Nerual signals - basics of synaptic transmission PDF

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Basics of synaptic transmission lecture notes...

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“Animal electricity” (sparks  electrically) • Luigi Galvani (1780’2 & 1790s) o Galvanism  electrophysiology “Vagusstoff” (soups  chemically) • Otto Loewi (1921) o Nobel prize (1936) • Study o He took a heart in a solution and stimulated the vagus nerve o Took fluid and added it to another heart which activated it Two types of synapses: 1. Electrical – gap junctions 2. Chemical – neurotransmitter Electrical synapses • Provide nearly instantaneous signal transmission o Direct current flow o Almost no synaptic delay o Typically large  small process Why use gap junctions? • Fast speed of propagation • Synchronize activity in cells • Transmission of metabolic signals between cells Chemical synapses • Release of neurotransmitter by presynaptic cell (exocytosis) • Crosses 20-40nm gam (synaptic cleft) • Neurotransmitter crosses gap & binds to receptor (membrane) in postsynaptic cell (reception) • Receptors execute effector function in target cell. • Need for mechanisms for: o Synthesizing neurotransmitter & packaging into synaptic vesicles for storage o Getting synaptic vesicles to release neurotransmitter at the appropriate time o Producing a response in postsynaptic cell o Removing neurotransmitter from synaptic cleft Ionotropic & metabotropic receptors • Neurotransmitter receptors can be divided into 2 groups according to the way receptor & effector functions are coupled. o Ionotropic (directly-gated) o Metabotropic (indirectly-gated)  2nd messenger

Ionotropic receptors • Significant synaptic delay of >0.3ms o Excitatory post synaptic potential (EPSP) o Inhibitory post synaptic potential (IPSP) Why use chemical synapses? • Can be excitatory or inhibitory • More flexible o Tend to produce more complex behaviors • Can undergo changes in effectiveness (plasticity) • Can provide amplification of signal o Allows small presynaptic cell to alter membrane potential of large postsynaptic cell. Neurotransmitters • Neurons use different neurocrines. o Vesicular storage (synaptic vesicles):  Neurotransmitter (small molecule)  Acetylcholine  Amines o e.g. dopamine, norepinephrine, serotonin  Amino acids o E.g. glutamate, GABA, glycine, histamine  Neuromodulator (neuroactive peptides)  e.g. opioids, vasopressin, oxytocin, tachykinins, somatostatins, prolactin, growth hormone, etc. o (gaseous neurotransmitters (CO, NO)) • But one neuron will only make one type of neurotransmitter (& possibly also a neuromodulator) Chemical synapses – an example • Neurotransmitter & neuromodulator can co-exist & be co-released by a neuron o For ex. Calcitonin gene-related protein (CGRP) is present in some spinal motor neurons along with acetylcholine  More in fast twitch than slow  Cranial & spinal motor nuclei o CGRP can increase muscle force by activating a 2nd messenger system. Neurotransmitters differ in their synthesis pathways. • neuroactive peptides - synthesized in soma & transported in synaptic vesicles, to synaptic terminal. • small molecule neurotransmitters - synthesized at synaptic terminal & transported into vesicles via a transporter pump.

Vesicular storage & release of neurotransmitter • after filling, vesicle are kept in a storage pool o synapsin • Vesicles can then be mobilized to readily releasable pool at synaptic terminal. o Docking & priming  SNARE complex (priming)  Voltage-gated Ca2+ channels (docking) • Two factors that are critical for neurotransmitter release 1. Presynaptic action potential (depolarization >45mV above Vrest) to open voltage-gated Ca2+ channels a. Voltage-gated Ca2+ channels remain open as long as depolarization >45mV continues (~ -20mV) – close upon repolarization. 2. Increase in intracellular Ca2+ in presynaptic terminal. Chemical synapses • Need mechanisms for: o Synthesizing neurotransmitter & packaging into synaptic vesicles for storage.  Getting synaptic vesicles to release neurotransmitter at the appropriate time. o Producing a response in postsynaptic cell. o Removing neurotransmitter from synaptic cleft. What causes Neurotransmitter Release? • Cd2+ prevents Ca2+ from flowing through open voltage-gated Ca2+ channels in the presynaptic terminal. o If Ca2+ entry is blocked, no transmitter is released. o Thus, Ca2+ is necessary for neurotransmitter release. SNARE complex – releasable pool • Synaptic vesicles docked next to voltage-gated Ca2+ channels o SNARE complex  SNARE = soluble NSF attachment receptor  NSF = N-ethylmaleimide sensitive fusion o Ca2+ catalyzes fusion (synaptotagmin) o Also mobilizes (synapsin) • Neurotransmitter released (exocytosis) Vesicle recycling & reuse • After vesicles have fused with membrane (for exocytosis), they can be reclaimed & refilled for reuse, or recycled back to soma (via retrograde axonal transport) for degradation. o Dynamin – important GTPase for endocytosis (retrieval of synaptic vesicle membrane) Amount of transmitter release • Release of neurotransmitter is graded. o Higher intensity (more action potentials/higher frequency)  more neurotransmitter released. Neuromuscular transmission • Motor end plate

o Motor neuron forms synaptic boutons o Active zone specialized for transmitter release  Acetylcholine (ACh) o ACh binding to nicotinic ACh receptors (nAChR) results in excitatory post-synaptic potential:  End-plate potential (EPP) – typically ~70mV  Triggers sarcolemmal action potential Postsynaptic response – ionic currents • End-plate potential (EPP) is produced by ionic current flowing through nicotinic ACh-gated receptors (IEPP) o Note: time course (release, open, capacitance, remove) • Membrane at end-plate can be voltage-clamped. • Thus it is possible to: o C o St ssion, o M . • Can also l ( ∆ Vm) resulting from current flow. • To determ urrent (IEPP), we can determine the reversal potential ge-clamp. o IE • EEPP = 0 m

