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Neurotransmitters (L7) Neuronal signaling and synapses -incoming signals enter the neuron through synapses located mostly on neuronal dendrites, specifically on dendritic spines -combining their effects determines whether/how often to fire an action potential ability to compare & combine different inputs is responsible for the computational power of the NS -output signals travel by way of a single axon leaving the neuron can be excitatory or inhibitory ELECTRICAL SYNAPSE -direct spread of current from one neuron to another through gap junctions – relatively rare in adult NS -advantages presynaptic signal is duplicated in postsynaptic cell; no delay in transmission of signal; no need to synthesize vesicles & neurotransmitters -disadvantages partial loss of functional individuality in coupled neurons -modulation **found in horizontal cells of the retina CHEMICAL SYNAPSES & NEUROTRANSMITTERS -neurotransmitters neuroactive chemical transmitters that allow communication between two cells *can be small molecules, larger peptides, or diffusible gases *first chemical synapse to be described was the neuromuscular junction (a nervemuscle synapse in which the neurotransmitter is acetylcholine, or Ach) -a single presynaptic terminal (usu. an axon) on the postsynaptic membrane (usu. A dendrite) of another neuron, separated by a synaptic cleft -transmitter vesicles & mitochondria are important to the excitatory or inhibitory functions transmitter substances released from the transmitter vesicles either excite or inhibit the postsynaptic neuron depending on whether the neuron contains excitatory receptors or inhibitor receptors, respectively *mitochondria provide ATP that supplies energy for neurotransmitter synthesis ELECTRICAL VS. CHEMICAL SYNAPSE Neurotransmi -7 steps of synaptic transmission: 1.synthesis & storage ssion 2.action potential & depolarization 3.activation of voltage-dependent Ca2+ channels 4.vesicle fusion & release 5.receptor binding 6.signal termination in the synaptic cleft 7.termination of postsynaptic intracellular signaling Postsynaptic effects of neurotransmi tters Neuromuscul ar junction -receptor proteins contain a binding component for the neurotransmitter that protrudes into the synaptic cleft; a transmembrane component, either: *an ion channel allowing passage of specific ion types OR a second messenger activator that extends into the cell cytoplasm & activates one or more substances within the postsynaptic neuron -somatic neuron axons are myelinated by Schwann cells -each motor axon terminal has clusters of vesicles filled with ACh AP causes vesicles to fuse with the terminal membrane *diffuses across synaptic cleft and through the basal lamina to reach postsynaptic receptors at troughs in the muscle surface across from vesicle clusters -presynaptic ending at each neuromuscular junction contained about 1000 active zones -a single AP in the motor axon simultaneous release of hundreds of vesicles full of Ach at closely spaced sites large EPSP -selective concentration of receptors on the postsynaptic membrane ensures that fast PSPs are spatially localized/restricted Receptors -neurotransmitter removal – Ach is split into acetate & choline by acetylcholinesterase in the synaptic cleft; choline is then transported back to the presynaptic ending for further synthesis of ACh -ionotropic receptors fast-acting, transmitter-gated ion channels -metabotropic receptors slow synaptic transmission; binding of neurotransmitter leads to altered concentrations of second messengers *modulates channel conductance; most are G protein-coupled receptors -the effect that a neurotransmitter has is determined by the receptor to which it binds *there are multiple receptors for most neurotransmitters – thus each is capable of different effects *the many subtypes of receptors make it possible to design drugs that target specific neuronal subsystems -AChR is a ligand (transmitter) – gated channel on the postsynaptic membrane -2 main categories of AChRs nicotinic & muscarinic -nicotinic (ionotropic receptor) only AChR found at neuromuscular junctions can produce muscle contraction (fast EPSP) -muscarinic (metabotropic, G protein-coupled receptor) found on smooth & cardiac muscle fibers & on many neurons can produce a decrease in HR through increased opening of K+ channels & slow IPSP -ion channels short-term effects (close within ms) cation channels allow mainly Na+ though (sometimes K+ and Ca2+) *open cation channels excite the neuron; thus neurotransmitters that open cation channels are excitatory *anion channels allow mainly Cl- ions though open anion channels inhibit the neuron; opening anion channels are inhibitory SECOND MESSENGER SYSTEMS -four main types of changes can occur with the activation of metabotropic receptors -opening specific ion channels through the postsynaptic cell member – e.g. opening of a potassium channel (prolonged opening) -activation of cAMP or cGMP in the neuron can activate metabolic processes that result in changes in cell structure that alter long term excitability -activation of one or more intracellular enzymes -activation of gene transcription can initiate formation of new proteins within the neuron that change the metabolic activity or structure **on activation by a nerve impulse, the alpha portion of the G-protein separates from the beta & gamma portions and is free to move within the cell cytoplasm Neuronal plasticity -ability to alter neuronal connections d/t experience existing synapses can be altered for long periods (hours/days) and maintained; new synaptic connections can form -learning & memory -repetitive stimulation of neuronal synapses can alter the strength of synaptic connections *short-term increases in strength are known as facilitation or potentiation *short-term decreases in strength includes depression, which can occur d/t highfrequency stimulation, and habituation (a slowly progressing decrease as a result of lowfrequency activation) Long-term potentiation (LTP) -establishment and modification of neuronal networks (through both excitatory & inhibitory synaptic transmission) are vital for normal brain functioning -potentiation elevated Ca2+ increases the odds of vesicle exocytosis the next time an AP arrives at the terminal -LTP repetitive stimulation of a particular synapse eventually leads to an increase in the strength of the synaptic connection *first discovered in hippocampus *learning & memory *depends on activation of glutamate receptor *can involve long-term increases in transmitter release, postsynaptic sensitivity (# of receptors), or both -neurons that fire together, wire together -strong candidates for synaptic changes in learning & memory -spines are connected to the dendrite by a narrow neck small changes to diameter of neck could lead to large changes in a spine’s electrical properties, ability to maintain altered concentrations of second messengers Long-term depression -shapes & numbers of dendritic spines change when learning occurs -specific synaptic connections are weakened -can result from strong synaptic stimulation (e.g. purkinje cells in the cerebellum; motor learning); persistent (low-frequency) weak synaptic stimulation (as in the hippocampus) -LTD thought to result from decrease in postsynaptic receptor density; also decrease in presynaptic neurotransmitter release *e.g. high-frequency bursts of APs can delete the synaptic vesicle pool, thereby decreasing the odds of synaptic vesicle exocytosis to the synaptic cleft Modulatory systems -together, LTD & LTP affect neuronal plasticity *LTD selectively weakens specific synapses to optimize synaptic strengthening caused by LTP (otherwise, LTP might go unchecked, increasing to a maximum level and hinder encoding of new information) -systems of neurons influence the excitability states of other networks within the CNS & alternations in modulatory systems produce a wide range of psychiatric disorders -neuropeptides (neuroactive peptides) usu. stored & released froim the same neurons as Large one of the small neurotransmitters molecule neurotransmi -metabolically expensive; present and effective at low concentrations tters -endorphins (endogenous substance with morphine-like actions) -substance P originally described as a smooth muscle relaxant isolated form gut, has been localized in synaptic endings in basal ganglia & DRG -enkephalins prominent role in pain-control circuitry -small neurotransmitters are each stores & released by separate sets of neurons and Small include: molecule *amino acids – glutamate, GABA, & glycine neurotransmi *biogenic amines – acetylcholine, serotonin, histamine, dopamine, norepinephrine, tters epinephrine *purine derivatives – ATP found in many neurons and other cell types; they can be released as a co-transmitter with other neurotransmitters Synaptic communicati on -variation in communication -use of different neurotransmitters -presence of several different types of receptors -activation of different down-stream pathways via these receptors -difference in time course of synaptic interaction Cholinergic pathway -cholinergic acetylcholine, Ach, mediates rapid, point-to-point transmission in PNS *mainly excitatory effect, sometimes inhibitory -cholinergic neurons of the CNS are brainstem, basal forebrain, and basal ganglia regulate general activity level of CNS neurons, particularly during phases of sleep-wake cycle and during learning Monoamines Noradrenergi -norepinephrine = noradrenaline, noradrenergic projection system c pathways -norepinephrine affects entire CNS *NE activates mostly excitatory receptors, some inhibitory receptors *secreted by postganglionic neurons of the sympathetic nervous system fight or flight; arousal, attention, stress/panic -main locations of neurons that (cell bodies) produce NE; locus ceruleus, lateral tegmental