2Outline Types of synapses Neurotransmitters Receptor types ElectricalChemicalNeurotransmittersCriteriaTypesReleaseInactivationReceptor typesIonotropicMetabotropicLigand bindingPlasticityOutline
3Electrical synapse: gap junctions ~3nm apartVery fast communicationDirect pore between cells, allows bidirectional flow of ions6 connexins= 1 connexonAllows rapid and synchronous firing of interconnected cellsExamples are contractions during childbirth or cardiac contractions
5Why would we need anything more? Why don’t our brains just use electrical transmission?
6Benefits of Chemical signaling 60+ different NTs and neuromodulatorsEach NT can have up to 15 different receptorsCo-localization of several NTs in one synapseOne neuron can have TONS of different synapsesSimple or complex post-synaptic responsesPost synaptic responses: differ in temporal action, more than just alterations in membrane potentialWhen you think about how complex our thoughts and actions are, and that this is basically a series of synaptic connections, it makes more sense that we would need to have this much complexity to make it happen
7The chemical synapse ~20-50 nm apart NTs released by pre- synaptic cell bind receptors on post-synaptic membraneEPSP, IPSP or complex responses*** The RECEPTOR determines the response, not the NT ***Binding of NT is transitory, the more NT in the synapse, the greater the receptor responses
8Criteria for NTs Synthesized in pre- synaptic cell Activity dependent releaseMechanism for deactivationPredictable pharmacological activity
9Major classes of neurotransmitters Small neurotransmitter moleculesSynthesized near axon terminalsAcetylcholine, monoamines, indolamines, amino acidsLarge neurotransmitter molecules- NeuropeptidesSynthesized in somahormonesenkephalin/ endorphinSoluble gassesnitric oxidecarbon monoxideWHY would small NTs be synthesized at terminals while large NTs in soma?-bc small NTs have dietary precursor components, Large NTs must be translated and transcribedEnk/end- work as endogenous morphine like molecules/NTs that decrease pain.Runners highSoluble gasses…. Don’t want to talk about, because not classical ---- but I have read estimations up to 2% of neurons in the brain use nitric oxide signaling.Soluble gasses.
10Small Neurotransmitters 1. Amino AcidsGlutamate/ Gamma-aminobutyric acid (GABA)MAJOR NTs in the CNS/ All over2. The MonoaminesCatecholaminesDopamine- DA- reward/movementNorepinephrine- NE –sympatheticEpinephrine-released from adrenalsIndolaminesSerotonin -5-HT3. Acetylcholine (ACh)Glut is major excitatory NT in CNS/ GABA is major inhibitory. Glut- long axon neurons. GABA is primarily in interneuron (in one nucleus--- in between the input/out put neurons in one nucleus.)In a way, you can can anything else a neuromodulator… because these are the major NTs in the CNS, all the rest regulate whats going along the GABA or glutamatergic connections.2. acetylcholine: contracts skeletal muscles/ ANS. Important in Alzheimer's disease in basal forebrain (Ach decreased)./ interneurons3. Biogenic amines. Catechol/indol refers to their molecular structure. Localized in small cell groups/ clusters within the brain. Not widespread/ dispersed like the amino acids, but are equally important. NO SMALL EFFECT. Axon collaterals to cortex/ high order functions……Da----- for example---- involved in addiction. VTA-- NAc. This pathway which utilizes DA transmission is vital to almost all kinds of addiction.
11L-Dihydroxyphenylalanin (L-Dopa) Amino AcidsGlutamateGABACatecholaminesTyrosineL-Dihydroxyphenylalanin (L-Dopa)DopamineNorepinephrineEpinephrineTyrosineHydroxylaseGlutamicAcidDecarboxylase(GAD)Important in understanding some of the examples of degradation. Just interesting to see that some NT that serve very different purposes in the CNS are precursors for each other. DA vs. NE. Stress response….. Fight of flight response.TYROSINE HYDROX IS RATE LIMITING FACTORParkinson’s- Da deficiency in pathways bt SN-striatum/ SN-GP. One treatment for PD is L-dopa.Glut is a precursor for GABA
12Nuclei are the home of the cell bodies of the neurons that make and release the respective NTs
13Then what? NTs are synthesized at terminal and packaged Or Neuropeptides are transcribed, translated, packaged and trafficked down to the terminalHow does an Action Potential initiate their release?
