MODULE 2: neurons Flashcards
4 electrical properties of ion movement
- current (I)
- measured in amperes, A
- rate of movement of electrically charged particles
- biological I ~ picoA = 10^-12 A - voltage (V)
- measured in volts, V
- force acting on charged particles to cause movement,
- due to an imbalance in charge distribution = a battery
- biological V ~ milliV = 10^-3 V - conductance (g)
- measured in siemens (S)
- ease with which charged particles can move
- biological g ~ nanoS = 10^-9 S - resistance (R)
- measured in ohms (Ω)
- resistance to movement of charged particles
- inverse of g (R = 1/g)
- biological R ~ mega W = 10^6 Ω
ohm’s law
The rate of movement of a charged particle (I) depends on
the force moving it (V) and the ease with which it can move (g)
I = gV
I = V/R
ionic equilibrium potential
ionic equilibrium occurs when forces exerted on an ion by concentration and electrical differences across membrane are equal and opposite –> NO NET ION FLOW
ionic equilibrium potention (Eion) is electrical potential which counter-balances force of ionic concentration gradient
calculated using Nernst equation
how potassium controls the resting membrane potential
K+ permeability is high and ratio of K+ across membrane is high —> RMP predominantly determined by K+
increasing extracellular K+ will strongly depolarise membrane (vice versa)
glial cells buffer changes in potassium concentration by taking K+ up and distributing it elsewhere through gap junctions between glial cells
whole cell patch clamping
method of recording electrical signals in neurones
- to measure potential, conductive pathway must be established across membrane
- glass pipette of salt water placed against membrane
- measure difference in potential between electrode tip and extracellular space via suction
- break membrane via suction, insert electrode, measure potential
- compare potential on inside and outside of cell
action potentials - firing mechanism
decision to fire occurs in axon hillock
needs depolarisation of MP from resting (-60mV) to threshold (-40mV)
this depolarisation is due to integrated sum of responses to all active synaptic inputs to neurone
this depolarisation activates VG ion channels - Na+ or K+
at threshold, Na+ VG ion channels rapidly open
positive feedback loop:
–> Na+ channels rapidly open due to positive MP
–> Na+ enters cell down gradients
–> positive charge accumulates on inside of cell mrmbrane
–> MP becomes more positive
–> repeat
this loop creates overshoot
VG K+ channels also slowly begin to open during rising phase, preventing MP from reaching E(Na)
at AP peak, open Na+ channels inactivate and no more open, more K+ channels open
As g(Na) decreases and g(K) increases, AP enters repolarisation
eventually, all Na+ channels close and open K+ channels hyperpolarise the membrane below RMP –> undershoot
electrical synapses
direct flow of electrical current between cells
–> fast, bidirectional, fail safe
current flows through connexons
–> protein ion channels which directly connect two cells via a gap junction
connexons have large pores which allow passage of ions and small molecules
opening of connexons regulated by intracellular calcium concentration
- -> high Ca2+ = closed
- -> low Ca2+ = open
electrical synapses important in cardiac muscle, smooth muscle, glial cells and in the embryonic brain
amino acids –> “the big 2 G’s”
glutamate (glu)
glycine (gly)
gamma-amino-butyric acid (GABA)
amines –> “the sidekick 6”
acetylcholine (ach)
dopamine
adrenaline
noradrenaline
serotonin
histamine
basic neurotransmitter functions
amino acids mediate fast excitatory (glu) and inhibitory (GABA, gly) synaptic transmission at most CNS synapses
ach mediates fast excitatory synaptic transmission at all neuromuscular junctions and some peripheral/central synapses via nicotonic ach receptors
amino acids, aines and peptides also mediate slow synaptic transmission at centra/peripheral synapses
many synpases contain both peptides (in large dense core vesicles) and aa’s or amines (in small clear synaptic vesicles) and can co-release both
neurotransmitter release mechanism
- AP invades presynaptic terminal from axon and depolarises
- depolarisation opens VG ion channels on presynaptic terminal and calcium enters
- calcium triggers exocytosis of neurotransmitter vesicle, diffusion across synaptic cleft
- neurotransmitter binds to postsynaptic receptors, opens ion channel
- postsynaptic potential is generated
synaptic vesicle cycle (recycling)
exocytosis of synaptic vesicle contents part of continuous recycling process
vesicle membrane is endocytosed and refilled with transmitter
refilled vesicles dock near active zone
docked vesicles primed for release through ATP-dependent process
Ca2+ entering through close VG ion channels triggers fusion of vesicle membranes with presynaptic membrane
–> Ca2+ channel thought to be synaptic protein in vesicle membrane which may bind 4 calcium ions at a time
neurotransmitter synthesis (amino acids, amines and peptides)
amino acids and amines:
- synthetic enzymes and precursors transported into NERVE TERMINAL
- these are subject to feedback inhibition from recycled neurotransmitters
- can be stimulated to increase activity via Ca2+ stimulated phosphorylation
peptides:
- peptide transmitters made from precursor proteins in the CELL BODY
neurotransmitter storage (amino acids, amines and peptides)
amino acids and amines:
- uptake from terminal to cytoplasm into vesicle involves transporter protein
- protein in vesicle membrane
- powered by pH gradient between outside and inside of vesicle
peptides:
