Section 6: ET - Neurons Flashcards
Neurons / nerve cells
The building blocks and instruments of communication in the brain
Neurons - size
20 microns in diameter
Dendrites extend ~1mm from cell body
Axon can be 1-2mm, or quite long (half a meter)
Neurons - types of communication
Electrical signals (dendrites, cell body, axon) Chemical signals (synapses) In a cycle (electrical responses lead to release of a chemical / neurotransmitter, which leads to electrical signalling)
Neurons - synaptic vs action potentials
Synaptic potential is transmission of electrical signals in dendrites spread towards cell body
Cell body can respond with an action potential, which once triggered is towards axon terminals
Axon terminals AKA…
Synaptic boutons
Dendrites, cell body and axon
Dendrites can be seen as input stage of info
Cell body seen as computing part which makes a decision whether to respond to a synaptic input
If cell body responds with action potential, it will be transmitted and lead to release of neurotransmitters at axon terminals
Cells - RMP and excitability
Almost all cells in body have -ve RMP
Only neurons and muscle fibres can suddenly respond with a transient change of this potential (i.e. action potential) in response to a stimulus - so they are excitable
Methods of measuring intracellular potentials
Microelectrode recording technique
Patch-clamp technique
Measuring intracellular potentials - microelectrode recording technique
Glass capillary (tip < 1 micron, but still has small opening) attached to microelectrode (filled with electrolyte to conduct current), connected to a voltmeter, and second pole outside in extracellular space
Measuring intracellular potentials - microelectrode vs patch-clamp technique
Microelectrodes:
Records RMP, APs and synaptic potentials in neurons or their processes
Can also be used to depolarise or hyperpolarise neurons if a current passes through them
Patch-clamp technique:
Same as above, but also records overall current which flows through cell membrane or a single ion channel
Measuring intracellular potentials - patch-clamp technique - drawbacks
Must fill pipette with electrolytes, otherwise current won’t be transmitted
Forms large hole and changes composition of inside of cell
Resting Membrane Potential (RMP)
Electrical potential difference (50-70mV) across the cell membrane which results from separation of charge
RMP - inside and outside cell
By convention, the potential outside the cell is defined as ‘zero’
Intracellular potential is (normally) below zero
RMP is due to…
Unequal conc of Na+ and K+ inside and outside the cell
Unequal permeability of cell membrane to these ions
Electrogenic action of Na-K pump (only a small contribution)
Approximate conc of K+ and Na+ inside and outside neurons
Conc of K+ inside much higher than K+ outside (5mM outside, 100mM inside)
Conc of Na+ outside much higher than Na+ inside (150mM outside, 15mM inside)
Results in conc gradients
Permeability of cell membrane at rest
Much more permeable to K+ than to Na+
How are conc gradients for K+ and Na+ maintained
By Na+/K+ pump
3/2 ratio: 3 Na+ out, 2 K+ in
Types of ion channels (have selective permeability to ions) in neurons
Non-gated (leak) channels - open at rest Gated channels (voltage, ligand, or mechanically gated) - closed at rest
Neuron cell membranes - leak K+ and Na+ channels
Many leak K+ channels but very few leak Na+ channels
At rest:
P(K+) / P(Na+) ≈ 40/1
where P is membrane permeability
Equilibrium potential
An intracellular potential at which the net flow of ions is zero despite a conc gradient and permeability
Zero net flow
Since K+ ion leaves, environment becomes -ve –> electrostatic force causes movement of ions back into cell as -ve environment attracts +ve ions - net flow is zero
Nernst equation
Used to calculate equilibrium potential for each ion
E(ion) = 61.5mV x log[ion]o / [ion]i
Only applies when a cell membrane is permeable to only ONE ion (i.e. has leak channels only for one specific ion)
Nernst equation - K+ and Na+
E(K) = -80mV, i.e. at -80mV at equilibrium potential for K+, there's a steady state where there's no net flow, gradients are maintained and same no of ions that leave the cell will be attracted by the -ve potential inside the cell E(Na) = +60mV
Calculating membrane potential from equilibrium potential
Equilibrium potential can be used to calculate membrane potential, but only in cells where the cell membrane is permeable to K+
Glia cells - RMP
Have leak channels only for K+ (not Na+), so RMP for glia cells = E(K) = -80mV
Neurons - leak channels and RMP
RMP affected by K+ leak channels AND Na+ leak channels
Neurons - leak channels and RMP - rule
The higher the permeability of the cell membrane to a particular ion, the greater the ability of this ion to shift the RMP toward its equilibrium potential
i.e. membrane potential inside cell could be anywhere between -80 and +60, but where it is exactly depends on relative permeability for ions
Neurons - RMP at rest
At rest, membrane permeability in neurons is much higher to K+ than to Na+ so RMP is closer to equilibrium potential for K+ (E(K)) than for Na+ (E(Na))
RMP - neurons vs glia cells
In neurons, RMP is less -ve than E(K) (approx -65mV) due to a small contribution of leak Na+ channels
Goldman equation
Calculates value of RMP taking into account both conc gradients AND relative permeability of resting cell membrane to K+ and Na+ ions
V(m) = 61.5 log {Pk[K+]o + PNa[Na+]o} / {Pk[K+]i + PNa[Na+]i}
V(m) = -65mV
Potential inside neurons - constant?
