Lec 10: fundamentals of NS (synaptic transmission between cells) Flashcards
name 2 types of synapses
electrical
chemical
by the end of 19th century, it was recognize that…..
transfer of info from one neuron to another occurs at specialized sites of contact
who discovered the synapse?
Charles Sherrington 1897
electrical synapse was proven by who???
Furshpan and Potter in crayfish in 1959
describe the discovery of the chemical synapse
- solid evidence given by Ottow Loewi (1921)
- Katz demonstrated fast transmission at NMJ chemically mediated
- Eccles studied synaptic transmission in the mammalian CNS using glass microelectrode (1951)
- last decade: new methods of studying molecules revealed that synapses are far more complex
describe the experiment that Otto Leowi perfomed
using frogs
- found vagusstoffll
- turned out to be ACh
- showing synaptic signalling using chemical messengers
- removed fluid from donor heart (close to vagus nerve), transplant fluid into recipient heart
- when removing fluid and stim the vagus nerve= slow HR
- bathe the recipient heart= slow HR
what is a synapse?
specialized junction where one part of a neuron contacts and communicates with another neuron or cell type
which direction does info flow in a synapse?
- neuron to target cell
- presynaptic–> postsynaptic
describe the structure of electrical synapses
6 connexins form channel= connexon
2 connexons (one from each cell) for gap junction channel
- pore of channels is large (1-2nm), all major cellular ions and small molecules pass directly from cytoplasm of one cell to another
what are the functional properties of electrical synapses?
- ions/small molecules equally pass in both direction
- cells are electrically coupled (facilitated by gap junctions)
- very fast, and if large synapse then fail-safe. AP in presynaptic neuron can produce (almost instantaneously) an AP in postsynaptic neuron
in invertebrate species (e.g. crayfish), electrical synapses are sometimes found between ____ and ___ neurons in neural pathways mediating ___ ___
sensory & motor neurons
mediating escape reflexes
how is a postsynaptic potential (PSP) generated?
in electrical synapses
- AP in presynaptic neuron can cause small amount of ionic current to flow across gap junction channels to other neuron
- generated by single electrical synapse
what are the 2 main components of electrical synapses?
1) gap junction coupling the dendrites of 2 neurons constitutes an electrical synapse
2) AP generated in one neuron causes a small amount of ionic current to flow through gap junction channels into 2nd neuron, inducing PSP
what is a synaptic cleft composed of
20-50nm wide
- filled with matrix of fibrous extracellular protein
what is the function of a synaptic cleft?
make the pre and post synaptic membranes adhere to each other (want proximal position)
what is a synaptic bouton?
axon terminal
what are synaptic vesicles?
50nm in diameter
- store NT used to communicate with postsynaptic neuron
what are secretory granules?
- larger vesicles, 100nm diameter
- contain soluble protein
- dark extracellular matrix
- large dense-core vesicles
what are membrane differentiation’s?
accumulations of proteins on either side of the synaptic cleft
what are active zones?
presynaptic site of NT release
**what is postsynaptic density?
contains receptors to translate intercellular signal (NT) to intracelular signal (chemical change/mem potential chagne)
inter–> intracellular signal
name 2 ways that synapses can be categorized by;
connectivity
synapse anatomy
describe how synapses can be categorized based on connectivity
which part of neuron is postsynaptic to the axon terminal
describe how synapses can be categorized based on synapse anatomy
size and shape
appearance of the pre and post synaptic membrane differentiations
main difference between Grays Type I and Type II synapses
type I= asymmetrical
- postsynaptic membrane is thick with appendages
type II= symmetrical
name the 4 types of CNS synapses
axodendritic (axon-dendrite)
axosomatic (axon-cell body)
axoaxonic (axon-axon)
dendrodendritic (dendrite-dendrite)
larger synapses have more/less active zones??
MORE
- adds to plasticity
inc active zone= inc/dec in cell survival?
INCREASE
is grays type 1 synapse usually excitatory/inhibitory?
excitatory
asymmetrical
is grays type 2 synapse usually excitatory/inhibitory?
inhibitory
symmetrical
what are NMJ?
– where?
neuromuscular junction
- occur between axons of motor neurons of spinal cord and skeletal muscle
neuromuscular synaptic transmission is ___ & ____
fast & reliable
T/F an AP in the motor axon always causes an AP in the muscle cell it innervates?
TRUE
what is the name of a terminal button of a motor neuron that makes contact with a muscle cell?
motor end plate
motor end plate releases NT _____ that causes…..
ACh
- causes muscle cell to contract
- direct contact
what are the 5 requirements of chemical synaptic transmission?
