Excitable Tissues: Neurons

• dendrite → receives input

• cell body → passively conducts electrical signals

• axon initial segment (hillock) → initiate action potentials (AP)

• axon → propagates AP

• axon terminals → releases chemical signals

outline the structure and function of neurons

because only they can suddenly response with a transient change to an action potential, all other cells have a negtive resting membrane potential

why are neurons and muscle fibres called excitable tissues

• electrical potential difference across cell membrane results from a separation of charge

• there are more negative charges inside the cell in comparison to the extracellular fluid

• this can be due to:

  • unequal concentrations of Na+ and K+ inside and outside the cell resulting in the electrochemical gradients driving the movement of these ions → higher K+ concentration inside, higher Na+ concentration outside

  • unequal permeability (P) of the cell membrane to these ions

what generates the resting membrane potential

1. non-gated (‘leak’) channels

   • these are open at rest (on-off state), allows for diffusion of ions

2. gated channels (voltage-gated, ligand gated, or mechanically gated)

   • these are closed at rest

• in cell membranes of neurons, there are many leak K+ channels, but very few Na+ channels

• therefore at rest: P_K+/P_Na+ = 40/1 (where P is membrane permeabilty)

outline the two main types of ion channels in neurons

an intracellular potential at which net flow of ions is zero according to its electrochemical gradient

what is equilibrium potential

• the equilibrium potential can be calculated for each ion by the Nernst equation

• E_ion = 2.3RT/zF x log[ion]_o/[ion]_i → 61.5mV x log[ion]_o/[ion]_i

• value for Na+ → quite positive, K+ → quite negative

what is the Nernst equation

• a way of calculating the value of the RMP taking into account both the concentration gradients AND the relative permeability of the resting cell membrane to K+ and Na+ ions

• V_m = 61.5 mV log (P_k[K+]_o + P_Na[Na+]_o/P_K[K+]_i + P_Na[Na+]_i)

• P_K = 40, P_Na = 1

what is the Goldman equation

• a brief fluctuation in membrane potential caused by a transient opening of voltage-gated ion channels which spreads, like a wave, along an axon

• action potentials occur after the membrane potential reaches a certain voltage called the threshold

what is an action potential

1. the frequency of action potentials encodes information (a language by which neurons communicate)

2. action potentials are a key element of signal transmission along (often very long) axons

what is the significance of action potentials

• start with resting membrane potential

• * = a slow depolarisation evoked by a stimulus

1. membrane potential reaches threshold, followed by fast depolarisation to ~ +30 mV (‘overshoot’)

   • when MP reaches the threshold there is a sudden activation (opening) of voltage-gated Na+ channels (P_Na increase)

   • at this moment P_K/P_Na is 1:20 (before it was 40:1), therefore MP shifts towards the E_Na+ towards +60 mV = overshoot.

2. repolarisation

   • opening of voltage-gated Na+ channels is short lating, as these channels inactivate quickly

   • this is followed by transient opening of voltage-gated K+ channels, leading to repolarisation

3. after-hyperpolarisation

   • after-hyperpolarisation AHP. Membrane potential shifts towards E_K+ since P_K/P_Na becomes ~ 100:1

• 1 + 2 = absolute refractory period

• 3 = relative refractory period

outline the three stages of action potentials (APs)

the voltage-gated Na+ channel has two gates:

• activation gate (voltage sensor)

• inactivation gate

States of the channel:

State	Activation gate	Inactivation gate	When
Resting (RMP)	Closed	Open	At rest, no Na⁺ flow
Activated (open)	Open	Open	At threshold — Na⁺ flows in
Inactivated	Open	Closed (blocks pore)	A fraction of a millisecond after opening
Back to resting	Closed	Open	Once membrane repolarises

outline the role of voltage-gated Na+ channels in AP

1. at RMP: activation gate closed, inactivation gate open → channel closed overall

2. at threshold: activation gate opens → Na+ flows into the cell along both the concentration gradient and the electrical gradient

3. Na+ influx stops because:

   • the inside becomes positive (approaches E_Na), reducing the driving force for further Na+ entry and

   • the inactivation gate closes (channel inactivates)

4. membrane repolarises → channel resets to the resting state (activation gate closes, inactivation gate reopens)

outline the sequence of events that occurs in a voltage-gated Na+ channel in an AP

• each action potential is an all-or-none event — once threshold is reached, the AP fires fully; it does not fire “partially”

