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Neurotransmitters Wednesday, January 20, 2016 Neuronal Signaling and Synapses - Each neuron may have a few hundred or 200,000 synaptic connections -> combination of their effects is how AP is controlled - Types of Synapses ○ Electrical synapse Allows direct spread of current from one neuron to another via GAP Junctions Rare in adult nervous systems (horizontal cells of retina) Advantages □ Presynaptic signal is duplicated in post synaptic cell □ No delay in transmission □ No need to synthesize vesicles or neurotransmitter Disadvantages □ Partial loss of functional individuality in coupled neurons ○ Chemical Synapses Uses NEUROTRANSMITTERS to communicate between cells Sequence of Events 1) Synaptic Vesicles filled with neurotransmitter are created and docked at presynaptic terminal via anterograde transport (via KINESIN) 2) Depolarization occurs due to AP 3) Depolarization causes VOLTAGE GATED CA+ CHANNELS to open and CA+ FLOWS INTO TERMINAL 4) Ca+ triggers fusion of synaptic vesicles with presynaptic membrane 5) Transmitter is released into synaptic cleft 6) Some of the transmitter molecules bind to receptors on POSTsynaptic membrane triggering a postsynaptic event (signal cascade) Receptor proteins have ionophore component that is either: ◊ Ion channel ◊ Second messenger activator 7) Transmitter molecules diffuse away from receptors or are cleared away by continued diffusion, enzymatic degradation, or active uptake This makes sure that the signal is meaningful and has appropriate amount of time to produce signal Release of neurotransmitters in Neuromuscular Junctions indicates a large EPSP but the selective concentration of receptors ensures that PSP are spatially localized and restricted □ Removal of these transmitter is by cleavage via Acetylcholinesterase into acetate and choline -> choline is transported back into presynaptic ending for further synthesis Receptors Define action of neurotransmitters □ Ionotropic ACh receptors are FAST, Transmitter-gated ion channels Generally Excitatory with Ach Example are Nicotinic Receptors at NMSK Junctions => Contraction (fast EPSP) Cation Channels let Na+ through => Excitatory Neuroanatomy Page 1 Anion channels let Cl- pass => Inhibitory □ Metabotropic receptors are SLOW and second messenger coupled Have longer effects usually with G-Proteins; 4 effects are: ◊ Usually prolonged opening of specific Ion channels ◊ Activation of cAMP/cGMP => alters long term excitability ◊ Activation of intracellular enzyme(s) ◊ Activation of gene transcription Generally Inhibitory with ACh Example are Muscarinic on Smooth/Cardiac Muscles and Neurons ◊ Decrease heart rate via increased K+ channels/slow IPS I. AchR is a ligand – gated channel on the postsynaptic membrane a. 2 main categories i. Nicotinic 1. Ionotropic receptor 2. Found at neuromuscular junction ii. Muscarinic 1. Metabotropic, G protein – coupled receptor 2. Found on smooth and cardiac fibers II. Second Messenger systems a. 4 main types of changes occur with the activation of metabotropic receptors i. Opening specific ion channels through the postsynaptic cell membrane ii. Activation of cAMP or cGMP in the neuron iii. Activation of one or more intracellular enzymes iv. Activation of gene transcription - Neuronal Plasticity ○ Neurons have ability to alter neuronal connections due to experience as seen with learning/memory formation ○ Repetitive stimulation can alter strength of synaptic connections Short term increases = Potentiation □ Could be by increases Ca+ levels => increase vesicle exocytosis next AP □ Long term potentiation (LTP) is seen during learning/memory in hippocampus Includes long-term increases in transmitter release, postsynaptic sensitivity (# of receptors) or both Increase in dendritic spine diameter could increase dendrites' ability to maintain concentrations of 2nd messenger Short term decreases = Depression □ Can occur due to high frequency stimulation (as seen in motor learning) or Habituation (low frequency