Unit 2 Notes Flashcards
movement at synapse
- ) voltage gated calcium channels open at synapse in response to depolarization caused by action potential
- ) calcium enters enters presynaptic neuron and binds to motor proteins which are on synaptic vesicles
- ) vesicles merge with presynaptic membrane
- ) insides released in synaptic cleft
- ) neurotransmitters bind to receptors on postsynaptic membrane
what makes AP start
- ) begin with receptor potential- graded (have to have high enough to open enough Na+ channels)
- ) greater graded potential, open more Na+ channels, depolarizes cell
- ) depolarize enough to hit threshold -> increase in Na+ conductance -> inward current of Na+
- ) conductance K+ also increases -> K+ outward to repolarize cell
voltage clamp experiments
-permits us to set membrane potential of cell almost instantaneously to any level and hold it there while recording current flow across membrane
capacitive current
- initial brief surge of current
- occurs b/c step from one potential to another alters charge in membrane capacitance
- due to membrane properties
early inward current
- due to Na+ inward current
- depolarize cell
leak current
-small K+ and Cl- outward current
why does current flip direction at +65 mV
- beyond 62 (Na+ equilibrium)
- with greater depolarization, Na+ inward current becomes smaller and then reverses to outward current
Na+ channels
- open quickly, so have inward current
- rises rapidly, but decreases to zero
K+ channels
- open slowly relative to Na+ channels
- outward current
- once developed, remains high
absolute refractory period
- no action potential is possible even with applied extracellular depolarization
- due to Na+ channels having an inactivation gate on them
relative refractory period
- can still get another AP, but would require a stronger stimulus
- due to K+ channels still open (slow to close)
- K+ conductance high (too high for Na+ to override)
- threshold returns to normal, K+ channels close, Na+ inactivation removed
Hodgkin and Hukley findings
Depolariztion of membrane leads to…
- ) activation of sodium conductance mechanism
- ) subsequent inactivation of that mechanism
- ) delayed activation of K+ conductance mechanism
inactivation
- decline to zero of Na+ current after it rises quickly
- occurs b/c the potential is greater than the equilibrium potential of Na+ (65 mV)
- occurs even if the cell is still depolarizing
potassium leaves cell
- ) depolarization decreased
- ) Na+ conductance decreases
- ) Na+ current decreases
- ) excess outward current causes repolarization
2 reasons nerve fiber can’t produce second AP immediately
- ) absolute refractory period- Na+ channel inactivation
2. ) relative refractory period- K+ channels slowly closing
CNS neuron
- brief spikes w/ high frequency
- activate and deactivate rapidly
- rapid repolarization
- rapid removal Na+ channel inactivation
- more AP/given time
gating currents
- generated by movement of charges in transmembrane helicies of ion channel
- helicies move in response to change in membrane voltage, opening or closing gate
ball-and-chain model
- responsible for inactivation of voltage activated Na+ channel
- ball = clump of AA on cytoplasmic side (Mg2+)
- chain = AA residues
- depolarize -> ball binds to site inside channel and blocks pore b/c positive charge of pall pushed out of inside and up channel when repelled by positive charge accumulated from depolarization
channelopathies
- channel being formed badly
- startle disease
- epilepsy, seizures- damage to K+ channels
- cell fires when not supposed to
gate closed
positive charge in pore is attracted to cytosol
depolarize cell and gate
more positive inside results in the positive charges of pore moving up and gate opening
importance of calcium
- keeps cell from being too excitable
- acts like a charge buffer on outside of membrane between + and - charges
- low Ca2+ environment- no charge buffer and membrane is more excitable (cells fire more readily)
lack of Ca2+
no buffer -> increase excitability of membrane (not good)
afterhyperpolarizaing potentials
- right after AP
- occurs b/c delayed rectifier channels continue to open for period that outlasts AP
- results in increasing K+ conductance, which drives membrane toward K+ equilibrium potential
Calcium-activated potassium channels
- Ca enters with Na
- leads to K channels opening
- brings the excitability of the cell down- diminishes response
- habituation
- cell essentially calms down
why doesn’t AP degrade
- signal refreshed along conduction
- axon is excitable along length
myelinated cell