• this contrasts with graded potentials (subthreshold depolarisations/hyperpolarisations), which vary continuously with stimulus strength

• AP amplitude is roughly constant (~100mV) and does not depend on stimulus intensity, as long as the stimulus is suprathreshold (above threshold)

what is the all-or-none principle

1. externally (experimental) — electrical stimulation via electrodes/battery

2. internally (physiological) — postsynaptic potentials build up at synapses

• if a stimulus is large enough to trigger an AP, adjacent voltage-gated channels open in sequence, propagating the signal along the axon

what are the two ways in which action potentials are evoked

• current follows the path of least resistance, two possible paths:

  1. outside the axon, from + to - electrode (does NOT affect RMP)

  2. across the membrane and inside the axon (this is the only path that can change RMP)

• effect of current direction across the membrane:

  Current direction	Effect	Location
  Outside → inside (at the anode, +)	Local hyperpolarisation (MP more negative)	Near + electrode
  Inside → outside (at the cathode, −)	Local depolarisation (MP less negative)	Near − electrode

  • anode (+) attracts anions

  • cathode (-) attracts cations

outline how APs are evoked externally

• APs are first generated at the axon initial segment (axon hillock) — this region has the lowest threshold, making it the trigger zone for APs

• depolarisation to threshold is driven by excitatory postsynaptic potentials (EPSPs), which spread passively from the dendrites toward the axon hillock

• once an AP is generated at the axon hillock, it is transmitted actively along the axon, away from the cell body

how are APs generated physiologically in CNS neurons

1. unmyelinated axons: smaller diameter (~1um); transmission of APs, slow, continuous

2. myelinated axons: larger diameter (5-10um); transmission of APs fast, ‘saltatory’ (in large steps)

• two stages of action potential transmission (in both types of axons):

  1. passive spread

  2. generation of action potentials

describe and outline the two types of axons

• when (subthreshold) depolarisation occurs at one region of the membrane:

  1. local depolarisation occurs at one point

  2. passive current flow occurs — both inside (axoplasm) and outside (extracellular) the axon

  3. this passively depolarises adjacent parts of the membrane

what is the passive spread of current

1. an action potential occurs at one point on the membrane

2. passive current flow spreads to adjacent regions

3. this depolarises the adjacent membrane to threshold

4. voltage-gated Na+ channels in the adjacent region open

5. a new, full-size action potential is generated in that adjacent region

6. this process repeats — effectively “regenerating” the AP at every point along the membrane

outline the sequence of events in AP transmission in unmyelinated axons

• conduction velocity in unmyelinated axons = 1m/sec

• although passive current flow itself is fast, the AP must be actively regenerated at every point along the membrane — and this regeneration takes time, slowing overall conduction

why is the speed of conduction in unmyelinated axons slow

• myelin sheath formed:

  • by oligodendrocytes in the CNS

  • by Schwann cells in the PNS

    • note: oligodendrocytes and Schwann cells are two types of glia cells

• myelination is discontinuous; interrupted at nodes of Ranvier

outline the structure of neurons with myelinated axons

• due to the insulating properties of myelin, there is less current dissipation as it flows along the axon

• note: passive conduction occurs in both directions (right and left)

outline how myelination increases passive spread of current

• myelination increases speed of AP conduction by increasing the efficiency of passive spread, and the fact that APs do not need to be regenerated at every part of the cell membrane

• APs are generated only at nodes of Ranvier (current flows passively between nodes)

• this process is called “saltatory conduction”

outline how myelination increases action potential conduction velocity

• less passive current loss

• less time for generation of AP

• less energy to maintain gradient ions

what are the benefits of myelination for AP

• due to the absolute refractory period (which lasts for 1-2ms)

• by the time the absolute refractory period is over, AP has already moved down the axon towards node 4

why does AP conduct in only one direction under physiological conditions in neurons

• axons and cell bodies of sensory neurons → input

• axons of motor neurones → output

• neurons forming the ‘autonomic nervous system’

what does the PNS contain

• when a stimulus (e.g. a mechanical stretch acting on a muscle spindle) acts on a sensory receptor, it does not immediately trigger an action potential

1. the stimulus evokes a graded depolarisation called the receptor potential

2. the receptor potential spreads passively to a more distally located “trigger zone”, where action potentials are generated (if threshold is reached)

3. from the trigger zone, APs then propagate along the axon (myelinated or unmyelinated) toward the CNS

outline the sequence in which action potentials are generated in sensory neurons

• dependent on stimulus strength (not all-or-none)