area, reticular formation of the brainstem alertness, mood -medulla oblongata area of the brainstem also contains adrenaline containing neurons (C1-C3); these neurons have very few projections into higher brain regionals & play a role on descending transmission & the autonomic nervous system LOCUS CERULEUS -meaning the dark blue spot, a named derived from its blue appearance in unstained brain tissue -the color is d/t light scattering from melanin in noradrenergic (producing or activated by norepinephrine) nerve cell bodies -involved with physiological response to stress & panic -principal site for brain synthesis of norepinephrine (noradrenaline) Dopaminergic -dopamine-containing neurons are scattered throughout the CNS pathways -substantia nigra – midbrain; projects to the striatum (caudate & putamen) facilitating voluntary movement degeneration of dopaminergic cells in the substantia nigra produces Parkinson’s disease -ventral tegmental area – midbrain; projects to part of the forebrain (prefrontal cortex) and parts of the limbic system implicated in neural systems that mediate reinforcement or reward as well as aspects of drug addiction and psychiatric disorders (schizophrenia) -members of the class of antipsychotic drugs called neuroleptics are antagonists of certain dopamine receptors -substantia nigra Substantia Nigra DOPAMINERGIC AGENTS -cocaine blocks reuptake of norepinephrine & dopamine -amphetamine causes enhanced neurotransmitter release (norepinephrine & dopamine) Serotongergic -serotonergic raphe neurons associated with mood control LSD exerts effects through serotonergic systems pathways -depression *SSRIs used to treat (Prozac) block serotonin reuptake, prolonging serotonin effect in the brain -MAOIs prevent breakdown of serotonin -serotonin projections also reach cranial blood vessels within the brain & pia mater where it cause vasoconstriction *also go to the thalamus (sensory integration) & hypothalamus (eating, sleeping, temperature) -SSRIs block reuptake into presynaptic terminal, keeping serotonin in the synapse longer -MAOIs monoamine oxidase inhibitors; inhibit the activity of the monoamine oxidase enzyme family, preventing breakdown of serotonin Histaminergic -VLPO – ventrolateral proptic nucleus of the hypothalamus is the contral center for arousal & sleep pathways -histamine regulates autonomic & neuroendocrine activities such as feeding, drinkin, & temperature; it can also regulate behavoris such as locomotion and arousal Excitation vs. inhibition -modulatory synapses neuromodulator + membrane receptor + G-protei intracellular signal cascade -excitatory synapses glutamate binds to fast, ligand-gated cation channels to generate and EPSP -inhibitory synapses GABA or glycine binds to ligand-gated anion channels to generate IPSPs -fast excitatory *PNS – Ach (nicotinic receptors) *CNS – glutamate -fast inhibitory *GABA (GABAA, mostly in brain) *glycine (mostly in spinal cord) Glutamate & GABA -glutamate the major transmitter for fast, brief, excitatory synaptic events in CNS *one of the transmitters at about 90% of CNS synapses *acts on 4 major types of receptors, 1 metabotropic *G-protein coupled) and 3 ionotropic (AMPA, NMDA, & kainite) *NMDA – responsible for some forms of long-term potentiation (LTP) -GABA (ʏ-aminobutyric acid) & glycine the major transmitters for fast, brief, inhibitory synaptic events in CNS *glycine localized to spinal cord; GABA everywhere **NMDA (N-methyl-D-aspartate) **AMPA (a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) EXCITOTOXICITY -normally, glutamate is rapidly taken back up into presynaptic terminal or surrounding glia so that postsynaptic exposure is minimized -prolonged exposure to glutamate (through excessive release or deficient reuptake) can injure or kill neurons – excitotoxicity *initiated by excessive Ca2+ entry through NMDA receptors -brain damage in stroke may involve release of toxic amounts of glutamate in response to anoxia GABA RECEPTORS -GABAA ionotropic receptors permeable to CL-b/c of the need for control of inhibition, GABAA receptors have other binding sites for different chemicals *the probable natural modulators of GABAA receptor are the metabolites of progesterone, corticosterone, & testosterone *benzodiazepines (i.e. diazepam- Valium) increase the frequency of channel opening & can increase the Cl- conductance of the GABAA receptor *barbiturates (i.e. phenobarbital) increase the duration of channel opening - GABAA receptor G-protein coupled metabotropic receptor linked to either the opening of K+ or suppression of Ca2+ channels Key concepts -steps in chemical synaptic transmission & Ca2+ involvement -neuromuscular junctions & Ach -ionotropic & metabotropic receptors -cholinergic, noradrenergic, dopaminergic, serotonergic, histaminergic, projection systems (primary locations of cell bodies, functions, & drugs that act on these systems) -glutamate & GABA -any clinically relevant details