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Introduction to CNS

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 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.

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Neurotransmitters exert their effects on neurons by binding to two distinct classes of receptors:

1- A ligand-gated channelThe 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.

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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

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Metabotropic receptors can also modulate voltage-gated 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.

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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

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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.

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Cellular Organization of the Brain1- Hierarchical Systemslarge 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.

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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 .

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2- Nonspecific or Diffuse Neuronal SystemsContain 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.

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Amino AcidsGlutamateExcitatory transmitter, released by exocytosis & cleared by

glutamate transporters present on surrounding glia. Acts on: Ionotropic receptors1-NMDA. permeable to Na+ & Ca2+ 2-Kainate & 3-AMPApermeable 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 trisphosphate - mediated intracellular Ca2+ release.

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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 separateGlutamate-mediated excitotoxicity may underlie the damage that occurs after ischemia or hypoglycemia in the brain

site.

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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.

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GABAInhibitory 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.

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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 ConvulsionsAre 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.

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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 coupledto G proteins that, either Inhibit Ca2+ channels or activate K+ channels.

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GlycineThe simplest amino acidBinds 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

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Glycine and NMDA ReceptorsGlycine 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.

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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.

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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.

AcetylcholineCholinergic pathways play an important role in cognitive functions, especially memory.

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NorepinephrineMost 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

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DopamineDA pathways in the brain1- 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

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3- nigrostriatal pathway coordination of movement.Disorder: Parkinson's disease4- 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.

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SerotonineMost 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).

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Bulimia: eating disorder

OCD: Obsessive–compulsive disorder

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HistamineThe 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.

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PeptidesOpioid peptides (enkephalins, endorphins),

neurotensin, substance P, somatostatin, cholecystokinin, vasoactive intestinal polypeptide, neuropeptide Y, and thyrotropin-releasing hormone.

Peptides often coexist with a conventional nonpeptide transmitter in the same neuron.

Nitric OxideNO modulates the release of several

neurotransmitters in the brain, such as acetylcholine, catecholamines, excitatory and inhibitory amino acids, serotonin, histamine, and adenosine.

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Endocannabinoidsanandamide 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.