Not constant - changes when ion conc changes or membrane permeability changes
Potential inside neurons - hyperpolarisation vs depolarisation
Hyperpolarisation:
Becomes more -ve
Potential inside cell moves closer to E(K) and away from E(Na)
Depolarisation:
Becomes less -ve
Potential inside cell moves away from E(K) and closer to E(Na)
Action potentials AKA
Spike
Nerve impulse
Discharge
What is an action potential (AP)
A brief fluctuation in MP caused by a transient opening of voltage-gated ion channels, which spreads like a wave along an axon
When do action potentials occur
After the membrane potential reaches a certain voltage called the threshold (~-55mV)
Why are APs significant
Info is coded in frequency of APs –> can be regarded as a form of language by which neurons communicate
A key element of signal transmission along axons
Stages of action potentials
- A slow and graded depolarisation evoked by a stimulus causes shift of MP from resting value to threshold
1. After membrane potential reaches threshold: fast depolarisation to ~+30mV (overshoot) for a short period of time
2. Process reverses direction and MP goes back down towards starting value - repolarisation
3. Becomes slightly more -ve than RMP before going back to RMP - after-hyperpolarisation (AHP)
Action potentials - refractory period
An important feature of nerve cells
A time during the action potential when the nerve cell isn’t excitable (i.e. after the first stimulus, it won’t evoke a second action potential during this period)
APs - absolute refractory period
Stages 1 and 2
Even if second stimulus is extremely powerful, won’t evoke an AP
APs - relative refractory period
If strong stimulus applied, may evoke another action potential
Harder for stimulus to reach threshold as MP is more -ve so has to increase by a higher amount
i.e. stronger stimulus needed to depolarise it to threshold
AP - stimuli
Can be…
Physical (electric current, light or mechanical stretch)
Chemical (drug or neurotransmitter)
Synaptic transmission caused by neurotransmitters can…
Depolarise cell membrane to threshold and evoke action potentials
What happens when MP reaches the threshold
There is a sudden activation/opening of voltage-gated Na+ channels
Extreme increased permeability to Na+
What are voltage-gated channels
Gated channels sensitive to voltage outside and become permeable when membrane depolarises
AP - opening of Na+ and K+ channels
Opening of voltage-gated Na+ channels are short lasting, as they quickly inactivate
P(K):P(Na) –> 1:20 –> MP shifts towards E(Na) –> overshoot
Followed by transient opening of voltage-gated K+ channels –> permeability to K+ becomes even higher –> repolarisation and AHP –> MP shifts towards E(K); P(K):P(Na) ≈ 100:1
When inactivated, goes back to RMP
Key role of voltage-gated Na+ channels in AP
When voltage threshold is reached, Na+ channels open and Na+ ions move into cell along both the conc and electrical gradient
Influx of Na+ slows down and stops when:
1. Inside potential becomes +ve (towards E(Na+)) and thus attracts Na+ ions less (electrostatic force decreases)
2. Na+ channels inactivate/close
Na+ channels: Activation gate
Residues which have a certain charge
Act as a voltage sensor and detect small changes in MP and change configuration
If there’s depolarisation that reaches threshold, activation gate opens –> Na+ diffuses from outside to inside of cell along their conc gradient
AP - stage 1 speed
Fast as there are 2 factors causing Na+ to move into cell
Conc gradient and -vely charged interior of cell
Why do nerve cells try to avoid a large influx of Na+
It would depolarise the cell –> loses MP potential
So, APs are short-lasting mainly because Na+ channels activate, but v quickly inactivate
Na+ channels: Inactivation gate
Sense depolarisation and changes conformation to block channel
Closes before activation gate closes (before MP reaches E(Na), usually stops at +30mV); double mechanism to prevent cell from getting too much Na+
AP - what happens if there’s too much Na+
If there’s too much Na+ for too long, it would destroy excitability
AP - amplitudes
The amplitude of APs is usually constant (≈100mV) and doesn’t depend on stimulus intensity, provided the stimulus is suprathreshold
Suprathreshold
Stimulus causes depolarisation which just slightly crosses the threshold
Evoking APs: Electrical stimuli
Axon where 2 electrodes are attached, connected to a battery with switch
Path from + to - outside cell provides a low R path –> current flow
In electrolytes, current is carried by ____
Ions (e.g. Na+ K+ Cl-)
Evoking APs: Electrical stimuli - paths of current
2 main paths
- Outside from + to -, doesn’t affect RMP
- Across membrane and inside axon; can affect excitability
Evoking APs - rule
When current generated by an outside source flows through the cell membrane from outside to inside –> accumulation of -ve charge inside cell under anode –> local hyperpolarisation (MP becomes more -ve)
When it flows from inside to outside –> accumulation of cations near cathode –> local depolarisation (MP becomes less -ve) - if this reaches threshold, there will be activation of voltage-gated AP
AP - stationary?