- facilitate current flow
- Nodes of Ranvier in between myelin
- lots of Na+ channels accumulated at nodes
spike initiation zone
- sensory nerve endings
- axon hillock
- spike initiation more likely at sites where there is a high density of voltage-gated sodium channels
distribution of sodium channels
-piled up densely at nodes of Ranvier and sensory nerve endings
orthodromic
- AP travels in one direction
- typically from soma to terminal
antidromic
- backward propagation
- usually experimentally driven
typical conduction velocity
10 m/s
length of AP
2 milliseconds
what determines spread of AP along membrane
axon structure
axon excitability
- depends on diameter (bigger -> faster)
- depends on # voltage-gated channels
habituation
adaptation so don’t respond vigorously every time
electrotonic potentials
as you increase distance from current passing electrode in nerve fiber, the potential become smaller and slower
*decay of response with distance is exponential
membrane resistance low relative to cytoplasm
current leaks outward through membrane before it can spread far
high resistance membrane
- allow significant portion of current to spread laterally before escaping to the external solution
- depends on surface area of fiber
length constant properties
- increases with membrane resistance
- decreases with internal longitudinal resistance
length constant
distance that a electric potential will travel along neuron via passive conduction
fiber diameter increase
- internal resistance decreases more rapidly than membrane resistance
- results in more membrane resistance than internal
- further conduction
why is potential rise slower at points more distant to electrode
internal longitudinal resistance reduces current flowing
what influences rate of AP propagation
- ) space constant- want large
2. ) time constant- want small
small time constant
membrane will depolarize to threshold quickly and conduction velocity will be high
saltatory conduction
- ions cannot flow easily in or out of high-resistance myelin, so AP “jumps” from one node of Ranvier to the next
- increases conduction velocity
electrically coupled
-special intercellular structures allow processes of one neuron to be in electrical continuity with the next (allow current flow between them)
cardiac, smooth muscle, epithelial, gland cells, and neurons
gap junction
- electrical synapse
- low resistance connection that allows transfer of electrical signals from one cell to the next
- collection of connexons
- fast link between pre and post synaptic cell
connexon
proteins that form aqueous channels between cytoplasms of adjacent cells
oligodendroglia
-myelinate in CNS
extrastriate area
- region of occipital cortex that is sensitive to motion and perception
- integration
- more complex receptive fields
- neural connections diverge
- motion, color, and form
myelogenesis
glial cell development
when are axons fully myelinated
- about age 25
- athletes peak in mid 20s
plasticity
-neural connections and networks change
higher peak
- action potential big
- fiber myelinated
synaptic transmission
- how cells communicate with one another
1. ) direct
2. ) indirect
direct communication
- ) chemical synapse (ionotropic)
2. ) electrical synapse
indirect communication
- via chemical receptor changes cell behavior, but not in regards to resting membrane potential
- g-protein coupled receptor (metabotropic)
electrical synapse (gap junction)
- incredibly fast transmission
- no lag
- presynaptic has full AP
- post synaptic has a much smaller AP- indicates that not a ton of ions actually go thru
chemical synaptic transmission
-secretion of specific chemical by a nerve terminal and its interaction with specific postsynaptic receptors
bouton
- nerve terminal swelling
- pre-synaptic membrane has electron dense regions with clusters of synaptic vesicles
- lots of mitochondria for ATP
excitatory post synaptic potential (EPSP)
synaptic potential that excites a post synaptic cell
inhibitory post synaptic potential (IPSP)
synaptic potential that inhibits a post synaptic cell
curare
block postsynaptic receptors, reducing end plate potential amplitude below threshold
ionophoresis
method of ejecting charged molecules, such as ACh, from pipettes
ACh and permeability
- ACh produces a nonspecific increase in permeability of the postsynaptic membrane to small ions (Na+, Ca2+, and K+)
- does not increase Cl- permeability
- general increase in cation permeability
reversal potential
- membrane potential at which a neurotransmitter causes no net current flow of ions through that neurotransmitters receptor channel
