WINDSOR UNIVERSITYSCHOOL OF MEDICINE

Dr.Vishal Surender.MD.

Nervous SystemSynapses

OBJECTIVES • describe the sites of synthesis and storage of small molecule transmitters in

nerve terminals • list the ionic mechanisms in the vesicular membrane that facilitate

transmitter storage • review the roles of extracellular and intracellular calcium ions in transmitter

release. • review the steps in the process of exocytosis of neurotransmitter • distinguish between the conditions necessary for release of small molecule

transmitters and the co-release of these transmitters and neuropeptides • describe the mechanisms for recycling of vesicular membrane following

exocytosis • describe the mechanisms that alter transmitter release owing to the actions

of toxins, drugs and other neurotransmitters • review the clinical correlations listed at the end of the lecture handout

Chemical Synapse• Functional connection between a neuron and another neuron or effector cell.

• These are the junctions where the axon or some other portion of one cell (the presynaptic cell) terminates on the dendrites, soma, or axon of another neuron or, in some cases, a muscle or gland cell (the postsynaptic cell).

axodendritic synapses axosomatic synapses axoaxonic synapses

4

CHEMICAL SYNAPSES: MECHANISM OF CONDUCTION OF EXCITATION

Neuromuscular JunctionDepolarization

Ca2+

Ca2+

Ca2+

Na+

Na+

Na+

Depolarizing muscle cell membrane

ROLE OF Ca++Ca2+ ions bind to Ca++ sensor protein on the membrane of synaptic vesicles which triggers binding of vesicles to the active sites of inner surface of presynaptic membrane and fusion of synaptic vesicles with the presynaptic membrane opening of the vesicles (exocytosis)

Clinical correlation.- Lambert Eaton Syndrome.

Molecular apparatus underlying Vesicle release

Synaptic Transmission (continued)

• NTs are released and diffuse across synaptic cleft.

• NT (ligand) binds to specific receptor proteins in postsynaptic cell membrane.

• *Chemically-regulated/Ligand gated ion channels open.– EPSP: depolarization.– IPSP: hyperpolarization.

• Neurotransmitter inactivated to end transmission.

Neurotransmitter -Types

Functional Classification of Neurotransmitters

• Two classifications: excitatory and inhibitory– Excitatory neurotransmitters cause depolarizations

(e.g., glutamate)– Inhibitory neurotransmitters cause hyperpolarizations

(e.g., GABA and glycine)

• Some neurotransmitters have both excitatory and inhibitory effects – Determined by the receptor type of the postsynaptic neuron – Example: acetylcholine.

• Excitatory at neuromuscular junctions• Inhibitory with cardiac muscle

Neurotransmitter Receptor Mechanisms

• Direct: neurotransmitters that open ion channels(cation/anion channels) Ionotropic– Promote rapid responses – Examples: Ach in ganglion and neuromuscular

junction• Indirect: neurotransmitters that act through

second messengersmetabotropic– Promote long-lasting effects– Examples: biogenic amines and peptides involved in

memory functions.

• Composed of integral membrane protein• Mediate direct neurotransmitter action • Action is immediate, brief, simple, and highly localized• Ligand binds the receptor, and ions enter the cells• Excitatory receptors

depolarize membranes(EPSP via Na+ entry)• Inhibitory receptors

hyperpolarize membranes(IPSP via entry of

K+ and/or Cl- channels )

Figure 11.22a

Direct/Ionotropic

G Protein-Linked Receptors

• Responses are indirect, slow, complex, prolonged, and often diffuse

• These receptors are transmembrane protein complexes

• Examples: muscarinic ACh receptors, neuropeptides(learning and memory), and those that bind biogenic amines

Indirect/metabotropic: second messengers

G-protein second messenger system

G Protein-Linked Receptors: Effects

• G protein-linked receptors activate intracellular second messengers including Ca2+, cyclic GMP, diacylglycerol, as well as cyclic AMP

• Second messengers:– Open or close ion channels– Activate kinase enzymes– Phosphorylate channel proteins – Activate genes and induce protein synthesis

Acetylcholine (ACh) as NT

• ACh is both an excitatory and inhibitory NT, depending on organ involved.– Causes the opening of chemical gated ion

channels.• Nicotinic ACh receptors:

– Found in autonomic ganglia and skeletal muscle fibers.

• Muscarinic ACh receptors:– Found in the plasma membrane of smooth and

cardiac muscle cells, and in cells of particular glands.