AP is not stationary - it moves in both directions away from point where it was generated
How are APs generated physiologically in CNS neurons
First generated in axon initial segment which has lowest threshold, and thus serves as the ‘trigger zone’ for APs
Depolarisation to threshold is evoked by EPSPs, which spread mainly passively from dendrites
Once generated, APs are transmitted actively along the axon away from cell body, but also from axon initial segment back to cell body
Axon initial segment AKA…
Axon hillock
Axon initial segment - excitability
Density of voltage-gated Na+ channel slightly higher in axon initial segment than in cell body or axons - axon initial segment slightly more excitable with slightly lower threshold
If there’s a depolarisation, it’s likely to reach the threshold and activate the voltage Na+ channels in this region
EPSPs are evoked in neurons by…
Synaptic transmission from pre-synaptic axons to dendrites, and (to a smaller degree) cell bodies
Types of axons
Unmyelinated axons:
Small diameter (~1μm)
Transmission of APs is slow and continuous
Myelinated axons:
Large diameter (5-10μ)
Transmission of APs is fast and saltatory (in large steps)
2 main stages of action potential transmission
Passive spread
Generation of APs
Passive spread of current - steps
- Subthreshold depolarisation at one region of the membrane
- Passive current flow (inside and outside axon)
- Depolarisation of adjacent parts of membrane and a loss of +ve charge outside –> flow of current in extracellular space
Passive spread of current - if one section of an axon is depolarised…
Potential diff leads to flow of current from + to - in both directions
Passive spread of current - distance
Only over short distance
Current quickly ‘dissipates’ as it flows along the axon
Usually within 1mm, there’s already little change in potential - very inefficient –> passive spread can’t be utilised by nerve cells with long axons
Action potential transmission in unmyelinated axons - steps
- Action potential - can be regarded as a depolarisation, except quite large (~100mV)
- Passive current flow
- Depolarisation of adjacent parts of membrane to threshold
- Voltage-gated Na+ channels in adjacent parts of membrane open
- New full size AP generated in adjacent parts of membrane
Speed of AP transmission in unmyelinated axons
≈ 1 m/sec
Passive current flow between 2 adjacent points is fast, but AP must be regenerated at every point on the membrane - takes time –> conduction velocity is slow
Speed of AP transmission in myelinated axons
≈ 20-100 m/sec
Much faster than in unmyelinated axons
Myelinated axons: Myelin sheath - formed by…
Oligodendrocytes in CNS
Schwann cells in PNS
Both are types of glia cells
Myelination
Discontinuous - interrupted at nodes of Ranvier (parts which aren’t covered by the myelin sheath)
Myelin sheath/segment and glia cells
Layers of cell membrane belonging to a glia cell
During development, glia cells approach axons and start to travel around them –> layers of membrane –> insulates axons from current
Sheets of myelin are ___ apart
Approx 1mm apart
Myelination - passive spread of current
Due to insulating properties of myelin, there’s less current dissipation as it flows along the axon
Spreads more efficiently to a more distant point of the axon - important functional significance
Passive conduction - direction
Both directions (right and left)
Myelination - AP conduction velocity
Myelination increases speed of AP conduction by increasing efficiency of passive spread
Also, APs don’t need to be regenerated at every part of cell membrane
Process known as saltatory conduction
Myelination - where are APs generated
Only at nodes of Ranvier (current flows passively between nodes) - can sometimes skip one node
Current tries to leave membrane through place with lowest resistance, i.e. node of Ranvier –> depolarises –> activates voltage-gated Na+ channels –> generates new AP, which uses its own passive current and spreads further away etc
Why (under physiological conditions) does AP conduct in only one direction
Passive current does flow back, but it’s unable to reactivate voltage-gated Na+ channels as they are in state of refractory
Absolute refractory period - mechanism by which nerve cells defend themselves from being reactivated too quickly and prevents APs from going back to where they came from
Myelination - size