- aka- equilibrium potential
differences between CNS synapses and neuromuscular junction
- ) principal excitatory transmitter is L-glutamate (not ACh)
- ) there are 2 glutamate ionotropic receptors (AMPA and NMDA)- neither structurally homologous to nicotine receptor
AMPA
- glutamate receptor in CNS
- similar permeability and function as nicotine receptor in neuromuscular junction
- mediates fast excitatory transmission throughout CNS
NMDA
- glutamate receptor of CNS
- blocked by Mg2+ at normal RMP
- not involved in fast signaling b/c of Mg2+
- gate slowly
- higher permeability to Ca2+
Mg2+ binding to NMDA channel
- binds extracellularly
- even if activated, current can’t flow until cell depolarized towards zero
- bound tightly b/c attracted to negative RMP
- binding loosens as cell depolarizes
NMJ inhibition
-increasing anion permeability
NMJ excitation
-increasing cation permeability
reciprocal inhibition
- due to way circuits are built
- when extensor firing, flexor is not
- inhibitory interneurons go to excitatory interneuron of one that should not be firing
interneuron
- neuron that forms connection between other neurons
- Ex: neuron from toe to spine -> interneuron in spine -> neuron to brain
presynaptic inhibition
- preventing EPSP from happening in first place
- or modulating transmitter release
- much more specific than post-synaptic inhibition
- often targets one input
- before synapse excitatory input shut down
- timing is everything
post synaptic inhibition
- basically shutting cell down
- preventing from fire
why delay in excitation
-neurotransmitter has to drift across synapse
post synaptic receptors and inhibition
-receptors on postsynaptic respond to GABA binding by opening Cl- binding
glycine without chloride extracellularly
- Cl- efflux
- no change in membrane potential or input resistance upon glycine binding to inhibitory channel
- no ions besides Cl- pass through inhibitory channels
inhibitory response key
-involves increase in Cl- permeability, so reversal potential for inhibitory current is equal to chloride equilibrium (-62 mV)
what binds and activates chloride channel
- GABA
- glycine
maximum presynaptic inhibitory effect
- impulse must arrive in inhibitory presynaptic terminal before action potential arrives in excitatory terminal
- timing is everything
autoinhibition
- glutamate and GABA spill over from synaptic cleft, back onto presynaptic terminals
- activates metabotropic (g protein) receptors
metabotropic receptors presynaptic terminal
- suppress calcium entry into the terminals
- reduce neurotransmitter release b/c no Ca2+ to bind to motor proteins carrying vesicles
- slower than presynaptic inhibition through ionotropic receptors, but lasts longer
delayed timing of presynaptic metabotropic receptors
-due to time takes for receptor to activate a g protein and inhibit Ca2+ channels
dystrophin glycoprotein complex
- links together the myofiber cytoskeleton, membrane, and ECM
- provides structural support for muscle cell
- plays a key role in AChR localization
rapsyn
- AChR-associated proteins
- key role in linking MuSK and AChRs to cytoskeleton
localizing ACh receptors
- plasticity- developing motor circuits
- how motor neurons make synapses with muscle tissue
- motor neuron releases agrin
- agrin affiliates with MuSK receptor post-synaptically
- MuSK interacts with other proteins in postsynaptic cell
- proteins aggregate cholernergic receptors
remembering
- changing circuits
- plasticity
long-term potentiation (LTP)
-change to synapse that makes cell more likely to fire (plasticity)
-associated with insertion of AMPA receptors at synapses
-change due to having more receptors in place
synapse strengthened
long-term depression (LTD)
- leads to forgetting
- connections are plastic
forgetting at cellular level
- LTD
- AMPA receptors retract
- synapse loses strength
what makes neuromuscular junctions
- agrin
- cholernergic receptors
where are electrical synapses
- ) reflex pathways where fast response is necessary
2. ) where electrical transmission assists in coordinating or amplifying activity of other neurons
crayfish escape reflex
- electrical synapse between pre and post synaptic neurons
* rectified- not bidirectional
rectify
- electrical coupling across electrical synapse goes in one direction only
- pre -> post synaptic cell
- not common of most electrical synapses, but present in crayfish
coupling ratio
- degree of electrical coupling between cells
- Ex: 1:4 means 1/4 presynaptic voltage appears on post synaptic cell
strong coupling