1) mechanism for synthesizing and packing NT in vesicles
2) mechanism for causing vesicle to release contents into synaptic cleft in response to presynaptic AP
3) mechanism for producing an electrical/biochemical response to NT in postsynaptic neuron
4) mechanism for removing transmitter from synaptic cleft
5) must occur very rapidly (to be useful for sensation/perception/control movement)
what happens to the firing of AP if there is excess accumulation of NT
- AP will not fire
- always be in recovery phase
what is a NT?
- chemical messenger
- traverse synaptic gaps between neurons when released by sending neuron
- travel across synapse bind to receptor sites on receiving neuron
- influence whether it will generate neural impulse
what are the 3 chemical categories of NT?
amino acids
amines
peptides
what are amino acids?
small organic molecules
NT
name 3 examples of amino acids
glutamate
GABA
glycine
where are amino acids stored?
synaptic vesicles
what are amines?
small organic molecules
NT
name 4 common amine examples
ACh
DA
histamine
5-HT
where are amines stored?
synaptic vesicles
what are peptides?
short amino acid chains (proteins)
(NT)
- larger molecules
name 2 common peptides
dynorphin
enkephalins
where are peptides stored?
secretory granules
T/F NT different classes of NT often co-exist in the same axon terminals?
TRUE
- amine + peptide
- amino acid + peptide
fast transmission uses which 2 types of NT?
amino acids or Ach(amine)
T/F slow transmission only uses peptides?
FALSE
- may use any of the 3 types of NT
describe the synthesis of AA and amines
enzymes are transported to the axon terminal and convert precursor molecules into NT molecules in the cytosol
describe the storage of AA and amines
transporter proteins load the NT into synaptic vesicles in the terminal where they are stored
describe the synthesis of peptides
- synthesis of precursor peptide (long peptide) in rough ER in cell body
- split in Golgi apparatus to yield the active one
- secretory vesicles with peptide bud off from the Golgi apparatus
- secretory granules are transported (axoplasmic) down the axon to the terminal where the peptide is stored
what are transporters?
proteins in vesicle membrane
take up and concentrate the amino acid and amine NT inside the vesicle
what makes the synthesis of Peptides different than AA/amines?
requires Golgi apparatus
during the synthesis of amine/AA, the precursor molecule is active/inactive then the NT molecule is active/inactive when stored in vesicles?
precursor= inactive
NT= active
describe the 4 steps to NT release
1) AP enters the axon terminal (terminal membrane depolarization)
2) voltage-gated Ca channels open (Ca activates proteins in vesicle and active zone)
3) activated SNARE protein complex guide synaptic vesicles to dock and fuse with presynaptic membrane active zone (NT release by exocytosis)
4) vesicle membrane recovered by endocytosis (recycled vesicle refilled with NT)
what is the important function of SNARE proteins?
docking
fusion of vesicles to synaptic membrane
what are exocytotic fusion pores?
where synaptic vesicles have fused with the presynaptic membrane and released their contents
what is a SNARE?
SNAP Receptor
what is a SNAP?
Soluble NSF attach protein
what are 2 types of SNAREs involved in binding?
v-SNARE (vesicle)
t-SNARE (Target)
describe the sequence of events of vesicle fusion
- v-SNARE on vesicle, and t-snare on membrane will grasp each other, and protein folding to form lock to keep vesicle in close proximity to membrane
- influx of Ca, facilitate interaction with SNAREs (requires energy, Ca recruit ATP)
- synaptobrevin & syntaxin act as adhesion molecule to facilitate association of vesicle with membrane
what is SNAP25??
t-snare complex
- associated with autism disorder
what is synaptobrevin?
adhesion protein on vesicle
what is syntaxin?
adhesion protein on membrane
secretory granules also release peptide NT by endocytosis/exocytosis?
exocytosis
how do secretory granules release peptide NT by exocytosis?
- Ca-dependent fashion
- not at active zones
- require high-frequency trains of AP and more Ca influx
- slower (50msec vs .2msec)
- also acts as gating mechanism
binding of a NT to specific rec protein in postsynaptic memrbane causes???
conformational change
- change in structure=change in function
2 classifications of NT receptors
transmitter-(ligand-)gated ion channels
G-protein coupled receptors
what are transmitter-(ligand-)gated ion channels
- # of subunits to form port?
- what type of receptor?
- membrane-spanning proteins
- 4-5 subunits to form pore with ligand binding domain
- ionotrophic receptor
describe how ligand-gated ion channels work?
