Intro to Neurotransmission - To View

8/4/2019 Intro to Neurotransmission - To View

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MD2020 Neuroscience

INTRODUCTION TO

NEUROTRANSMISSION

Anna Marie BabeyRm 226 BMTVS Bldg

Ph. 4781 6992

Email: [email protected]


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Neurotransmission

location communication = synapse

transmitting neuron =presynaptic neuron

recipient neuron =post-synaptic cell

gap between cells = synaptic cleft

drive for transmission = synaptic potential


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Neuron-to-Neuron Neurotransmission

3 types of synapses: axon onto dendrite axon onto axon axon onto cell body

single cell can synapse ontonumerous other cells

Source: Marieb & Hoehn

Source: Squire et al., Fundamental Neuroscience 2nd Ed


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Nature of Neurotransmission

direct physiological action e.g. NMJ = muscle activation, sympathetic synapse

at SA node increases HR

link in chain e.g. incoming sensory neuron in spinal cord, activates

ascending sensory pathways headed to thalamus,then connects to all points beyond

modulatory influence positive or negative influence on transmission of

another neuron


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Transmitting a Signal

saltatory conduction

incoming AP triggerssynaptic potential

driven by Ca+2

influxthrough voltage-gated Ca+2 channels

mobilises synapticvesiclestopresynapticmembrane

Source: Marieb & Hoehn


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Synaptic Vesicles

NT packaged into synaptic vesicles in preparation for release

release is quantal fixed number of vesicles released per fixedamount of Ca+2

Source: Squires, et al. Fundamentals of

Neuroscience. 2nd Ed


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Neurotransmitters

3 classes:

amines acetylcholine (ACh), noradrenaline (NA),

serotonin (5HT)

amino acids glutamate, -aminobutyric acid (GABA),

glycine, aspartate

peptides enkephalins, substance P, neuropeptide Y


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Neurotransmitters

classically synthesised in axon terminal &packaged into synaptic vesicles

rate-limiting step activity of an enzyme, substrateavailability, etc

BUTpeptide transmitters synthesised in cellbody & transported to axon terminal (*)

packaging demands presence of activetransport into vesicles

generally driven by pump such as proton (H+)

pump of ACh or NA terminals


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Synaptic Vesicles

Note: not allproteins associatedwith vesicles areshown


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Vesicle Mobilisation

in response to Ca+2, tethered vesicles aremobilised to presynaptic membranes

many proteins involved botulinumtoxins (e.g. Botox) = enzymes

targetting synaptic proteins, particularly AChsynapses

Zigmond, et al. Fundamentals ofNeuroscience. Academic Press. 1999


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Neurotransmitter Release vesicle membrane anchored to

presynaptic membrane to createrelease pore

NOTE: dont need to know thenames of the proteins, just thatthey anchor & create pore

NTs enter synaptic cleft &passively diffuse to post-synapticmembrane

estimated 200-500 vesicles perterminal

estimated 1014 to 1015

synapses per mammalianbrain

Source: Squires, et al., Fundamental Neuroscience. 2nd Ed


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Communication

post-synaptic cell receives NT signal via

ligand-selective protein interactions ligand-gated ion channels ( = ionotropic) e.g. nicotinic acetylcholine receptor

channels at NMJ

neurotransmitter receptors (= metabotropic) use second messenger-linked process

mediated by G proteins linked to eitherion channels or enzymes e.g. beta adrenergic receptors of SA

node


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Signal Termination

intent of neuronal activity =punctuatedresponse notongoing stimulation

therefore quick termination of signal = discreteevent

2 methods:

synaptic enzyme= destroy NT & stop signalling

e.g. acetylcholinesterase (AChE) breaks AChinto acetic acid + choline

rapid re-uptake(transport) into one or both ofpre-synaptic & post-synaptic cells

e.g. uptake 1 protein in NA


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Signal Termination

2 fates for NTs taken back up into pre-

synaptic terminals: recycling

NT re-packaged into synaptic vesicles,

decreasing de novosynthesis

enzymatic degradation

NT broken down into metabolites measurement of NT metabolites in CSF =

common way to estimate activity of NTpathways


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Synaptic Monitoring

pre-synaptic terminal requires way to monitorNT release

express autoreceptors(= eyes of synapse)

triggers feedback block of further NTrelease

keeps signalling discrete & punctuated most autoreceptors negatively coupled to

adenylate cyclase to decrease cAMP

production loss of cAMP closes Ca+2 channels to stop

vesicle mobilisation & release


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An Example synthesis driven by

cholineacetyltransferase

(CAT)

rate-limiting step of

ACh synthesis =uptake of cholineinto terminal bycholine carrier

signal termination byacetylcholinesterase(AChE)

Presynapticterminal(send)

Post-synaptic

terminal(receive)

ACh synthesis

ratelimitingstep

signal

termination

Autoreceptor


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Regulation of Receptor Responses

if NT available for more than punctuated,

short-term delivery, receptor activity alteredas reaction to on-going stimulation

desensitisation

reduction in response that NT elicits dueto loss of sensitivity of receptor

down-regulation reduction in response to NT based on lossof number of receptors


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Regulation of Receptor Responses

if certainNT in specificpathways availablefor more than punctuated, short-term

delivery orif antagonist is administered formore than short-term exposure, receptoractivity altered as reaction to on-goingstimulation

supersensitivity marked increase in response that NT

elicits due to loss of sensitivity of

receptor

up-regulation increase in response to NT based on

increased number of receptors


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Neuromodulation = fine-tuning (volume control) of signal

extremely diverse group NTs from adjacent synapse

metabolic products (e.g. adenosine, ATP, H+)

hormones (e.g. oestrogen)

gases (e.g. nitric oxide, carbon dioxide)

etc.


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Neuromodulation

some NTs released into extracellular fluid

instead of into synaptic cleft creates broad distribution of signal across brain

brain stem, cortex, thalamus, cerebellum,

spinal cord

causes synchronous activation of disparateregion to elicit markedly different responsefrom synaptic activity

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