- resistance of junction between cells must be low
- must have reasonable match between sizes of pre and post elements
chemical and electrical synapses together
- chemical presynaptic potential is preceded by electrical presynaptic potential
- occurs widely in vertebrates
electrical synaptic transmission advantage
- ) absence of synaptic delay
- ) more reliable
- ) less likely to fail due to synaptic depression or toxins blocking
- ) intracellular transfer of Ca2+, ATP, and cAMP
blend of neurotransmitter
- each neuron has own specific blend
- cotransmitters
- typically dominated by a certain nt
how to identify neurotransmitter
- ) synthesized and stored by cell
- ) released
- ) produces effect in target cell
- ) removed from cleft
identify serotonergic structure
- identify serotonin synthesizing enzymes
- identify synaptic vesicle transporters
- identify reuptake transporters
- don’t find degradative NZs
- look at slide for rest
methods of localizing neurotransmitter systems
- ) immunocytochemistry
- ) in situ hybridization
- ) microionophoresis
immunocytochemistry
-using fluorescently labeled secondary antibodies to identify neurotransmitter and structures
in situ hybridization
- uses labeled complementary DNA strand to localize specific sequences
- bright areas show mRNA for particular neurotransmitter
microionophresis
- using micropipette to push out positively charged current
- looking at synaptic function
- is synapse using chemical you think it is
ACh release
- little released at rest (continuously synthesized)
- bunch released at stimulation
- can act on both ionotropic and metabotropic receptors
blocked cholenergic reuptake
- blocks choline from re-entering cell
- release of ACh drops significantly
- supports that choline is necessary for ACh to by synthesized
ACh synthesis
- made from acetyl CoA and choline
- acetyl CoA and choline brought together by choline acetyltransferase
- ACh transporter puts into vesicle with ATP
- vesicle releases ACh in cleft
- AChE breaks excess ACh into acetate and choline
- choline brought back into cell (acetic acid diffuses away)
classical low molecular weight neurotransmitters
-produced within axon terminal from cellular metabolites and are incorporated into small synaptic vesicles for storage and release
Ex: ACh and NE
neuropeptide transmitters
- synthesized in cell body
- packaged in large dense-core vesicles, and shipped down axon
- slow process
reducing ACh cytoplasmic concentration
- sequester ACh into vesicles
* balance between synthesis and vesicular uptake is critical
feedback inhibition
- rate-limiting step in a biosynthetic pathway is inhibited by the final product
- Ex: norepinephrine
catecholamines
- dopamine
- norepinephrine
- epinephrine
- no fast NZ to degrade in cleft- typically take back up
cocaine and NE
- blocks mechanism that brings NE back into cell
- NE in cleft longer -> drives pleasure response
NE, dopamine, and epinephrine accumulation
- all 3 inhibit tyrosine hydroxylase
- inhibition doesn’t occur until steady state is reached- rate of synthesis is equal to rate of degradation and release
tetrahydrobiopterin
- necessary cofactor for tryptophan hydroxylase in serotonin synthesis
- necessary cofactor for tyrosine hydroxylase in NE synthesis
tryptophan
- found in meats, grain, and dairy
- neurons can’t synthesize, so must be transported from blood into CSF
Factors influencing serotonin abundance
- ) amount of tryptophan in blood
2. ) amount of available tetrahydrobiopterin
pyridoxal phosphate
-cofactor necessary for GABA synthesis
glutamate synthesis
- major excitatory neruotransmitter in brain
- synthesized from glutamine in releasing neurons
- after release some taken up in presynaptic cell, most taken up by glial cells
- glial cells convert to glutamine and release at nerve terminals
- nerve cell converts glutamine to glutamate
amino acidergic neurotransmitters
- GABA
- glutamate
- glycine
solute carrier transporters (SLC)
- mediate accumulation of transmitters in synaptic vesicles
- some transport more than one nt (b/c not enough different kinds for all nts)
- poor substrate specificity
axonal transport
-movement of mitochondria, synaptic vesicles, lipids, and proteins along axon from neuron cell body to axon terminal
anterograde
-soma to terminal
retrograde
- terminal to soma
- used for recycling or degradation of membrane-enclosed organelles in cell body
- crucial for movement of nerve growth factor from axon to cell body
tracers
- used to map synaptic connections by visualizing axons and cell bodies
- fluorescently labeled structures are observed during axonal transport
