WINDSOR UNIVERSITY SCHOOL OF MEDICINE

1. WINDSOR UNIVERSITYSCHOOL OF MEDICINE Dr.Vishal Surender.MD. Nervous System Synapses

2.  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

3. 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). axosomatic synapses axodendritic synapses axoaxonic synapses

4. CHEMICAL SYNAPSES: MECHANISM OF CONDUCTION OF EXCITATION

5. 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.

6. Excitatory and inhibitory synaptic connections mediating the stretch reflex provide an example of typical circuits within the CNS

7. Neurotransmitter -Types

8. 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

9. 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 messengersmetabotropic • Promote long-lasting effects • Examples: biogenic amines and peptides involved in memory functions.

10. Direct/Ionotropic • 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 • Inhibitory receptors hyperpolarize membranes Figure 11.22a

11. Indirect/metabotropic: second messengers G Protein-Linked Receptors • Responses are indirect, slow, complex, prolonged, and often diffuse • These receptors are transmembrane protein complexes • Examples: muscarinicACh receptors, neuropeptides(learning and memory), and those that bind biogenic amines

12. G-protein second messenger system

13. 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

14. 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. • MuscarinicACh receptors: • Found in the plasma membrane of smooth and cardiac muscle cells, and in cells of particular glands.

15. 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

16. G Protein-Operated ACh Channel Muscarinicreceptor

17. Acetylcholinesterase (AChE) • Enzyme that inactivates ACh. • Present on postsynaptic membrane or immediately outside the membrane. • Prevents continued stimulation. - neostigmine

18. 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

19. 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.

20. 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.

21. 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.

22. 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 adenylatecyclase, converting ATP to cAMP. • cAMP activates protein kinase, phosphorylating other proteins. • Open ion channels.

23. 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.

24. http://www.if-pan.krakow.pl/pjp/pdf/2009/5_761.pdf See for example in Current Neuropharmacology 2007;5(2):135-47.The neurobiological bases for development of pharmacological treatments of aggressive 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

26. Dopamine as NT Dopamine has five types of receptor Five known metabotropic receptors affecting adenylylcyclase activity fall into two main groups: • 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.

27. Axons project into: • Nigrostriatal dopamine system: • Nuerons in substantianigra send fibers to corpus straitum. • Initiation of skeletal muscle movement. • Parkinson’s disease: degeneration of neurons in substantianigra. • 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.

28. 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

29. 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.

31. Clinical Correlations • 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.

32. Therapeutic Drugs Act within the CNS on ReceptorsAnti-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.

33. 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.