memory. NMDA is activated only when there is simultaneous firing of two or more neurons (Kainate & AMPA ). This is due to the voltage-dependent block of the NMDA pore by extracellular Mg2+. Activation of neighboring synapses,mg2+ is expelled and the channel opens. NMDA also requires the binding of glycine to a separate site. Glutamate-mediated excitotoxicity may underlie the damage that occurs after ischemia or hypoglycemia in the brain 15

Compounds can alter the activity of this receptor through 6 distinct sites: 1-transmitter binding site, binds to L-glutamate & open channel that permits entry of Na & Ca. 2- Glycine site. L- Glu is ineffective unless the site that binds Glycine is also occupied. 3-a site binds noncompetitive antagonists, Ketamine, phencycline (PCP) The hallucinogenic substance (PCP, "angel dust") can induce psychosis. 4- A voltage-dependent Mg²+ binding site. 5- An inhibitory divalent cation site near the mouth of the channel that binds Zn²+ to produce voltage dependent block. 6- A polyamine regulatory site whose activation by spermine and spermidine facilitates NMDA receptor mediated transmission. 16

GABA Inhibitory neurotransmitters, which are typically released from local interneurons. Interneurons that release glycine are restricted to the spinal cord and brainstem, whereas interneurons releasing GABA are present throughout the CNS, including the spinal cord. Glycine receptors selectively permeable to Cl. Strychnine, which is a potent spinal cord convulsant selectively blocks glycine receptors. GABA is formed by α-decarboxylation of L- glutamic acid, catalyzed by glutamic acid decarboxylase (GAD) pyridoxal phosphate is a cofactor in the synthesis of GABA, which is why seizures occur in Vitamin B6 deficiency. Terminatin by active transport into the astrocyte glial cells. 17

GABA receptors are divided into two main types: GABAA and GABAB. GABAA receptors are selectively permeable to Cl & selectively inhibited by picrotoxin & bicuculline, both cause generalized Convulsions Are the major inhibitory receptors in CNS. Believed to be in a continuous tonically activated state. Site of action of many clinically important drugs. Involved in mediating anxiolytic, sedative, anticonvulsant, muscle relaxant, and amnesic activity. 18

The channel conducts chloride ions. This will hyperpolarize the neuron & decreases the depolarizing effects of an excitatory input, thus depressing excitability. GABAB receptors are metabotropic, selectively activated by the antispastic drug baclofen. These receptors are coupled to G proteins that, either Inhibit Ca2+ channels or activate K+ channels. 19

Glycine The simplest amino acid Binds to a receptor which makes the post-synaptic membrane more permeable to Cl - ion. This hyperpolarizes the membrane, making it less likely to depolarize. Thus, glycine is an inhibitory neurotransmitter. It is deactivated in the synapse by reabsorption by active transport back into the pre-synaptic membrane. Glycine Receptor (GlyR) Strychnine-sensitive glycine receptor strychnine-insensitive glycine receptor 20

Glycine and NMDA Receptors Glycine opens NMDA receptor channel of Glutamate receptors. This effect is strychnine- insensitive. This effect involves allosteric regulation of the NMDA receptor complex through a distinct Gly binding site. Main effect of glycine is to prevent desensitization of the NMDA receptor during prolonged exposure to agonists. Strychnine is a glycine antagonist it inhibits inhibition. The resultant spinal hyperexcitability is what makes strychnine a poison. 21

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ASPARTIC ACID (ASPARTATE) Primarily localized to the ventral spinal cord. Aspartate opens an ion-channel and is inactivated by reabsorption into the pre-synaptic membrane. Apartate is an excitatory neurotransmitter, which increases the likelihood of depolarization in the postsynaptic membrane. Aspartate and glycine form an excitatory/inhibitory pair in the ventral spinal cord comparable to the excitatory/inhibitory pair formed by glutamate & GABA in the brain. 23

Acetylcholine Cholinergic pathways play an important role in cognitive functions, especially memory. The primary cholinergic input to the cerebral cortex comes from the basal nucleus of Meynert, also known as the nucleus basalis, impaired in senile dementia of the Alzheimer's type. has wide projections to the neocortex. It is one of the nuclie which is It is suggested that this nuclie plays a role in learning and memory. 24

Norepinephrine Most NE neurons are located In the locus caeruleus or the lateral tegmental area of the reticular formation. Most regions of CNS receive diffuse noradrenergic input. All noradrenergic receptor subtypes are metabotropic. Involved in sleep, wakefulness, attention and feeding behavior. Primary excitatory. Appears to modulate Fear/flight/fight system. Too much: mania. Too little: Depression 25

Dopamine DA pathways in the brain 1- mesolimbic pathway: (Pleasure center) Associated with pleasure, reward & goal directed behavior. Heroin, cocaine, nicotine, sex and even good tasting food (Chocolate) cause the release of DA which causes pleasure. Disorder: schizophrenia 2- mesocortical pathway Associated with motivational and emotional responses. Disorder: schizophrenia 26

3- nigrostriatal pathway coordination of movement. Disorder: Parkinson's disease 4- tuberoinfundibular pathway Regulates secretion of prolactin & involved in maternal behavior. Disorder: hyperprolactinaemia 5 dopamine receptors D1-like (D1 and D5). D2-like (D2, D3, D4). All D receptors are metabotropic. Dopamine generally exerts a slow inhibitory action on CNS neurons. 27

Serotonine Most serotonin(5-ht,) pathways originate from neurons in the raphe. 5-HT acts on 14 receptor subtypes, all are metabotropic except the ionotropic 5-HT3. Low levels of serotonin are also associated with depression, panic disorders, and Obsessive-Compulsive Disorder (OCD). 28

Bulimia: eating disorder OCD: Obsessive compulsive disorder 29

Histamine The majority of histamine containing neurons are confined to the tuberomammillary nucleus (TM) TM Fire in pattern that varies with behavioral state, high during waking and slow or silent during slow wave sleep. Functions: Epilepsy Pain perception. Food & water intake. Thermoregulation. Autonomic activity. Hormone release. 30

Peptides Opioid peptides (enkephalins, endorphins), neurotensin, substance P, somatostatin, cholecystokinin, vasoactive intestinal polypeptide, neuropeptide Y, and thyrotropinreleasing hormone. Peptides often coexist with a conventional nonpeptide transmitter in the same neuron. Nitric Oxide NO modulates the release of several neurotransmitters in the brain, such as acetylcholine, catecholamines, excitatory and inhibitory amino acids, serotonin, histamine, and adenosine. 31

Endocannabinoids anandamide and 2-arachidonoylglycerol. Endogenous cannabis-like substances derived from arachidonic acid, They bind to a family of G-protein-coupled receptors, CB1 & CB2 receptor. Endocannabinoids are released upon demand from lipid precursors, and serve as retrograde signaling messengers in GABAergic and glutamatergic synapses, as well as modulators of postsynaptic transmission. Mediates the psychoactive effects of cannabis. Cannabinoids act as neuromodulators for a variety of physiological processes, including motor learning, synaptic plasticity, appetite and pain sensation. 32