kinesin
- accessory factor
- powers anterograde transport along microtubule tract (toward terminal)
dynein
- accessory factor
- powers retrograde transport along microtubule tract (toward soma)
how is direction of organelle movement regulated
-specific receptors for either kinesin or dynein on surface of organelles
mechanisms for transmitter removal from synaptic cleft
- ) diffusion
- ) degradation
- ) uptake into glial cells or nerve terminals
* prompt removal is crucial for normal synaptic function
direct excitatory neurotransmitter in CNS
glutamate
direct inhibitory nts in CNS
GABA and glycine
indirect transmitters
- ACh
- neuropeptides
- monoamines
- ATP
- all act on G protein-coupled receptors (ACh and ATP also act on ionotrophic)
glutamate
- excitatory transmitter of CNS
- activates both AMPA and NMDA receptors
GABA and glycine receptors
-homologous to ACh receptors, but permeable to Cl- instead of cations
site of ACh release cholinergic receptors CNS
- major difference between CNS and PNS cholinergic systems
- release at varicosities (swellings) along axon that don’t make contact with post synaptic neuron
- still fast
volume transmission
-neurotransmitter is released distal to receptors (variscosities) and must diffuse to receptor
-behave more like hormones
Ex: ACh in cortex
Alzheimer’s disease
-degeneration of the basal forebrain cholinergic neurons and of their cortical and hippocampal terminals
biogenic amines
- NE, histamine, dopamine, serotonin
- influence attention, sleep, arousal, and mood
- volume transmission out of unmyelinated axons
- activate G-protein coupled receptors
locus coeruleus
- part of pons where noradreneric neurons are concentrated
- Ex: norepinephrine big player
raphe nuclei
- concentration of serotonergic neurons in brain stem
- regulate sleep wake cycle and food intake
dopamine
- intermediate in NE pathway unless neuron lacks dopamine hydrozylase
- role in pleasure and reward
dopaminergic neurons
- concentrated in brain stem- substantia niagra
- concentrated in ventral tegmental area- goes to frontal lobe (pleasure)
- control prolactin secretion
cocaine
- inhibits dopamine transporter and increases dopamine levels (feels good)
- nicotine also increases levels, but by different mechanism
histamine
- anti-inflammatory and causes drowsiness
- histamine-containing neurons abundant in hypothalamus
Substance P
-neuropeptide involved in pain
Opioid peptides
- involved in control of pain
- activate inward rectifying K+ channels, inhibiting neurons
orexins
- neuropeptides that regulate sleep and appetite
- glucose and leptin inhibit orexin release
- ghrelin stimulates release
oxytocin and vasopressin
-affect social behavior
-oxy- milk (cuddley)
vaso- thirst
enkephalins
-neuropeptide related to opiate that inhibits neurotransmitters in the pathway for pain and emotion
treatment for depression
- SSRIs
- serotonin remains in cleft longer
why does AP only go one way
-once it starts region behind is refractory
large dendrite
- synaptic potential larger b/c more channels
- synaptic potential will spread farther toward cell body
Golgi vs Ramon and Cajal
- Golgi: thought neurons were continuous with one another
- Ramon and Cajal: thought neurons were within contact with one another
- both were correct
Gap junction key points
- ) speed
2. ) crayfish escape reflex
ACh channel closing
-ACh is rapidly hydrolyzed in cleft by AChE, so concentration falls quickly, preventing further channel opening
Postsynaptic and presynaptic inhibition differences
- ) post- reduces excitability of entire cell
2. ) pre- specific, aims at particular input, so post can respond to other inputs
ionotropic presynaptic inhibition receptors
-channels respond to rapidly upon transmitter binding
microtubules
- organelles (vesicles and mitochondria) attach to microtubules, which use ATP to transport along track in axons
- have polarity with positive end pointing toward terminal
- responsible for fast axonal transport
ACh left in synapse for too long
- receptor becomes desensitized
- muscle becomes refractory
- paralysis
- AChE crucial when this happens
feel good
-dopamine and serotonin
Parkinson’s
- loss of dopaminergic cells in substantia niagra
- substantia niagra big role in output of movement
rate limiting step catecholinameinergic neurons
- hydroxylation of tyrosine
- coversion of tyrosine to dopa via tyrosine hydroxylase
MAO
- monoamine oxidase
- bound to outer membrane of mitochodria
- helps degrade excess dopamine (not rapid like AChE)
ambien
dumps massive amounts of serotonin
