Wk3 L8 - Synaptic Integration and Summation

Nerve Cell Excitability

• Nerve cells have varying excitability; the axon hillock is the most excitable region where action potentials are usually initiated, due to a high density of voltage-sensitive Na+ channels.

• Dendrites have very few voltage-sensitive Na+ channels, resulting in no action potentials; they conduct signals passively.

Neurons as Computational Units

• Neurons integrate synaptic inputs and apply a form of logical processing (AND, OR, NOT functions).

• Excitatory and inhibitory inputs together shape neuronal output.

Excitatory Postsynaptic Potential (EPSP)

• Occurs when excitatory neurotransmitters (e.g., glutamate) bind to postsynaptic receptors, leading to depolarisation.

• They are conducted passively along dendrites, towards the axon hillock

• Brings the membrane potential closer to the action potential threshold.

• Example: Activation of AMPA receptors by glutamate allows Na+ influx.

• Synaptic input at point A generates a large response.

• Response spreads passively along the dendrite to points B and C.

• Amplitude decreases and time course slows due to dendritic resistance and capacitance.

• Small further decrement occurs when the signal traverses the cell body (which has low internal resistance).

• Signal fails to reach threshold and does not evoke an action potential at the axon hillock (D).

• Diagram shows 3 excitatory postsynaptic potentials (EPSPs) — A, B, and C.

• All 3 EPSPs are the same size (they have the same strength) at their synapses.

• They all produce different levels of change in electrical charge (depolarization) at a specific part of the neuron called the axon hillock.

• The farther away a signal is from the axon hillock, the weaker it becomes. This is called decrement.

Inhibitory Postsynaptic Potential (IPSP)

• Occurs when inhibitory neurotransmitters (e.g., GABA, glycine) bind to receptors, leading to hyperpolarisation.

• They are conducted passively along dendrites, towards the axon hillock

• Moves the membrane potential further away from the threshold, making it less likely to fire an action potential.

• Their conduction from the dendrite is also “electrotonic” and hence decremental - they get smaller and slower along the dendrite

• Example: Activation of GABA_A receptors allows Cl- influx.

Shunting Inhibition

Is when inhibitory input reduces the effect of the excitatory input, preventing the depolarisation from reaching the threshold for an action potential.

• Some inhibitory synapses open Cl- channels near the soma, effectively "short-circuiting" incoming EPSPs.

• This prevents excitation even if excitatory synapses are active.

Spatial Summation of EPSP and IPSP

• When the EPSP (excitatory postsynaptic potential) is present alone, it is suprathreshold, meaning it reaches above the threshold for triggering an action potential (red trace).

• The IPSP (inhibitory postsynaptic potential) alone causes significant hyperpolarization at the axon hillock (blue trace).

• When both inputs are evoked together, the IPSP reduces the amplitude of the EPSP, bringing it below the threshold (subthreshold). This results in a complex compound synaptic potential (purple trace), caused by the different time courses of the EPSP and IPSP.

Spatial Summation

• Multiple synaptic inputs from different locations on the dendrite or soma combine.

• If excitatory inputs dominate, they increase the chance of reaching threshold.

• If inhibitory inputs dominate, they reduce excitatory effects and prevent action potentials.

• Example: Two identical fast EPSPs from different axons (red and blue traces) don’t reach threshold on their own, but when summed, they reach threshold and trigger an action potential (purple trace) at the axon hillock.

Temporal Summation

• Repeated synaptic inputs at the same location add up over time.

• Rapid successive signals allow weak inputs to build up and possibly reach threshold.

• Two subthreshold EPSPs from successive action potentials can summate to exceed threshold and trigger an action potential.

• A single fast EPSP often fails to reach threshold.

• Low-frequency EPSPs do not summate as each decays before the next arrives.

• Higher frequency stimulation leads to greater summation and increased peak amplitude.

• Summation is non-linear and approaches a limit—the reversal potential.

• Even at the highest frequency, the peak cannot exceed the reversal potential.

Shapes of Action Potentials and Synaptic Potentials

Synaptic Reversal Potential

• The reversal potential is the membrane voltage at which no net ion flow occurs through a receptor's ion channels.

• If a neurotransmitter opens only K⁺ channels, the membrane potential (Vm) moves toward EK (-90mV).

• If a neurotransmitter opens only Na⁺ channels, Vm moves toward ENa (+50mV).

• If a channel is permeable to both K⁺ and Na⁺, the resulting Vm depends on the relative permeability of each ion, calculated using the Goldman equation.

• Example: Nicotinic receptors

  • Acetylcholine (ACh) opens ion channels that allow both Na⁺ and K⁺ to pass.

  • These channels are slightly more permeable to Na⁺, so Vm moves toward +5mV (not +50mV or -90mV).

  • This +5mV is the reversal potential for nicotinic synapses.

• When repeated synaptic stimulation occurs:

  • EPSPs summate but never exceed the reversal potential (+5mV).

  • This is because once Vm reaches the reversal potential, ion movement no longer drives further depolarization.

Why Summation is Non-Linear

• As the membrane potential gets closer to the reversal potential, the driving force decreases.

• This is why summation does not always result in a simple additive effect.

Driving Force: Non-linear Synaptic Summation

The driving force is the difference between the membrane potential and reversal potential.

• Resting Membrane Potential (RMP) = -68mV.

• Nicotinic synapse activation: When acetylcholine is released at a nicotinic synapse, it opens ion channels that allow ions to flow. This causes the membrane potential (Vm) to move toward the reversal potential, which for nicotinic receptors is around +5mV.