- packaged into vesicles which bud off golgi apparatus in cell body
- then transported along axon terminals = anterograde transport
neurotransmitter recovery / degredation
neurotransmitters must be removed from synaptic cleft because postsynaptic receptors will desensitise if stimulated too much
diffusion:
- diffused away from synaptic cleft in extracellular space
re-uptake:
- re-uptake into nerve terminal via transporters (vesicles)
glial cells:
- uptake into glial cells by transporters
enzymes:
- enzymatic breakdown in synaptic cleft
- acetylcholinesterases rapidy break down ACh
inotropic glutamate receptors
main excitatory neurotransmitter in CNS (~90% of synapses)
4 protein subunits around central ion pore
–> permeable to sodium, potassium and sometimes calcium
three types:
1) AMPA –> fast rising and falling, generally not permeable to calcium
2) NMDA –> slower rising and falling, always calcium permeable, voltage dependent block of ion pore of Mg2+ ion (prevents other ions moving through at -70mV)
3) kinate –> similar to AMPA but function not understood
nicotinic, GABA and glycine receptors
common channel structure
- -> 5 protein subunits in each receptor
- -> arranged in ring around ion pore
- -> positively charged to attract anions
GABA receptor:
- inhibitory structure in forebrain
- numerous subunits
- subunits have many sites for binding drugs and endogenous factors which modulate receptor activity
- major target for sedative drugs- several intracellular phosphorylation sites influenced by 2nd messenger systems
- drugs modulate activity of ion channel so it becomes easier to open and stays open for longer
glycine receptor:
- important in brain stem and spinal cord
- glycine composed of alpha and beta subunits
- mutation leads to “startle disease”
- –> reduces Cl- flow
- –> thus reduces synaptic inhibition
- –> tetanic muscle spasms in response to stimulation
GPCRs and neurotransmitters
- slow synaptic transmission due to delayed activation and long time course
- don;t have integrated ion channel in protein structure –> response not immediate
- can directly GP gated ion channels or modulate activity via phosphorylation
GLUTAMATE
ligand-gated ion channel –> AMPA, NMDA, kainate
GPRC –> metabotropic glutamate
GABA
ligand-gated ion channel –> GABA(A)
GPRC –> GABA(B)
ACh
ligand-gated ion channel –> nicotinic
GPRC –> muscarinic
mechanisms of postsynaptic inhibition
1) hyperpolarisation
- if resting MP more positive than ionic equilibrium potential for Cl- ions, MP will hyperpolarise when Cl- channels open
- MP becomes further away from threshold
2) shunting inhibition
- if resting MP is ~ionic equilibrium potential for CL- ions, MP will not change significantly because there is no driving force
- Cl- channels still opened
- this lowers MP resistance at synapse and allows current to leak out across membrane
- shunts other synaptic inputs to neurone
mechanisms of presynaptic inhibition
- neurotransmitter released by first synapse
- binds to receptor on second synapse
- this reduces neurotransmitter release by second synaptic terminal
- —> decrease in excitability in second presynaptic terminal due to activation of K+/Cl- channels
- —> reduced opening of Ca2+ channels in second presynaptic terminal
spacial and temporal summation
spatial –> summation of simultaneously active synapses at different locations on dendritic tree
temporal –> summation of asynchronously active synapses, either different or same synapses
short-term synaptic plasticity
when presynaptic neurones dire at rapid rates, synaptic responses can change with each successive AP
changes are transient –> synaptic responses will return to original amplitude within sec/min after firing rates slow
responses can become larger (facilitation) or smaller (depression)
synaptic facilitation –> produces greater than normal summation, enabling excitatory inputs to reach AP threshold quicker
synaptic depression –> produces less than normal summation, increasing time taken for EPSPs to summate to AP threshold
hebbain model of synaptic plasticity
“when an axon of cell A is near enough to excite cell B and persistently takes part in firing it, some growth process or metabolic change takes place such that A’s efficiency as one of the cells firing B is increased”
i.e. cells that fire together wire together
this underlines human learning and memory
long-term synaptic plasticity in the hippocampus
long-term potentiation (LTP) –> persistent increase in synaptic responses induced by high-frequent stimulation
long-term depression (LTD) –> persistent decrease induced by infrequent stimulation
removal or damage to hippocampus impair memory formation but no effect on memory already formed
signalling in the hippocampus
signals enter from entorhinal cortex
–> perforant path (excitatory synapse)
dentate gyrus, axons, mossy fibres
–> excitatory synapse release glutamate
CA3 region, parental cells (schaffer collateral, SC)
–> excitatory synase on other side of hippocampus
CA1 region, paramental cells
to induce LTP at CA3 and CA1, SCs are stimulated with high frequency tetanus –> significant membrane depolarisation –> summation of EPSPs
mechanism of LTP induction
transmitter at CA3 and CA1 is glutamate –> activates postsynaptic AMPA and NMDA receptors
NMDA only allows Ca2+ into postsynaptic cell is MP is sufficiently depolarised (removes Mg2+ block) by summation of AMPA EPSPs
influx of Ca2+ through NMDA chanels essential for LTP
increase in postsynaptic Ca2+ enhances eactivity of many protein kinases
blocking NMDA receptors or postsynaptic kinase prevents LTP