Size matters - non-myelinated may conduct more slowly, but have smaller diameter
Volume of CNS limited by skull, so can have more thinner than thicker - compromise between speed of conduction and size
PNS contains axons of…
Sensory neurons - connected to receptors and transmit information to CNS via nerves. unipolar
Also axons of motoneurons and the autonomic nervous system
How are APs generated in sensory neurons? - Receptor potential
When a stimulus acts on receptors in sensory neurons, it doesn’t immediately evoke APs
First, it evokes a graded depolarisation (the receptor potential)
Receptor potential spreads passively to more distally located ‘trigger zone’ where APs are generated
APs spread along the (un)myelinated axon towards CNS
Where is information about strength of stimulus coded in sensory neurons
In the amplitude of the receptor potential and the frequency of APs (analog-to-digital converter)
Muscle spindles
Sensory fibres sensitive to stretch
Contains ion channels which are stretch sensitive and gated by displacement of cell membrane –> opens some channels –> small local depolarisation of most distal part of axon –> activates channels permeable to cations –> small depolarisation (receptor potential)
Muscle neurons - structure
Cell body has no dendrites
Part which enters the CNS is the synaptic terminal
Muscle neurons - parts of axon
2 parts; distal (towards muscle fibre) and proximal (towards synaptic terminal)
Receptor potential - graded
If stimulus is small, receptor potential is small
Trigger zone contains…
Voltage-gated Na+ channels
How is a ‘message’ transmitted from one neuron to another neuron?
Synaptic transmission
Often via chemical synapses
Axon of pre-synaptic neuron makes contact with dendrite of receiving neuron - axon-dendritic synapse
Communication with CNS
How a ‘message’ transmitted from a neuron to a muscle fibre
Synaptic transmission between a motoneuron and a muscle fibre
Neuromuscular junction = end plate
Neuromuscular junction as a model of (excitatory) synaptic transmission - stages
Presynaptic AP
Increased presynaptic Ca2+ permeability; Ca2+ influx (voltage-gated Ca2+ channel)
Release of transmitter by exocytosis
Reaction of transmitter with postsynaptic receptors (neurotransmitter: acetylcholine - ACh)
Activation of ligand-gated ion channels
Postsynaptic EPP and AP
EPPs
End-plate potentials
Transient opening of ion channels selective to both Na+ and K+ (non-selective cationic channels)
Always suprathreshold - once AP is triggered, it’s transmitted along the muscle fibre
Synaptic delay
Transmission of information from synapses have a slight delay
Quite short ~0.5ms
Main types of chemical synapses in the CNS
Excitatory synapses: depolarisation of the postsynaptic membrane called the Excitatory Postsynaptic Potential (EPSP), e.g. neuromuscular junction
Inhibitory synapses: hyperpolarisation of the postsynaptic membrane called the Inhibitory Postsynaptic Potential (IPSP)
Excitatory synapses
Neurotransmitters mainly glutamic acid (glutamate) or ACh. Amino acids
Ionic mechanism: transient opening of channels permeable to Na+, K+ and sometimes Ca2+ (non-selective cationic channels)
Inhibitory synapses
Neurotransmitters mainly GABA (gamma-aminobutyric acid) or glycine. Amino acids
Ionic mechanism: usually transient opening of K+ channels
Hyperpolarisation
Classification of neurotransmitters based on chemical structure
Small molecule neurotransmitters (Classical neurotransmitters)
Neuropeptides (Neuromodulators)
Small molecule neurotransmitters
Usually fast action (ms) and direct on postsynaptic receptors
Amino acids: glutamate, GABA, glycine Acetyl choline (ACh) Amines: serotonin (5-HT), noradrenaline, dopamine
Neuropeptides
Large molecule chemicals that have an indirect (metabotropic) action on postsynaptic receptors, or modulatory action on effects of other neurotransmitters
Slow (s to min) and usually more diffuse action
Several dozens identified which may be involved in communication between neurons
Many are putative neurotransmitters
e.g. Neuropeptide Y, substance P, kisspeptin, enkephaln
Factors determining synaptic action
Type of neurotransmitter/neuromodulator
Type of neurotransmitter receptor / channel complex expressed in the postsynaptic membrane
Amount of neurotransmitter receptor present in postsynaptic membrane - synaptic plasticity; LTP or LTD
Synaptic plasticity - LTP and LTD