• First synaptic input:

  • The difference between the membrane potential (-68mV) and the reversal potential (+5mV) gives a driving force of 73mV.

  • This driving force moves the membrane potential toward +5mV, but other ion channels are open, so the potential only reaches -58mV, not +5mV.

• Second synaptic input:

  • If another identical synaptic input occurs when the membrane potential is at -58mV, you’d expect it to add the same 10mV change, bringing Vm to -48mV.

  • However, because the membrane potential is now closer to the reversal potential, the driving force is reduced to 63mV (the difference between -58mV and +5mV).

  • This means the second synaptic input contributes only 7mV instead of 10mV, and the membrane potential reaches -51mV (not -48mV).

• Why this happens:

  • The driving force (the difference between the membrane potential and reversal potential) gets smaller as the membrane potential moves closer to the reversal potential.

  • As Vm nears the reversal potential, synaptic inputs have less effect because there’s less difference in voltage to drive ion movement.

• Final point:

  • When the membrane potential exactly reaches the reversal potential (+5mV), the driving force becomes 0, meaning no further changes in Vm will occur from synaptic inputs, and the membrane potential is "fixed" at that level.

Presynaptic Inhibition

• Axo-axonic synapse: Neuron A synapses onto Neuron B (A → B).

• Action potential in A: No effect on Neuron C because A does not contact C directly (blue trace).

• Action potential in B: Evokes a fast EPSP in C (red trace).

• Presynaptic inhibition: When an action potential in Axon A is followed by a signal in Axon B, the EPSP in C is smaller (purple trace).

  • Reason: The action potential in Axon A releases a transmitter that reduces the release of neurotransmitter from Axon B’s terminal.

  • This results in a weaker response in Neuron C, as less neurotransmitter is released at B’s synapse.

Autoinhibition

• Autoinhibition: A phenomenon where a train of fast EPSPs from a single axon progressively decreases in amplitude.

  • Cause: The released neurotransmitter inhibits its own release from the presynaptic terminal.

Mechanism of Autoinhibition

1. Neurotransmitter release: Each presynaptic action potential releases neurotransmitter (green) that binds to postsynaptic receptors (blue), causing an EPSP in the postsynaptic cell.

2. Autoreceptor activation: As neurotransmitter accumulates, it binds to autoreceptors on the presynaptic terminal (pink), leading to presynaptic inhibition.

   • This acts as a "brake" on neurotransmitter release, reducing the effect of further action potentials.

3. Example: Cholinergic synapses in the gut demonstrate this autoinhibition mechanism.

Factors Contributing to Transmission "Run-down" or Depression

• Post-synaptic receptor desensitisation: Receptors become less responsive after prolonged stimulation.

• Alterations in Ca²⁺ sensitivity: Changes in calcium levels can affect the release mechanism.

• Post-synaptic inhibition: Inhibitory receptors (which cause hyperpolarisation) can further reduce synaptic transmission.

Membrane Resistance (Rm)

• Rm depends on the number of open ion channels.

  • More open channels = lower Rm.

  • Fewer open channels = higher Rm.

• When a synaptic potential opens ion channels, it leads to a change in Rm.

Measuring Changes in Rm Using Ohm's Law

• Ohm’s Law: V=I×RV = I \times RV=I×R

  • V = Voltage (membrane potential)

  • I = Current

  • R = Resistance (Rm)

• We can measure changes in Rm during synaptic potentials by injecting constant current pulses into the cell and observing the resulting voltage changes.

• The relationship can be expressed as:

  • δV = I × Rm

  • Where δV is the change in voltage.

Effect of IPSP on Rm

• During an IPSP (Inhibitory Postsynaptic Potential), K⁺ channels open.

  • This lowers Rm because more channels are open for ions to flow through.

  • Hyperpolarising current pulses injected into the cell will get smaller as Rm decreases (from Ohm’s Law).

• This proves that the IPSP is due to channels opening, not closing.

Substance P and Membrane Resistance

• Substance P acting on the NK3 receptor:

  • Causes the closure of post-synaptic K⁺ channels that are normally open (leak channels).

  • K⁺ leak channels contribute to the resting membrane potential (RMP).

  • Result: Depolarization of the cell body and an increase in membrane resistance (Rm).

• Substance P and GPCR Activation:

  • Activates a GPCR that leads to the closure of K⁺ channels.

  • This results in depolarization of the cell and a reduction in Rm.

Implications for Signal Processing

• Temporal summation allows weak signals to build up over time.

• Spatial summation allows multiple signals from different locations to combine and potentially trigger an action potential.

1. Dendritic Properties and Signal Processing

   • Dendritic Spines

     • Act as micro-compartments that isolate and regulate synaptic activity.

     • Affect synaptic plasticity, which is critical for learning and memory.

   • Active Conductance in Dendrites

     • Some dendrites contain voltage-gated ion channels that amplify or regulate synaptic signals.

     • This can influence spatial summation and the likelihood of action potential initiation.

2. Inhibitory Control and Neural Circuits

   • Feedforward and Feedback Inhibition

     • Feedforward inhibition: An excitatory neuron activates an inhibitory neuron, which then suppresses another neuron.

     • Feedback inhibition: A neuron excites an inhibitory neuron that then inhibits the original neuron (self-regulation).

3. Clinical Relevance and Disorders Related to Synaptic Integration

   • Epilepsy

     • Results from excessive excitatory activity due to poor inhibitory control.

     • Abnormal summation leads to runaway neural firing (seizures).

   • Neurodegenerative Diseases

     • Diseases like Alzheimer’s affect dendritic structure and synaptic integration, impairing cognitive function.