- closed –> open
- NT binds to specific sites
- induce conformational change
describe what happens when different ions pass through ligand-gated ion channels
- Na and K = are excitatory, depolarization
Cl= inhibitory, hyperpolarizaiton
T/F activation of ligand-gated ion channels is slow and medicated by amino acids and amines
FALSE
- activation=rapid
name 2 excitatory NTs, and occurs to post-synaptic potential?
- ACh or glutamate gated channels
- permeable to Na
- depolarization
- excitatory
- excitatory postsynaptic potential (EPSP)
name 2 inhibitory NTs, and occurs to post-synaptic potential?
- Glycine, GABA
- permeable to Cl
- hyperpolarization
- inhibitory
- inhibitory postsynaptic potential (IPSP)
fast chemical synaptic transmission is mediated by what groups of NT?
amine and AA
structure of GPCR?
receptor protein with ligand binding domain and connected to G-protein consisting of an alpha, beta and gamma subunit
3 steps to GPCR action
1) transmitter (ligand) binds to receptor in postsynaptic membrane
2) receptor activated G-proteins, which dissociate and become free to move along the intracellular face of postsynaptic membrane
3) activated G-protein alpha unit activated ‘effector’ proteins
what are effector proteins?
- G-protein-gated ion channels in membrane
- enzymes that synthesize 2nd messengers
what is a role of 2nd messengers?
can activate additional enzymes in the cytosol that can regulate ion channel function and alter cellular metabolism
what type of receptor is GPCR?
metabotrophic
= synthesis of new receptors
describe effector proteins in relation to g-protein-gated ion channels in membrane
- binding of rec
- result in activation of G protein
- which activates the G-protein gated-ion channel
describe effector proteins working with 2nd messengers
- rec cascade from outside to inside of cell that results in communication with nucleus, changes in chromatin, histone modification, expression of other receptors (etc.)
describe the function of ACh receptor in heart vs skeletal muscle
HEART: metabotrophic ACh receptor is coupled be a G-protein to a K channel.
- bind to muscarinic rec
- slows rhythmic contraction
- cause slow hyperpolarization of cardic muscle cells
SKELETAL MUSCLE: receptor is ACh-gated ion channel
- permeable to Na
- ACh induces contraction by causing rapid depolarization of muscle fibers
- activation of gamma/beta unit, K channels open
where are NT receptors found?
membrane of presynaptic axon terminal
what are auto-receptors?
- sensitive to NT
- GPCRs
activation of autoreceptors leads to ….
inhibition of NT release
- may act as brake on release of NT
what does autoreceptor do to the presynaptic terminal?
allows it to self-regulate
what has to occur before another round of synaptic transmission can happen?
NT in synaptic cleft must be cleared
what type of diffusion does AA and amine NT undergo?
simple diffusion
explain reuptake of NT
- by action of specific transporter proteins in the presynaptic memrbane
- once inside cytosol, enzymatically destroyed or reloaded into synaptic vesicles
- NT transporters exist in membranes of glia surrounding synapse, which assist in removal
where does enzymatic destruction (hydrolysis) occur?
in synaptic cleft
- hydrolysis= splitting of H bonds
explain enzymatic destruction
ACh is removed at NMJ by enzyme acetylcholinesterase deposited in the cleft
what is the importance of NT removal?
desensitization
- nerve agents, insecticides
what is neuropharmacology?
study of effects of drugs on the NS
what are receptor agonists?
mimic/facilitate actions of NT
name 2 examples of receptor agonists
- Nicotine activated nicotinic ACh rec in skeletal muscle and CNS (cause muscle relaxation)
- morphine activated mu-opiate rec in brain
what are 2 types of receptor inhibitors?
- nerve agents
- receptor antagonists
what are nerve agents
inhibit the enzyme AChE (
what are rec antagonists?
oppose/block actions of NT
what is an example of a rec antagonist?
curare
- arrow-tip poison
- bind tightly to ACh rec
- block aciton of ACH at NMJ
- result in inhibition of function (paralysis)
describe effects of venom from female black widow spider
- affects ACH neurotransmission
- affects sympathetic neurotransmission
- act presynaptically to releaseACh, NE and GABA from sensory motor neurons and endocrine cells
- prevents relaxation of muscle, cause tetany (constant, strong painful muscle contractions) and rigidity
name 3 ways that drugs impact the brain
- alter amount of NT released at synapses
- mimic/facilitate action of NT
- block action of NT
effect of nicotine on brain
- stimulated reward center to release DA, promote feelings of euphoria
- mimic actions of ACh= inc HR and BP
effect of marijuana on brain
- THC interferes with synapses (incl reward centers)
- produces euphoria
- reduces concentration and muscle coordination
effect of ecstasy (MDMA)
- cause overproduction of 5-HT
- short-term feelings of pleasure
- cause cardiac arrest, inc body temp, rapid and permanent brain damage
effect of cocain
- target neurons in reward center
- prevent reuptake of Da
- inc energy levels, euphoria
- addictive, heart attacks
effect of methamphetamine
- pass directly through membranes of neuron
- inc release of DA, blocks Da transporter from pump DA back into transmitting neuron
- inc energy levels, euphira
- aggressiveness, delusions, psychosis
EPSP–> AP depends on…
- name the 4 principles of synaptic integration
1) integration of EPSP
2) contribution of dendritic properties
3) inhibition
4) modulation
the postsynaptic neuron integrates 1000s of synaptic ____ (ionic/chemical signals) and give rise to simple form of ___ = AP
inputs
outputs
transformation of EPSP–> AP constitutes a ____ ____
neural computation
what is synaptic integration?