Ligand-Operated ACh Channels

• Most direct mechanism.

• Ion channel runs through receptor.

• Permits diffusion of Na+ into and K+ out of postsynaptic cell.

• Inward flow of Na+ dominates .– Produces EPSPs.

Nicotinic Receptor

G Protein-Operated ACh Channel

Muscarinic receptor

Fate of neurotransmitter

After a transmitter substance is released at a synapse, it must be removed by:-

• Diffusion out of synaptic cleft into surrounding fluid

• Enzymatic destruction e.g. Ach esterase for Ach

• Active transport back into pre-synaptic terminal itself e.g. norepinephrine

Neurotransmitter bound to a postsynaptic neuron: Produces a continuous postsynaptic effectBlocks reception of additional “messages”

Acetylcholinesterase (AChE)• Enzyme that

inactivates ACh.– Present on

postsynaptic membrane or immediately outside the membrane.

• Prevents continued stimulation.

- neostigmine

ACh in PNS and CNS

• Somatic motor neurons synapse with skeletal muscle fibers.– Release ACh from boutons.– Produces end-plate potential (EPSPs).

• Depolarization opens VG channels adjacent to end plate.

• Myasthenia Gravis

Central cholinergic neurons project to widespread areas of the cortex and cholinergic activity is responsible for a wide range of behaviors. Disruption of cholinergic function can produce amnesia, and anticholinergic medications, at toxic levels, are known to produce delirium and delusions.

Neurochemical and neuropathological degenerative findings in the central cholinergic system have been consistently reported in Alzheimer's disease.Cholinergic excess or hyperactivity has been postulated to play a role in depression and aggressive behaviors.

Synaptic properties

1. One-way conduction

2. Synaptic delay

3. Synaptic inhibitionTypes:

A. Direct inhibition Occurs when an inhibitory neuron (releasing inhibitory substance) act on a post-synaptic neuron leading to its hyperpolarization ex- Glycine.

B. Indirect inhibition This happens when an inhibitory synaptic knob lie directly on the termination of a pre-synaptic excitatory fiber. Ex- pain gating.

C. Reciprocal inhibition Inhibition of antagonist activity is initiated in the spindle in the agonist muscle. Impulses pass directly to the motor neurons supplying the same muscle and via branches to inhibitory interneurones that end on motor neurones of antagonist muscle.Ex- Knee gerk,see image next slide.

4. Summationa) Spatial summation. When EPSP is in more than one synaptic knob at same

time.b) Temporal summation. If EPSP in pre-synaptic knob are successively repeated

without significant delay so the effect of the previous stimulus is summated to the next

FACTORS EFFECTINF SYNAPATIC TRANSMISSION

1) pH Changes- Alkalosis - ↑ neuronal excitability (i.e., epileptic seizures)Acidosis - ↓ neuronal excitability (i.e., coma)

2) Drugs and chemicalsCaffeine (coffee and tea), theophylline (tea) and theobromine (cocoa): ↓ threshold of neuronal excitation →↑ excitability Strychnine: inhibition of action of inhibitory NT (i.e., glycine) → overwhelming effects of excitatory NT (i.e., tonic muscle spasm)Anesthetics: ↑ threshold for excitation → ↓ synaptic transmission (+ ↓ responsiveness of postsynaptic membranes to NT (lipid soluble anesthetics

Monoamines as NT

• Monoamine NTs:– Serotonin.– Epinephrine.– Norepinephrine. Catecholamines– Dopamine.

• Released by exocytosis from presynaptic vesicles.

• Diffuse across the synaptic cleft.• Interact with specific receptors in

postsynaptic membrane.

Inhibition of Monoamines as NT

• Reuptake of monoamines into presynaptic neuron.

• Enzymatic degradation of monoamines in presynaptic neuron by MAO-monoamine oxidase.

• Enzymatic degradation of catecholamines in postsynaptic membrane by COMT-catechol-O-methyltransferase.

Mechanism of Action• Monoamine NT do not

directly open ion channels.

• Act through second messenger, such as cAMP.

• Binding of norepinephrine stimulates dissociation of G-protein alpha subunit.

• Alpha subunit binds to adenylate cyclase, converting ATP to cAMP.

• cAMP activates protein kinase, phosphorylating other proteins.

• Open ion channels.

Serotonin as NT

• NT (derived from L-tryptophan) for neurons with cell bodies in raphe nuclei(brain stem).

