Cells and Membrane Potential Vocabulary

Overview of Problem Set 2.1: Cells and Membrane Potential

• Goal of the Assignment: To complement class material and strengthen understanding of the nervous system cells, resting potentials, and action potentials.

• Administrative and Submission Instructions:     * Submissions can be independent or group-based.     * Group work is strongly encouraged to foster discussion.     * Questions should not be divided among members; the entire group should work on all questions together.     * Group submissions require all names to be listed on the answer sheet.     * Group members must join the same "Self-selected 2.1" group on Canvas.     * One person submits the .pdf to Canvas, which populates for all members.     * Independent submitters do not need to join a Canvas group.

Non-Neuronal Cell Types and Associated Neurological Disorders

• Alzheimer’s Disease:     * Clinical Description: Characterized partly by an inability to clear amyloid protein plaques that accumulate outside of neurons.     * Dysfunctional Cell Type: Microglia.     * Justification: Microglia function as the immune defense within the nervous system. Their role is to destroy and clear substances or debris that should not be present; in Alzheimer’s, they fail to clear the amyloid plaques.

• Amyotrophic Lateral Sclerosis (ALS):     * Clinical Description: Glutamate is not efficiently cleared from the extracellular space, resulting in excitotoxicity.     * Dysfunctional Cell Type: Astrocytes.     * Justification: Astrocytes regulate the exchange of materials neurons require and are responsible for clearing neurotransmitters (like glutamate) from the extracellular space to prevent toxicity.

• Multiple Sclerosis (MS):     * Clinical Description: Characterized by the progressive loss of the myelin sheath on axons.     * Dysfunctional Cell Type: Oligodendrocytes.     * Justification: Oligodendrocytes are responsible for forming the myelin sheath around neurons. In MS, these cells cannot keep up with the immune system's destruction of the sheath or replace it fast enough.

• Stroke and Vascular Complications:     * Clinical Description: Post-stroke, blood vessels may widen to improve flow, which can lead to brain lesions.     * Dysfunctional Cell Type: Astrocytes.     * Justification: Astrocytes are directly connected to the nerves of the blood supply and contribute significantly to the regulation of the blood supply.

• Schizophrenia:     * Clinical Description: Brain white matter, comprised of tracts of axons, frequently appears abnormal.     * Dysfunctional Cell Type: Oligodendrocytes.     * Justification: Since white matter is primarily composed of the myelin sheath, and oligodendrocytes produce that sheath, abnormalities in white matter indicate oligodendrocyte dysfunction.

Dynamics of Charged Particles and Membrane Gradients

• Analysis of Particle $Z^+$:     * Concentration Gradient: The direction is determined by the relative density of the particles on either side of the membrane.     * Electrical Gradient: The direction is determined by the overall charge distribution on either side.     * Flow Prediction: The number of $Z^+$ particles crossing is dependent on the permeability of the membrane and the combined strength of the chemical and electrical gradients.

• Analysis of Particle $A^+$ (Scenario Variation):     * Permeability Change: A hypothetical scenario where the membrane is impermeable to $Z^+$ but becomes permeable to $A^+$.     * Comparison of Flow: Requires determination of whether fewer or more $A^+$ particles would flow compared to $Z^+$ in the previous scenario.     * Directionality: Requires determination of whether $A^+$ flows in the same or a different direction compared to $Z^+$.

The Resting Membrane Potential and Ion Channels

• Baseline Potential: At rest, a neuron maintains a potential of approximately $-65\,mV$.

• Active Transport: The $Na^+/K^+$ pump actively expels $3\,Na^+$ ions from the cell for every $2\,K^+$ ions it brings inside.

• K+ Leak Channels:     * These channels are open during the resting state.     * They allow $K^+$ to flow slowly out of the cell.

• Pharmacological Manipulation of Leak Channels:     * Drug Action: A drug that blocks the $K^+$ leak channel prevents the outward flow of $K^+$ ions.     * Impact on Potential: If these channels are blocked, the membrane potential becomes less negative (closer to $0\,mV$) than the resting potential of $-65\,mV$.

Action Potential Mechanics and Ionic Flux

• Directional Analysis of Ion Flow: For any diagram representing the steps of an action potential (labeled 1 through 5), the following must be identified:     * Which specific ion channels are open (e.g., voltage-gated $Na^+$ or $K^+$).     * The direction of flow: into the neuron or out of the neuron.

Advanced Neuropharmacology and Electrophysiology

• Dendrotoxin (Developed by Prof. Allston):     * Mechanism of Action: Blocks voltage-gated $K^+$ channels.     * Experimental Context: Observed via patch clamp electrophysiology.     * Effect on Action Potential Peaks: Students must determine if the action potential peaks will be taller, shorter, or remain the same height when the drug is applied to the solution.

• Axotoxin (Developed by Dr. Brighton):     * Mechanism of Action: Blocks voltage-gated $Na^+$ channels with "weak affinity."     * Binding Kinetics: The drug frequently binds to and falls off the channels.     * Cellular Impact: At any given moment, there are fewer available voltage-gated $Na^+$ channels to open compared to a drug-free state.     * Generation of Action Potential: The presence of Axotoxin likely impairs or alters the threshold and speed of action potential generation due to the reduction in available sodium channels.