Lecture3 SynapticTransmission.html

Lecture 3Synaptic transmission Module 202 Neuroscience & Behaviour Natasha Sigala [email protected] The presentation is for personal use only and must not be copied or used outside of BSMS Learning Outcomes Define and explain what a synapse is. Explain types of synapse Name types of...

Lecture 3Synaptic transmission Module 202 Neuroscience & Behaviour Natasha Sigala [email protected] The presentation is for personal use only and must not be copied or used outside of BSMS Learning Outcomes Define and explain what a synapse is. Explain types of synapse Name types of synapse based on their location Define what a neurotransmitter is Compare a chemical synapse in the CNS and at the neuromuscular junction Describe the structure and function of a chemical synapse, and name its components Explain the mechanism of action of Botox and Tetanus toxins Explain the concept of the tripartite synapse List some of the roles of glia in synaptic transmission and function Outline Chemical signals and synapses (location, structure) Synaptic transmission The tripartite synapse Glial cells (glia) and regulation of synaptic connectivity Neurotransmitters: synthesis storage release recovery and degradation 3 General categories of synapses Chemical: Majority Electrical: Simpler structure and function Faster Passive signal transmission Bidirectional Minority, but particularly common in development Allow synchronised electrical activity among populations of neurons Synaptic Transmission 5 Neurotransmitters & Chemical Synaptic Transmission how information is passed from one neuron to another or to the effector organ, i.e. muscles and glands, at the chemical synapses Lecture on Neurotransmitters, synthesis and release Lecture on Receptor Activation and Signal Transduction Lecture on Drug effects on neurotransmitter systems and function 6 Chemical synapse - location (a) axodendritic (b) axosomatic (c) axoaxonic (from Bear, Connors & Paradiso) 7 Chemical Synapse - Structure The presynaptic terminal synaptic button cytoskeleton mitochondria synaptic vesicles active zone synaptic cleft (from Bear, Connors & Paradiso) 8 9 Neuromuscular junction Synaptic transmission On an action potential reaching the synaptic terminal, neurotransmitter molecules are released from the presynaptic neuron and diffuse across the synaptic cleft to the postsynaptic membrane. Receptors recognize the neurotransmitters and initiate a response: 1) Direct excitatory or inhibitory neurotransmission: the membrane of the next cell becomes slightly depolarized or hyperpolarised. 2) Neuromodulation: alters the presynaptic cell’s ability to release more transmitter or the postsynaptic cell’s ability to respond 10 Criteria that define a neurotransmitter: synthesized in the neuron present in presynaptic terminal and released in amounts sufficient to exert a defined effect on the postsynaptic neuron or effector organ. when administered exogenously (as a drug) it mimics the action of the endogenously released transmitter. specific mechanism exists for removing it from the synaptic cleft 11 12 Sequence of events in a typical chemical synapse transmission Synaptic vesicle release and recycling Pool of vesicles above the active zone is anchored to the cytoskeleton by synapsin - Action potential to presynaptic terminal, voltage gated Ca2+ channels open, Ca2+ flows into the cytoplasm - Ca2+ activates Calcium calmodulin activated kinase II (CaMKII) which phosphorylates synapsin. P-synapsin can no longer bind to the cytoskeleton, vesicles dock to the active zone (from Purves 2nd ed) 13 Synaptic vesicle release and recycling SNARE* complex at active zone docks vesicles to the plasma membrane * SNAP (Soluble NSF Attachment Protein) RECEPTOR (from Purves 2nd ed) 14 Mechanisms of exocytosis during neurotransmitter release 15 Mechanisms of exocytosis during neurotransmitter release 16 Synaptic vesicle release and recycling vesicle membrane is rapidly recovered via ENDOCYTOSIS, new vesicles bud off and are refilled with transmitter 17 Cleavage of SNARE proteins by clostridial toxins 18 Sites of proteolysis that blocks neurotransmitter release. Botulinum toxin (BoTX) neuromuscular transmission ACh Tetanus toxin (TeTX) interneurons at spinal cord, GABA, Gly only the two deadliest toxins… Botox and Tetanus – prevent transmitter release Botulinum and tetanus toxins (from bacteria Clostridium botulinum and tetani respectively) Botox acts directly at the neuromuscular junction. The muscles lose all input and so become permanently relaxed (treatment of muscle spasms). Tetanus toxin inhibits the release of Glycine and GABA at inhibitory neurons, resulting in dis-inhibition of cholinergic neurons, which causes permanent muscle contraction. 19 Diseases that affect the presynaptic terminal 20 Membrane transporters (amino acids, amines and ACh) red star shows site of action for anumber of drugs Vesicular transporters powered by proton gradient ATPase proton pump loads up vesicles with H+ making vesicles acidic (pH5.5) compared to neutral pH of cytoplasm (pH7.2) e.g. 1 glutamate traded for 1 H+ (counter-transport mechanism) Plasma membrane transporters powered by electrochemical gradient [Na+] higher outside / [K+] higher inside Glutamate co-transported with 2 Na+ (from Bear, Connors & Paradiso) 21 For the glia enthusiasts… 22 Nature, 2010, 468: pp.162 The tri-partite synapse Nature, 2010, 468: pp.224 Glia do a lot more than support synaptic transmission. They express neurotransmitter receptors, which allows them to respond to synaptic activity by changing intracellular levels of Ca2+ They coordinate synapse formation and elimination with secreted and cell-surface associated signals They control synapse formation, function, plasticity and elimination. They are crucial during development, for learning and memory, as well as in disease. Glia and disease Reactive gliosis following injury (relevant for CNS regeneration potential) Role in aberrant synapse formation, linked with epilepsy and neuropathic pain Brain cancer HIV-induced dementia Neuroinflammatory response of depression Other neurodegenerative diseases, such as Alzheimer’s, glaucoma and prion disease, through aberrant synaptic stripping Some take-home points and questions synaptic transmission relies on the release of neurotransmitters in response to an action potential reaching the presynaptic terminal synaptic communication is essential for information processing in local circuits, and throughout the nervous system Synapses are targeted by a variety of drugs and toxins During synaptic communication, it is important to turn signals off as much as it is to turn them on How are these processes regulated - both endogenously and with drugs? Glial cells support neurons, but also regulate synaptic connectivity 25 The tetanus toxin inhibits the release of neurotransmitters of which cells? Select the single best answer from the list below. Astrocytes Cholinergic neurons that innervate muscles GABAergic neurons Glutamatergic neurons Inhibitory interneurons at the spinal cord Reading materials Bear, Connors & Paradiso, Neuroscience: Exploring the Brain 2nd ed or 3rd ed, Chapter 5 & 6 Carlson, Physiology of Behaviour 9th or 11th ed , Chapter 2 & 4 http://www.williams.edu/imput/synapse/index.html Purves et al, 4th or 5th ed, Neuroscience Kandel, Schwartz & Jessell, 4th ed, Principles of neural science Chapters 10-16 27