• Regulation of mood, behavior, appetite, and cerebral circulation.

• SSRIs (serotonin-specific reuptake inhibitors):prozac– Inhibit reuptake and destruction of serotonin,

prolonging the action of NT. – Used as an antidepressant.

• Reduces appetite, treatment for anxiety, treatment for migraine headaches.

See for example in Current Neuropharmacology 2007;5(2):135-47.Theneurobiological bases for development of pharmacological treatments ofaggressive disorders by Siegel A, Bhatt S, Bhatt R, Zalcman SS:http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2435345/pdf/CN-5-2-135.pdf

http://www.if-pan.krakow.pl/pjp/pdf/2009/5_761.pdf

Dopamine as NT

• D 1 - like (D 1 and D 5) yield an increase in production of cAMP

• D 2 - like (D 2 , D 3 and D 4) inhibit production of cAMPr neurons with cell bodies in midbrain.

Dopamine has five types of receptorFive known metabotropic receptors affecting adenylyl cyclase activity fall into two main groups:

Axons project into:Nigrostriatal dopamine system:

• Nuerons in substantia nigra send fibers to corpus straitum.

• Initiation of skeletal muscle movement.• Parkinson’s disease: degeneration of neurons in

substantia nigra.Mesolimbic dopamine system:

• Neurons originate in midbrain, send axons to limbic system.

• Involved in behavior. • Addictive drugs:-Promote activity in nucleus

accumbens(striatum). Cocaine, schizophrenia.

Norepinephrine (NE) as NT

• NT in both PNS and CNS.• PNS:

– Smooth muscles, cardiac muscle and glands.• Increase in blood pressure, constriction of arteries.

• CNS:– General behavioral arousal.

– amphetamines

Amino Acids as NT• Glutamic acid and aspartic acid:

– Major excitatory NTs in CNS.• Glutamic acid:

– NMDA receptor involved in memory storage.• Glycine:

– Inhibitory, produces IPSPs.– Opening of Cl- channels in postsynaptic membrane.

• Hyperpolarization.– Helps control skeletal movements.

• GABA (gamma-aminobutyric acid):– Most prevalent NT in brain.– Inhibitory, produces IPSPs.

• Hyperpolarizes postsynaptic membrane.– Motor functions in cerebellum. Ex-huntingtons chorea.

Neurotransmitter Decreased Function Increased Function

AcetylcholineMemory impairment, delirium, delusions

Aggression, depression

Dopamine Dementia, depression

Psychosis, anxiety, confusion, aggression

Serotonin Depression, aggression Anxiety

Norepinephrine Depression, dementia Anxiety, aggression

GABA Anxiety Reduce anxiety and aggression

• Botulinum Toxin • Microinjection of botulinum toxin has been used to treat

dystonias (irregular and troublesome clonic contractions of muscle). One effect is the block of ACh release. It has also been used in cosmetic surgery to reduce facial wrinkles.

•

• Snake Venom • The venoms of some snakes contain a component (beta-

bungarotoxin) that binds irreversibly to actin and possibly other cytoskeletal components in cholinergic nerve endings, and blocks ACh release. Resulting paralysis can prove fatal if the subject is not ventilated.

Clinical Correlations

Therapeutic Drugs Act within

the CNS on Receptors

Anti-anxiety drugs act on GABAA

receptor channels

Benzodiazepines and barbiturates: inhibition in the amygdala involved with the development of fear and anxiety. The binding pocket for benzodiazepines is located in a subunit cleft between gamma and alpha1 subunits Agonist binding site for GABA is located between alpha1 and beta2 subunits.

Therapeutic Drugs Act within the CNS on

ReceptorsSeveral drugs are used to treat mood disorders

Clinical depression: •Selective serotonin re-uptake inhibitors (SSRIs; e.g.Prozac, in preference to the former use of tricyclic anti-

depressants).• •Noradrenaline re-uptake inhibitors

MAO inhibitors to reduce the degradation of noradrenaline and serotonin.

In a normal, healthy muscle, what occurs as a result of propagation of an action potential to the terminal membrane of a motor neuron?

A) Opening of voltage-gated Ca+2 channels in thepresynaptic membraneB) Depolarization of the T tubule membrane followsC) Always results in muscle contractionD) Increase in intracellular Ca+2concentration in the

motor neuron terminalE) All of the above are correct