Lecture 2 Notes — Neurons: Action Potentials, Synapses, and Membrane Potentials

Action potential and encoding of stimulus intensity

• Action potential is an all-or-nothing event: once threshold is reached, an AP occurs and has the same size each time. If threshold isn’t reached, no AP occurs.
• The brain encodes stimulus intensity not by bigger APs, but by:
  • the number of action potentials generated (frequency) and
  • the rate at which they fire (frequency over time).
• Examples from the lecture:
  • Weak stimulus: small receptor potential leads to a few APs at the axon hillock; relatively few APs and modest neurotransmitter release.
  • Stronger stimulus: more APs generated, larger overall neurotransmitter release due to more spikes.
  • Strongest/longer-lasting stimulus: even more frequent APs and longer-lasting firing, leading to more sustained neurotransmitter release.
• Therefore, the intensity of a stimulus is coded by the number and frequency of APs, not by changes in AP amplitude.
• Threshold variability across textbooks:
  • Typical reported threshold is around
    $V_{th} \in [-65\ \text{mV},\ -50\ \text{mV}]$
  • Some sources place it at -50 mV, others at -65 mV; the exact value varies and is not strictly fixed.
• The rate of firing of a neuron reflects stimulus strength: faster firing implies a stronger input.
• The instructor encouraged questions for discussion boards and review sessions before exams.

Molecular basis of membrane potentials: basics

• The membrane is a phospholipid bilayer that is semi-permeable: some ions can cross more easily than others.
• Resting membrane potential arises from ion distributions across the membrane:
  • Inside: high potassium (K⁺) and large organic anions (A⁻, which are negatively charged and relatively immobile inside).
  • Outside: high sodium (Na⁺), chloride (Cl⁻), and calcium (Ca²⁺).
• Importantly, the cell interior is electrically negative relative to the outside at rest, due to these distributions.
• The membrane potential is the voltage difference across the membrane: inside vs outside.

Ionic forces at rest: two key players

• Two forces move ions across membranes:
  • Electrostatic pressure (electrical force): opposites attract and like charges repel. This tends to pull ions toward opposite charges across the membrane.
  • Diffusion: ions move from areas of high concentration to low concentration (Brownian motion).
• At rest, these forces are opposing and are regulated by the membrane’s permeability (which ions can move and when).
• Directional tendencies without channels:
  • Sodium (Na⁺) tends to move into the cell due to the negative interior.
  • Chloride (Cl⁻) and calcium (Ca²⁺) tend to move according to their gradients but are regulated by channels/transporters.
  • Potassium (K⁺) tends to diffuse out of the cell due to its higher inside concentration, opposing the negative interior.

Ion channels and transporters

• Two main ways ions cross membranes:
  • Ion channels: selective openings in the membrane that allow one type of ion to move through when open.
  • Transporters (pumps): actively move ions against their gradients, using energy (usually ATP).
• Ion channels are not always open; they open under specific conditions (gating).
• Transporters/pumps actively maintain ion balance and gradients; a key example is the sodium–potassium pump.

Gate mechanisms for ion channels

• Gate concept: a channel is either open or closed depending on the stimulus.
• Types of gates:
  • Voltage-gated ion channels: open or close in response to a specific membrane voltage. A particular voltage must be reached to open the channel.
  • Chemically (ligand) gated channels: open in response to a chemical stimulus (neurotransmitter binding).
• The lecture notes initially used chemically mediated channels (ligand-gated) as a primary example before moving to voltage-based gating.

