1. PTP 512 Neuroscience in Physical Therapy Introduction Neurotransmitters Min H. Huang, PT, PhD, NCS

2. Concepts you should already know before this lecture Cell membrane ion channels Resting membrane potential Local potential – Temporal summation – Spatial summation Action potential EPSP IPSP

3. Types of Synapses in the CNS

4. HETEROSYNAPTIC PLASTICITY

5. Presynaptic Inhibition and Facilitation Axoaxonic synapses mediate presynaptic inhibition and facilitation, e.g. present in the spinal cord to regulate the propagation of information to the brain. Interneurons regulate the ability of the presynaptic neurons to release neurotransmitters by changing the amount of Ca ++ influx to the presynaptic neurons.

6. Presynaptic Facilitation 1 Interneuron 2 Presynaptic neuron 3 Postsynaptic neuron  1 release transmitters  Transmitters bind to receptors on 2  This causes 2 to release more transmitters into the synaptic cleft between 2 & 3 when an action potential arrives

7. Presynaptic Inhibition 1 Interneuron 2 Presynaptic neuron 3 Postsynaptic neuron  1 release transmitters  Transmitters bind to receptors on 2  This causes neuron 2 to release less transmitters into the synaptic cleft when an action potential arrives

8. SYNAPSE Syn – together Haptein – to clapse

9. http://www.ncbi.nlm.nih.gov/books/NBK11164/ Electrical vs. Chemical Synapse

10. TypeElectricalChemical Length of synaptic cleft 3.5 nm20-40 nm Cytoplasmic continuity YesNo StructureGap junction Presynaptic vesicles Postsynaptic receptors Agents of transmission Ion current (electrical) Neurotransmitters (chemical) Synaptic delayVirtually absent> 1-5 ms Direction of transmission BidirectionalUnidirectional

11. Dobrunz, 2002 Chemical Synapse

12. Synaptic Communication Lundy’s CD - Synapse

13. Synaptic Communication Total # of action potentials reaching the presynaptic terminal directly influences the amount of neurotransmitter released ↑excitatory stimuli to the presynaptic neuron cause increased # action potentials reaching the presynaptic terminal ↑duration of excitatory stimuli to the presynaptic neuron cause a longer series of action potentials reaching the presynaptic terminal

14. NEUROTRANSMITTERS AND NEUROMODULATORS

15. What is a Neurotransmitter? It is synthesized in the neuron It is present in the presynaptic terminal It is released in amounts sufficient to exert an action on the postsynaptic neuron or effector organ It is removed from the synaptic cleft by a specific mechanism – Synaptic vesicle cycling http://neuroscience.uth.tmc.edu/s1/cha pter05.html http://neuroscience.uth.tmc.edu/s1/cha pter05.html Schwartz, 2005

16. What is a Neurotransmitter? When administered “exogenously” (e.g. drugs) in reasonable concentration, it mimics the action of the endogenously released neurotransmitter exactly. It activates the same ion channels or second messenger system in the postsynaptic cell. Some define neurotransmitters to include neuromodulators that act away from the synaptic cleft (Blumefeld, 2010). Schwartz, 2005

17. What is a Neuromodulator? Act at a distance away from the synapse Modulate activity of many neurons Released into extracellular fluid The same chemical substance can act either as a neurotransmitter or neuromodulator Effects last minutes to days Neurotransmitters and neuromodulators can be released simultaneously

18. Functions of Neurotransmitters Mediate communication between neurons or the end-organs through fast excitatory (EPSP) or inhibitory (IPSI) postsynaptic potentials (<1 ms) – Directly opening ligand-gated ion channels on postsynaptic membrane Slow-acting neuromodulation, occurring over 100ms to minutes – Indirect opening ion channels or activation the cellular signaling cascades

19. Neurotransmitter Receptors Receptors are often named according to the neurotransmitters to which they bind, e.g. GABA A, GABA B, 5-HT receptors The same neurotransmitter may bind to several types of receptors, e.g. Serotonin The effect of neurotransmitters on a postsynaptic neuron is determined by the type of receptors present on its membrane, e.g. Ach, Norepinephrine

20. Signal Transmission Mechanisms: Direct Activation of Ion Channels Neurotransmitters bind to receptors that are part of the ligand-gated ion channels and directly open the ion channels. Lundy’s CD