LTP: long-term potentiation
LTD: long-term depression
Main subtypes of glutamate receptors
AMPA receptor - opens and is permeable to Na+ and K+
NMDA receptor - opens and becomes permeable to Na+, K+ and Ca2+
Kainate receptor
Glutamate - excitotoxicity
Too much Ca2+ can cause unwanted activation, known as excitotoxicity
Too much glutamate and thus activation of NMDA receptor can cause excessive entry of Ca2+ and damage/destroy the cell body
e.g. stroke
Neurotransmitter inactivation (and recovery)
Diffusion away from the synapse
- Enzymatic degradation in synaptic cleft (e.g. acetylcholine esterase degrades ACh)*
- Re-uptake (for most amino acids and amines) and re-cycling*
Specific neurotransmitter transporters
Involved in presynaptic membrane
Deals with one chemical, which connects with transporter –> conformation changes –> shift of molecule across membrane and is released on other side against conc gradient
e.g. glutamate transporter, dopamin transporter, serotonin transporter
Each neuron receives thousands of ____
Synapses
Some excitatory, some inhibitory
Each individual synapse when activated produces….
A v small (~0.1mV) postsynaptic potential at axon initial segment
Potentials decay when passively conducted from dendrites (current dissipates)
To depolarise the initial segment to threshold, EPSPs need to be enhanced - requires action of many synapses in a closer space of time to induce larger depolarisations
Temporal and spatial summation of post-synaptic potentials at axon initial segment: Subthreshold, no summation
A single AP through an excitatory neuron doesn’t increase MP enough (doesn’t reach threshold) –> no AP generated at axon
Temporal and spatial summation of post-synaptic potentials at axon initial segment: Temporal summation
Multiple APs through the same excitatory neuron within a smaller timeframe increases MP (high frequency) enough to reach threshold –> generates AP
(i.e. increased amplitude of EPSPs by same subset of excitatory synapses contacting a single neuron)
Temporal and spatial summation of post-synaptic potentials at axon initial segment: Spatial summation
Inputs through multiple dendrites at same / similar times
(more excitatory synapses converging on a single neuron are simultaneously activated)
E1 + E2 is enough to reach threshold –> generates AP
Temporal and spatial summation of post-synaptic potentials at axon initial segment: Spatial summation of EPSP and IPSP
Interplay between excitatory and inhibitory synapses
Activation of an inhibitory synapse results in almost no change in MP (events cancel out each other) –> no AP generated
Cell body is covered by…
Pre-synaptic terminals
Local anesthetics block…
Voltage-gated Na+ channels
With switch closed and current flowing between electrodes on an unmyelinated axon, APs will first be evoked where?
Next to the cathode (-ve electrode)
What happens to the value of E(K) using Nernst equation when extracellular conc of K+ increases?
Value of E(K) becomes more -ve
What happens to neurons when extracellular conc of K+ ions increase?
They depolarise
and so they hyperpolarise when extracellular conc of K+ ions decrease
AP: What happens when K+ channels in the cell membrane close?
APs are generated by a neuron more frequently
(this is because opening of K+ channels is responsible for relative refractory period due to hyperpolarisation of neuron, so less hyperpolarisation = more likely to reach threshold = more APs)
Ca2+ and synaptic vesicles
Influx of Ca2+ through voltage-gated channels causes fusion of synaptic vesicles with the plasma membrane of pre-synaptic terminals
Axon colaterals
Branches that may occur along an axon
Effect of blocking voltage-gated Na+ channels on MP
No change in MP
Most immediate response of depolarising a pre-synaptic membrane
Voltage-gated Ca2+ channels in membrane open
An AP releases neurotransmitters by…
Opening voltage-gated Ca2+ channels in axon terminals
Are APs graded
No
Influx of Ca2+ through voltage-gated Ca2+ channels cause…
Fusion of synaptic vesicles with plasma membrane of presynaptic terminals
Removal of neurotransmitters
Can be removed by:
Diffusion
Enzymatic breakdown
Uptake to presynaptic terminals or adjacent cells
Can’t be removed by exocytosis
Reduction of intracellular ATP results in…
MP moving towards E(K+)
Duration of AP in neurons excluding after-hyperpolarisation (AHP)
~1ms