process by which multiple synaptic potentials combine within one postsynaptic neuron
what do we see with patch-clamp recording from transmitter-gated ion channel
look at channel opening within the membrane wall
- permit measurement of ion movements through single channels
- use pipette, suck bit of membrane, include ion channel in clamp
- ionic current passes through channels when channels are open
- in presence of NT, they rapidly alternate between open and close
name the 3 components of synaptic integration
1) AP triggers small EPSP in postsynaptic neuron
2) spatial summation
3) temporal summation
what is spatial summation
when 2+ presynaptic inputs are active at the same time
individual EPSPs add together
what is temporal summation
when the same presynaptic fiber fires APs in quick succession
individual EPSPs add together
describe the contribution of dendritic properties to synaptic integration
- current of synaptic contact must spread down dendrite and the soma
- and cause membrane of the spike-initiation zone to be depolarized beyond threshold, before AP can be generated
the effectiveness of excitatory synapse in triggering AP depends on….
how far the synapse is from the spike-initiation zone
&
on the properties of the dendritic membrane
the amount of depolarization decreases exponentially with inc/dec distance
inc distance = less depolarization
EPSP–> AP output depends on (4)
1) # of coactive excitatory synapses
2) distance the synapse is from spike-initiation zone
3) properties of dendritic membrane
4) inhibitory synapses
function of inhibitory synapse in EPSP–> AP output
take the membrane potential away from the AP threshold
exert powerful control over neuron output
what is shunting inhibition?
inhibiting current flow from soma to axon hillock
- inward movement of Cl anions, negate the outward flow of pos ions
- inhibiting current flow from soma to axon hillock
when are IPSPs generated? (during shunting inhibition)
when ion channels are opened causing hyperpolarization of membrane (mem potential more than -65mV)
where are the grays type 1/excitatory synapses found
spines
where are the grays type 2/inhibitory synapses found?
clustered on soma and near axon hillock
describe modulation of synapses
many synapses with GPCR do not direcly evoke EPSP/IPSO but modifies the effectiveness of EPSP generated by other synapses= modulation
what is an example of modulation
norepinephrine-B receptor
- binding of NE to rec triggers cascade of biochemical events within the cell to produce the 2nd messenger cAMP
describe the 5 steps in modulaton by NE rec
1) binding of NE to rec activates G-protein in the membrane
2) G-protein activates the enzyme adenylyl cyclase
3) adenylyl cyclase converts ATP into cAMP
4) cAMP activates protein kinase
5) protein kinase causes K channel to close, by attaching P group to it
what is optogenetics?
switch on and off light-sensitive neurons
- combines genetic recombination and optics to control neurons within body
what are the 4 parameters for conducting an optogenetic experiment?
- construct with 4 variable components
- light activated ion channel expressed in specific sub-population of neurons
- illumunate neurons to modulate activity
- modulation depends on type of channel
name the 4 variable components to construct within an optogenetics experiment
1) viral vector
2) promoter gene
3) opsin gene
4) reporter gene
describe light-induced CO2 avoidance behaviour
- try and escape out of red area
- change behaviour in concordance with escape response
- place rec in cell and cause over-excitation
describe feeding behaviours with optogenetics experiment
- photoactivation of inhibitory VgatBNST–> LH circuit
- stimulates feeding behaviour (inc energy dense food)
behavioural deficits in psychiatric diseases hypothesized to arise from elevations in ….
cellular balance of excitation and inhibition (E/I balance) within neural microcircuitry
describe social interaction with optogenetics experiment
mouse injected with CaMKII’-SSFO virus in medial prefrontal cortex and is placed with novel male juvenile
- social interaction regulated by dis-balance between excitation and inhibition
- absence of light activation= social animal
- with nerve impulses= heightened anti-social behaviour