The synapse: structure and sequence of events

• Key terms:
  • Presynaptic cell: the sending neuron.
  • Postsynaptic cell: the receiving neuron (often a dendritic spine or postsynaptic membrane).
  • Axon terminal: end of the presynaptic neuron containing vesicles with neurotransmitter.
  • Synaptic gap (cleft): the small space between pre- and postsynaptic membranes.
• Sequence of synaptic transmission:
  • An action potential arrives at the axon terminal of the presynaptic neuron.
  • This triggers release of neurotransmitter-containing vesicles into the synaptic cleft.
  • Neurotransmitter diffuses across the synaptic gap and binds to receptors on the postsynaptic membrane.
  • Receptors act as locks for the neurotransmitter key; binding opens ion channels (neurotransmitter-gated ion channels).
  • The ion channels then allow ions to flow, changing the postsynaptic membrane potential (graded potential).
  • The neurotransmitter does not enter the postsynaptic cell; it is released into the synapse and then cleared (reuptake, degradation, or diffusion).
• Three possible postsynaptic outcomes (depending on the ion channel opened):
  • Sodium channel opens → sodium influx → depolarization → excitatory postsynaptic potential (EPSP).
  • Potassium channel opens → potassium efflux → hyperpolarization → inhibitory postsynaptic potential (IPSP).
  • Chloride channel opens → chloride influx (negative ion entering) → hyperpolarization → IPSP.
• The same synapse is typically specialized for a specific type of response (excitatory or inhibitory) determined by the ion channel type that the neurotransmitter receptor gates; a given synapse is typically not two different channels at once (though different synapses on the neuron can be excitatory or inhibitory).

Receptor types: ionotropic vs metabotropic

• Ionotropic receptors (ligand-gated ion channels): a fast, direct coupling between transmitter binding and ion channel opening; the receptor and the channel are part of the same protein complex. Features:
  • Direct, fast, but short-lived effects.
  • One receptor directly gates a single ion channel.
• Metabotropic receptors: receptor activation triggers a cascade via a G protein and second messenger systems, which then opens ion channels indirectly. Features:
  • Slower onset, but longer-lasting effects.
  • A single receptor can influence multiple ion channels through signaling cascades.
• Many synapses exhibit both types simultaneously, contributing to complex temporal dynamics of signaling.

Neurotransmitter-receptor coupling: lock-and-key metaphor

• Neurotransmitter binds to its receptor (the lock).
• This binding causes the ion channel to open (the key turning the lock).
• After opening, the neurotransmitter dissociates and is cleared from the synapse.
• Receptor-channel arrangements:
  • Ionotropic: directly linked receptor and channel (fast, short-lived).
  • Metabotropic: receptor triggers a signaling cascade that modulates ion channels (slower, longer-lasting).

Graded potentials and neural integration at the soma

• Incoming signals are graded changes in membrane potential caused by ion flow through ligand-gated channels at the postsynaptic membrane.
• EPSP: local depolarization due to Na⁺ entering; brings the neuron closer to threshold.
• IPSP: local hyperpolarization due to K⁺ leaving or Cl⁻ entering; pushes membrane away from threshold.
• Neural integration: summation of EPSPs and IPSPs from multiple synapses determines whether the axon hillock reaches the threshold to fire an action potential.
• If sufficient positive charge accumulates to reach threshold at the axon hillock, an action potential is generated; otherwise, ions diffuse away and the sodium–potassium pump helps restore resting conditions.

Action potential initiation and consequences (opening topic for next section)

• The next topic to be covered is the actual action potential: its generation, propagation, and what makes it a robust, all-or-nothing signal across the neuron.
• Key concept to remember: integration at the dendrites and soma determines whether the axon hillock reaches threshold to trigger the AP, after which the AP propagates along the axon.

Practical, ethical, and real-world relevance

• Understanding how neurons code intensity via frequency and spike count informs medical approaches to treat neurological disorders and to design neural prosthetics and pharmacological interventions.
• Drugs that affect neurotransmitter receptors, ion channels, or the Na⁺/K⁺ pump can profoundly alter excitatory/inhibitory balance, impacting cognition, mood, and motor control.
• Ethical considerations arise in neuromodulation therapies (e.g., deep brain stimulation) and in research aimed at altering neural signaling, underscoring the need for careful assessment of risks, benefits, and consent.