EPSP Reversal Potential • One can determine reversal potential (EPSP) from either synaptic current (IPSP) or synaptic potential (Vm , PSP) Chemical Synapses • Need mechanisms for: o Synthesizing neurotransmitter & packaging into synaptic vesicles for storage. o Getting synaptic vesicles to release neurotransmitter at the appropriate time. o Producing a response in postsynaptic cell. o Removing neurotransmitter from synaptic cleft  degradation, reuptake.

Inactivation of Neurotransmitters • Limit action • Avoid desensitization 1. Neurotransmitters can be returned to axon terminals for reuse or transported into glial cells. 2. Enzymes inactivate neurotransmitters. 3. Neurotransmitters can diffuse out of synaptic cleft.

Life cycle of Acetylcholine 1. Acetylcholine (ACh) is made from choline and acetyl CoA. 2. In the synaptic cleft ACh is rapidly broken down by the enzyme acetylcholinesterase. 3. Choline is transported back into the axon terminal and is used to make more ACh. Events at Neuromuscular Junction • Action potential depolarizes synaptic terminal • Voltage0gated Ca2+ channels open. • Ca2+ enters synaptic terminal. • Synaptic vesicles fuse with plasma membrane. o Synaptic vesicle membrane recycled o Vesicles from storage pool mobilized • ACh released into synaptic cleft o ACh inactivated by AChE o Choline transported back into cell for reuse. • ACh binds to nAChR o ACh comes off receptor; can rebind to receptors until degraded by AChE • ACh-activated channels open allowing Na+ & K+ to flow • Muscle cell depolarizes • Voltage-gated channels open & action potential is triggered in muscle cell • Muscle contracts NMJ vs Central Synapses Neuromuscular junction • EPP is ~70 mV & typically elicits a sarcolemmal action potential. • Muscle fibers are innervated by only one motor neuron. • Excitatory (in vertebrates). • One neurotransmitter – acetylcholine (in vertebrates). Central synapses • EPSP/IPSP typically ~ 0.2–1 mV, so neurons must integrate many inputs to reach threshold. • Receive 100’s – 1000’s of inputs. • Can be both excitatory & inhibitory. • Many different neurotransmitters. Some Central Neurotransmitters Excitatory • Glutamate • Aspartate Inhibitory • GABA • Glycine

Both • • • •

Acetylcholine (ACh) Norepinephrine (NE) Serotonin (5-HT) Dopamine (DA)

Knee jerk (stretch) reflex as model system • Stretch of patellar tendon activates muscle sp

paths.

Knee Jerk Reflex Circuit • Activation of Ia sensory afferent in quadriceps results in: o Excitatory postsynaptic potential (EPSP) in agonist motor neuron & o Inhibitory postsynaptic potential (IPSP) in antagonistic motor neuron Central Synapses – Excitation • EPSPs (excitatory postsynaptic potentials) o Glutamate  Brain & spinal cord  E.g. Ia sensory neuron o Receptors  Ionotropic (AMPA, NMDA)  Metabotropic

smooth, coordinated movement

Glutamate Receptors • Most neurons, including somatic () motor neurons, have both NMDA & non-NMDA (AMPA) receptors. o For example, important in learning & memory, rhythmic behaviors. NMDA receptors • At Vrest channel is blocked by Mg2+. o Removal requires depolarization of ~ 20–30 mV. o Ca2+ activates Ca2+ dependent signaling molecules. Central Synapses – Inhibitory • IPSPs (inhibitory postsynaptic potential) o Glycine  Mostly in spinal cord  E.g. Ia inhibitory interneuron  Ionotropic, Clo GABA (-aminobutyric acid)  Mostly in brain  GABAA  9ionotropic, Cl-) & GABAB (metabotropic)



Synaptic Integration • Normal brain activity on. o Ionotropic & metabotropic receptors. • Summation of inputs at trigger zone determines whether or not an action potential occurs (& how many, frequency) & thus, how much neurotransmitter is released. o Passive properties ( & ). o Location & type of synapse. • For example, motor neurons receive ~ 50,000 – 80,000 synaptic inputs (both excitatory & inhibitory). o Typically always active at some level.  = level of muscle activity (muscle tone) • Central synapse PSPs are only ~ 0.2–1 mV. • A single Ia afferent produces a synaptic potential that’s only a fraction of a mV in a motor neuron. o Threshold is ~ 15 mV above Vrest o If afferent fires at higher frequency  temporal summation. • Central synapse receive 100s – 10,000s of inputs. • Motor neurons also receive inputs from many Ia afferents. o For example soleus muscle in cat has 100 muscle spindles, and each motor neuron receives input from most/all Ia afferents. o Spatial summation...