21. Signal Transmission Mechanisms: Indirect Activation of Ion Channels Neurotransmitters bind to receptors that are separate from the ion channels, and indirectly open the ion channels by activating the G- protein. This process involves changes in the metabolism of the cell. Lundy’s CD

22. Signal Transmission Mechanisms: Activating Intracellular Signaling Activation of the G- protein second- messenger system can trigger the intracellular signaling cascade. This process has long lasting effects on regulating genes expression and neuronal growth. Byrne, 1997

23. Termination of Synaptic Transmission Removing neurotransmitters – Diffusion: remove a fraction only – Enzymatic degradation: e.g. acetylcholinesterase – Reuptake: most common, e.g. serotonin Reuptake Desensitizing receptors by – Receptor internalization: folding the postsynaptic membrane containing the receptors into the cell – Receptor inactivation

24. Common Neurotransmitters and Neuromodulators Amino Acid —GABA —Glutamate (Glu) —Glycine (Gly) Cholinergic —Acetycholine (ACh) Amine —Dopamine (DA) —Serotonin (5-HT) —Norepinephrine (NE) Peptide —Substance P —Endorphins

25. Amino Acid: GABA Fast-acting MAJOR inhibitory neurotransmitter found in the entire CNS, e.g. inhibitory interneurons in spinal cord Prevents excessive neural activity Barbiturates mimics the action of GABA and are used for sedation, as anticonvulsants. Baclofen, a muscle relaxant to control muscle spasticity, increases presynaptic release of GABA

26. Amino Acid: Glutamate (Glu) Fast-acting MAJOR excitatory neurotransmitter found in the entire CNS Involved in learning and memory Glutamate is present in a wide variety of foods, e.g. MSG Overactivity of glutamate may cause seizures Excitotoxicity: Excessive glutamate may produce neuronal damage or death, e.g. TBI or CVA (X1000 higher than normal)

27. Glutamate Receptors AMPA: ligand gated receptor NMDA: ligand- and voltage-gated receptor – Postsynaptic neuron must depolarize when the Glu binds to the NMDA receptor in order to open the gate – Prolonged opening of ion channels resulting in long-term potentiation (LTP) Metabotropic glutamate receptor: indirect activation by G-protein pathway

28. NMDA Receptor Channel is permeable to Na+, Ca++, K+, opens and closes very slowly. LTP plays an important role in neuroplasticity. Byrne, 1997

29. Acetylcholine (ACh) MAJOR neurotransmitters in PNS, ANS – Fast-acting effect: act at neuromuscular junction, e.g. Nicotinic receptors – Slow-acting effect: regulate HR, ANS function, e.g. Muscarinic receptors Primary as a neuromodulator in CNS – Controls locomotion, arousal – Facilitate attention, memory, learning

30. ACh Receptors Nicotinic ReceptorMuscarinic Receptor Byrne, 1997

31. NicotinicMuscarinic Bind nicotineBind muscarine Linked to ion channelsLiked to 2 nd messenger system through G protein Fast and brief response Slow and prolonged response Located at neuromuscular junctions, autonomic ganglia, and some CNS Found on myocardial muscle, certain smooth muscle, in some CNS regions Mediate excitationMediate inhibition and excitation

32. Cholinergic Projection Systems Blumefeld, 2010

33. Acetylcholine Applying electrical stimulation to pontomesencephalic region of the brainstem elicits coordinated locomotor movements. Drugs that block the cholinergic transmission in the brain causes delirium and memory deficits. Degeneration of cholinergic neurons in the basal forebrain may be associated with memory decline in Alzheimer’s disease

34. Myasthenia Gravis (MG) ACh receptors on muscle membranes are destroyed. Weakness becomes more severe with repetitive use of a muscle. Rx: Anticholinesterase inhibits the cholinesterase from breaking down ACh.

35. Myasthenia Gravis (MG) Reduced EMG amplitudes over repetitive muscle contractions.

36. Case: a 12-year-old girl with cerebral paly She walks on her toes and exhibits a scissor gait, with legs strongly adducted with each step. Standard physical therapy has not resulted in any significant improvements.a scissor gait Her physicians want to inject a small amount of Botulinum toxin (Botox) into the gastrocnemius and adductor magnus muscles of both legs to reduce involuntary muscle activity and improve gait.