14Exocytosis Ca++ facilitated SNARE Proteins Voltage-gates Ca++ channels in the axon terminal open from AP and allow CA++ to enter. SNARE proteins allow vesicle to dock to the internal membrane, Ca++ enables SNARE proteins to fuse the vesicular and cell membranes together, allowing NT release into the synapseBOTOXSNARE Proteins
15What happens to NTs after release? Diffusion through synapse to post-synaptic cellNT binding to receptors is TRANSITORY, more NT around to bind, the greater the receptor effects…….Uptake and recycledEnymatically broken downTaken up by glia cells, released later, like a sponge to soak up excessPassive diffusion away (can have distal effects)
162 Main Types of Receptors IonotropicLigand-gated ion channelsDirectly alters the membrane potentialMetabotropicSlower, but can have greater effects2 types:G-protein coupledTyrosine Kinase receptorsIonotropic receptors are ion-specific, when the NT binds and produces a conformational change to open the pore, the pore is wide enough to allow specific ions to pass through
17Ionotropic Receptors Excitatory (EPSP) or Inhibitory (IPSP) responses K+, Na+, Ca++CL-Some can be ligand and voltage-gated (NMDA)Slow ionotropic: closes K+
18Complex effects of metabotropic receptors NO PORE, but binding can initiate:2nd messenger systemOther products could open ion channelsModulate enzyme activityRegulate ion channels in membraneInitiate gene transcription/translationRegulation of ion channels, both ligand gated (to alter the sensitivity of a cell to NT) and voltage gated, to alter electrical excitability and firing properties
19What happens to NTs after release? Diffusion through synapse to post-synaptic cellNT binding to receptors is TRANSITORY, more NT around to bind, the greater the receptor effectsNT must be clearedremoval just as important as releaseMultiple things can happen….Uptake and recycledEnymatically broken downTaken up by glia cells, released later, like a sponge to soak up excessPassive diffusion away (can have distal effects)
21Glial Sponge Glial cells can act as buffers for excess NTs Can process and release NTsPassive diffusion away from the synapseWhy?Distal effects, some cells have very distal receptors, if the receptor is able to identify an NT that has passively diffused away, there is TOO much, so the receptor initiates a negative feedback mechanism to release less NT
22NT binding to receptor shape-specific Lock and key arrangementEndogenous vs. exogenousDrugs work because we already have the receptors in place to receive themDrug actions are so intense because they cause actions so far above and beyond what endogenous compounds doAgonistsAntagonistsFull vs. partialCompetitive vs. non- competitiveAllostericAllosteric- modifies the receptor to be more or less effected by the natural NTCompetitive: based on affinity of the ligand to the receptor
23Receptor agonists and antagonists Full, partial, competative, non-competative, allosteric
24Organization dictated by experience Synapses can grow and retract, continually being altered by usePlasticity can occur in a variety of ways:Create new synapsesStrengthen or weaken existing synapsesBreak old connectionsLTPTolerance to drugs: can up or down regulate receptor numbers
25Synaptic connections change over time These are microglia, but I want you to see how cells move and interact, neurons do this too!
26Putting it all together: Neuropharmacology Tolerance develops due to cellular and receptor alterations in response to chronic drug useThe changes also mediate withdrawal symptomsWithdrawal= opposite of drug effectsDepression is most likely not due to a lack of serotonin (i.e. SSRIs)…Serotonin receptor is metabotropicSevere alcohol withdrawal can kill you:SeizuresGlutamate excitotoxicityAlcohol= agonizes GABA, GABA receptors are down regulated because there was too much inhibition, cold-turkey= not enough GABA to keep inhibited= overly excitedIn an addicted state= drug + altered brain morphology = normal