stimulation) □ Long term depression (LTD) is thought to result from decreases in receptor DENSITY or decreased neurotransmitter RELEASE LTD + LTP work together to optimize synapses/neuronal plasticity Neuroanatomy Page 2 Neurotransmitters/Modulatory Systems - Variation in synaptic communication is caused by 4 characteristics Different Neurotransmitters Different receptors Activation of different pathways by receptors Difference in time courses of synaptic interactions ○ This allows the possibility of designing drugs that target specific neuronal subsystems - Neuropeptides ○ Large molecules that are stored/released from same neurons as small neurotransmitters ○ Are metabolically expensive => are effective even at low concentrations ○ Endorphins => Morphine-like ○ Substance P => smooth muscle relaxant ○ Enkephalins => Pain control - Small Neurotransmitters ○ All are stored/released by separate sets of neurons o Amino acids glutamate, GABA, glycine o Biogenic amines acetylcholine, serotonin, histamine, dopamine, nor/epi o Purine Derivative ATP ○ Cholinergic ACh Neurons located in Brainstem, Basal forebrain, and basal ganglia Function is to regulate general activity level of CNS neurons, particularly during sleepwake cycle and learning □ mediate rapid, point to point transmission in PNS (mainly excitatory) ○ Norepinephrine (NE) Neurons located in Locus Ceruleus (Pons), Lateral tegmental area, and reticular formation of brainstem □ Locus Ceruleus is blue-ish spot near Pons involved with physiologic responses to stress and panic Function are mostly EXCITATORY and affects entire CNS -> Flight/Fight and Alertness/Mood Dopaminergic Neurons are scattered throughout CNS □ Substantia Nigra => Facilitates VOLUNTARY MOVEMENT Degeneration is implicated in Parkinson's Disease □ Ventral Tegmental Area => Functions in REINFORCEMENT/REWARD as well as DRUG ADDICTION/SCHIZOPHRENIA ○ Serotonergic Are from RAPHE Neurons => associated with Mood Elevation SSRI (selective serotonin reuptake inhibitors) and MAOI (Monoamine oxidase inhibitors) are used to treat Depression □ SSRI = Block reuptake into terminal => keep serotonin in synapse longer □ MAOIs = inhibit oxidase => stops serotonin breakdown ○ Histaminergic Neurons are located in Hypothalamus, Reticular formation in midbrain Neuroanatomy Page 3 Functions in Alertness and SLEEP WAKE Cycles Drugs and their effects - Cocaine ○ Blocks REUPTAKE transporter of NE and DOPAMINE - Amphetamine ○ Causes enhanced NE and DOPAMINE RELEASE - Marijuana ○ Cannabis binds to cannabinoid receptors present in brain => Hinders GABA Inhibition -> More dopamine activation (I.E. stops GABA from inhibiting Dopaminergic neurons) - Ecstasy (MDMA) ○ Acts simultaneously as a STIMULANT AND HALLICUINOGEN because it is similar to amphetamines and LSD ○ Blocks REUPTAKE Pumps for various neurotransmitters ESPECIALLY SEROTONIN Excitation vs Inhibition - Excitatory synapses activate cation channels to increase EPSP ○ Glutamate is for Fast, Brief, EXCITATORY sypatic events in CNS Prolonged exposure to glutamate (via increase release or decreased reuptake) can INJURE/KILL Neurons □ Brain damage in stroke can release toxic amounts of glutamate ○ ACh for fast EXCITATORY in PNS - Inhibitory synapses activate anion channels to decrease IPSP ○ GABA/Glycine are for Fast, Brief, INHIBITORY synaptic events in CNS Glycine is localized to Spinal cord; GABA is everywhere GABAa receptors are highly controlled IONOTROPIC, receptor permeable to Cl, with many bonding sites for different chemicals □ Benzodiazepines (Valium) => increase channel opening FREQUENCY thus increase Cl- conductance □ Barbituates => increase DURATION of channel opening GABAb receptors are METABOTROPIC, G-proteins linked to K+ opening or Ca+ closure - Modulatory Synapses neuromodulator + membrane receptor + G protein intracellular signal cascade ○ Prolonged exposure to glutamate can injure or kill neurons excitotoxicity Initiated by excessive Ca2+ entry through NMDA receptors Neuroanatomy Page 4 Neuroanatomy Page 5