37. Questions By what mechanism could the injection of Botox reduce involuntary muscle activity? At the neuromuscular junction, ACh acts via a ligand-gated receptor. Is the action of ACh on the nicotinic, ligand-gated receptor the same as its action on the muscarinic, G- protein-mediated receptor? The effect of Botox lasts about 12 weeks. Too much ACh leads to spasm or tremor Too little ACh leads to paralysis or delirium

38. Amines: Dopamine (DA) Produced in substantia nigra of basal ganglia and ventral tegmentum Primarily an inhibitory effect in CNS All DA receptors are 2 nd messenger systems to suppress the activity of Ca++ channels. Affects motor activity, motivation/reward behavior, and cognition

39. Dopamine Projecting System BG Limbic Prefrontal Movement Reward Working Memory Addiction Attention

40. Neurologic Conditions Associated with Dopamine (DA) Parkinson’s Disease Case: ↓DA in basal gangliaCase Depression/Cognitive: ↓DA in forebrain Drug addiction: cocaine and amphetamines interfere with DA reuptake into the presynaptic neurons, allowing DA to activate receptors repetitively Schizophrenia: too much DA Schizophrenia

41. Amines: Serotonin (5-HT) Produced in raphe nuclei and GI tract Serotonin regulates sleep-wake cycle, cognition, perception of pain, breathing, temperature, movements, and mood. Serotonin is associated with depression, anxiety, obsessive-compulsive disorder, aggressive behavior, certain eating disorders (release serotonin ↓appetite) Serotonergic neurons ↓firing during sleep

42. Amines: Serotonin (5-HT) Serotonin is “happiness hormone”. Serotonin ↓perception of pain. Low levels of serotonin are associated with depression. Prozac (antidepressant) is a selective inhibitor of serotonin reuptake (so serotonin stays in the synaptic cleft longer to bind with receptors) SIDS may be associated with defected serotonergic neurons.

43. Serotonin Projecting System Noradrenergic Projecting Systems Blumefeld, 2010

44. Norepinephrine (NE) Regulate functions of ANS, thalamus, and hypothalamus Modulate attention, sleep-wake cycle – Noradrenergic neurons ↓firing in sleep – Attention-deficit disorders if often treated with medications that enhance NE transmission ↑level of NE is associated with vigilance, ↑alertness, and “fight-or-flight” response

45. Norepinephrine (NE) Noradrenergic neurons involve in sympathetic functions such as blood pressure control Similar to Serotonin, NE also ↓perception of pain in the CNS, and plays a role in many psychiatric syndrome – ↓NE can cause depression – ↑NE can cause anxiety (panic attack)

46. Serotonin Projection System Noradrenergic Projecting Systems Blumefeld, 2010

47. Histamine Found mainly in the hypothalamus. Found mostly outside the nervous system in mast cells that mediate immune responses and allergic reactions. Role of histamine in the brain – Maintain the alert state – Excitatory effects on thalamus Antihistamine medications can cause drowsiness by blocking CNS histamine receptors

48. Peptides: Substance P Released from the terminals of some sensory nerve fibers Neurotransmitter function in the nociceptive pathway – stimulates free nerve endings at the site of injury and transmit pain signals from the periphery to the CNS Neuromodulator function in the chronic pain syndrome – increase pain perception

49. Peripheral sensitization following cell damage. Pain signals cause the free nerve endings to release substance P. 5-HT outside the nervous system stimulates the nociceptive free nerve endings. SP-substance P H-histamine 5HT-serotonin Hauser, 2010

50. Peptides: Endogenous Opioids (endorphin, enkephalin, dynorphin) Body’s natural pain killers Inhibit CNS neurons involved in the perception of pain Exercise increases endogenous opioids

51. Nitric Oxide (NO) An free radical, highly reactive, diffusible gas molecule with neuromodulator effects NO is important in the regulation of cerebral blood flow, neurotransmission, long-term potentiation, excitotoxicity (i.e. neuronal death) NO cause blood vessels to dilate NO in excess is toxic to cells

52. Review What would be the functional implication of presynaptic facilitation and inhibition? Describe the structure of a chemical synapse and the events of signal transmission at the synapse. Compare and contrast neurotransmitters versus neuromodulators. Discuss the functions of neurotransmitters and the associated clinical implications.