• not voltage-gated — generated via ligand-gated or mechanically-gated channels, depending on receptor type

what are the properties of receptor potential (a graded potential)

• the amplitude of the receptor potential

• the frequency of the resulting action potentials

what is information about stimulus strength encoded by

1. action potential arrives at presynaptic terminal

2. voltage-gated Ca2+ channels open

3. Ca2+ enters the terminal

4. synaptic vesicles fuse with the membrane

5. neurotransmitter (acetylcholine) is released by exocytosis

6. neurotransmitter (acetylcholine) binds to receptors on the postsynaptic membrane

7. Na+ and K+ ion channels open, producing a postsynaptic potential

8. neurotransmitter is removed/inactivated

outline the stages of synaptic transmission

1. excitatory synapses → depolarisation of the postsynaptic membrane called the excitatory postsynaptic potential (EPSP)

2. inhibitory synapses → hyperpolarisation of the postsynaptic membrane called the inhibitory postsynamic potential (IPSP)

what are the two main types of chemical synapses in the CNS

• produce excitatory synapses

• effect:

  • depolarisation

  • membrane becomes less negative

  • neuron moves closer to threshold

• main neurotransmitters:

  • glutamate → most common excitatory neurotransmitter in the CNS

  • acetylcholine (ACh) → also excitatory in many situations

• ionic mechanism:

  • EPSPs occur when channels open that allow:

    • Na+ entry

    • K+ movement

    • sometimes Ca2+ entry

  • result:

    • positive charge enters cell → depolarisation → EPSP

outline EPSPs

• produced by inhibitory synapses

• effect:

  • hyperpolarisation

  • membrane becomes more negative

  • neuron moves further from threshold

• main neurotransmitters:

  • GABA → major inhibitory neurotransmitter in the brain

  • glycine → important inhibitory neurotransmitter in the spinal cord

• ionic mechanism:

  • usually caused by opening K+ channels

  • result:

    • K+ leaves cell → cell becomes more negative → hyperpolarisation → IPSP

outline IPSPs

• also called classical neurotransmitters

• characteristics:

  • fast acting

  • millisecond effects

  • direct action on receptors

• examples:

  • amino acids

  • acetylcholine

  • amines

outline small-molecule neurotransmitters

• also called neuromodulators

• characteristics:

  • large molecules

  • slow acting

  • seconds to minutes

  • usually indirect effects

• examples:

  • Neuropeptide Y (NPY)

  • Substance P

  • Kisspeptin

  • Enkephalin

outline neuropeptides

1. type of neurotransmitter

   • examples:

     • glutamate → usually excitatory

     • GABA → usually inhibitory

2. type of receptor

   • the same neurotransmitter can produce different effects depending on the receptor present

   • example:

     • glutamate

       • has several receptor subtypes

       • therefore glutamate can produce different responses in different neurons

3. number of receptors present

   • more receptors → stronger response

   • this leads to synaptic plasticity

     • the ability of synapses to change strength

       • long-term potentiation (LTP)

         • increased synaptic strength

         • important for learning and memory

       • long-term depression (LTD)

         • reduced synaptic strength

describe and outline the three factors that determine synaptic action

1. diffusion

   • neurotransmitter drifts away from the synapse

2. enzymatic degradation

   • example: acetylcholinesterase

     • ACh → acetylcholinesterase → breakdown products

3. reuptake

   • transporters take neurotransmitter back into the presynaptic neuron

   • the neurotransmitter can then be recycled

outline the three mechanisms in which neurotransmitters are inactivated

• each neuron receives thousands of synaptic inputs

• some are:

  • excitatory (EPSPs)

  • inhibitory (IPSPs)

• the neuron must combine all of these signals

• summation is needed as a single synapse produces only a tiny change (~0.1mV) at the axon initial segment, this is far too small to reach threshold

outline what neuronal integration is and why its needed

• multiple EPSPs arrive from the same synapse in rapid succession

  • EPSP + EPSP + EPSP = larger depolarisation

• if large enough, action potential is generated

what is temporal summation

• EPSPs from different synapses occur simultaneously

  • EPSP1 + EPSP2 + EPSP3 = larger depolarisation

• can bring membrane to threshold

what is spatial summation

• cell death caused by excessive neuronal excitiation

• mechanism:

  • excess neurotransmitter release (usually glutamate) → excess activation of glutamate receptors → excess Ca2+ entry → cell damage → apoptosis (programmed cell death)

outline what excitoxicity is