Fourth lecture.pdf

Detailed Lecture Notes: Neuronal Signaling Mechanisms Introduction Lecture Overview: ○ Some material may feel like a review for those with a strong neuroscience background. ○ The next lectures will delve deeper into new material. ○ Importance of revisiting te...

Detailed Lecture Notes: Neuronal Signaling Mechanisms Introduction Lecture Overview: ○ Some material may feel like a review for those with a strong neuroscience background. ○ The next lectures will delve deeper into new material. ○ Importance of revisiting textbook chapters as supplemental reading. Neuronal Signaling Overview Core Problem in Cell Signaling: ○ Most cells struggle to achieve: Fast signaling Long-range signaling Precision in signaling ○ Example: Blood signaling is long-range and somewhat targeted but not fast. ○ Neurons are unique in their ability to achieve all three. Significance of Neuronal Signaling: ○ Underpins all types of behavior, from complex cognitive tasks (e.g., playing chess) to motor activities (e.g., playing an instrument). ○ Behavioral Implementation: All behaviors are made possible by neurons and their signaling capabilities. Key Features of Neuronal Signaling 1. Speed: ○ Neurons achieve temporal precision, crucial for behaviors where milliseconds matter (e.g., predator evasion). ○ Action Potentials: Typically last about 1 millisecond; in motor control regions, they can be as short as 0.5 milliseconds.  Allow for remarkable temporal precision, essential for high-speed behaviors and sensory processing. ○ Neuronal Timing: Example: Neurons in the brainstem can time events at kilohertz speeds, enabling precise auditory processing and motor coordination. 2. Propagation: ○ Myelinated Axons: Myelination is crucial for fast signal propagation, especially over long distances. Maximum Velocity: Myelinated axons can transmit signals at speeds up to 100 meters per second. Myelination is particularly important for long-distance axons, such as those extending from the spinal cord to the toes. ○ Importance of Long-Range Signaling: Consistent and precise signaling is necessary even over distances of up to a meter. Failures in precision can lead to incorrect motor actions (e.g., flexing instead of extending a foot). 3. Target Specificity: ○ Development and Plasticity: During development and throughout life, neurons select specific targets for synaptic connections. ○ Synaptic Diversity: Synapses can be excitatory, inhibitory, ionotropic, or metabotropic. Neurons release neurotransmitters selectively, ensuring precise communication. ○ Synaptic Precision: Even neurons releasing multiple types of neurotransmitters do so in a highly targeted manner. This specificity is crucial for maintaining the precision required for complex neural networks. Important Slides Mentioned Key Diagrams: ○ Schematic of neuron signaling highlighting temporal precision and long-range capabilities. ○ Illustrations of action potentials and myelinated axon signaling.  Note on Myelination: ○ Remember that myelination is used for long-distance signaling, not for short distances. Conclusion Neuronal Challenge: ○ Neurons need to balance speed, precision, and long-range signaling to support complex behaviors. ○ Understanding these mechanisms is crucial for further studies in neurobiology and behavior. These notes should provide a detailed overview of the lecture content, capturing key points while correcting any transcription errors based on context. Let me know if you need further clarification or additional notes! Lecture Notes on Cell Membranes and Ion Channels Key Points: 1. Introduction to Cell Membranes ○ Fundamental Features: Cell membrane is a lipid bilayer. The lipid bilayer is non-polar and thus inhibits the passage of ions across it. 2. Ion Transport Across Membranes ○ Ions are highly restricted from crossing the lipid bilayer due to its non-polar nature. ○ Cells control ion concentration inside and outside the membrane by utilizing ion channels. ○ These channels are crucial for neuron signaling, allowing rapid transmission across long distances. 3. Ion Concentrations ○ Typical Ion Concentrations: Sodium: Higher outside the cell. Potassium: Higher inside the cell.  Calcium: Very low inside the cell due to its strong effects on neurons; typically stored or chelated inside. ○ External calcium levels can vary in experiments (physiological range ~1.2 mM; in studies often ~2-2.5 mM). 4. Ionic Gradients and Forces ○ Two Key Forces on Ions: Concentration Gradient: Pushes ions from high to low concentration. Voltage Gradient: Affects ions based on the membrane potential (e.g., -70 mV inside the neuron). ○ Potassium example: High inside, low outside. Concentration gradient pushes potassium out, voltage gradient pushes it in. 5. Nernst Potential and Ion Equilibrium ○ Nernst Potential: A calculation to determine the exact voltage where the forces (concentration and voltage) are balanced, causing no net movement of the ion across the membrane. Important Note: This potential is also known as equilibrium potential or reversal potential. 6. Nernst Equation ○ Equation Components: R: Universal gas constant. T: Temperature in Kelvin (Celsius + 273.15). Z: Ion valence. F: Faraday constant. [Ion]out / [Ion]in: Concentrations outside and inside the cell. ○ This equation is vital for calculating the equilibrium potential for any ion. 7. Practical Application of Nernst Equation: ○ Use the equation to determine the Nernst potential for potassium using room temperature as the standard. ○ Example calculation yields a Nernst potential for potassium around -80 to -100 mV. 8. Impact of Temperature on Nernst Potential: ○ Effect of Increased Temperature: Increasing temperature (e.g., to body temperature) makes the Nernst potential more negative. This is due to the temperature's role in increasing the numerator in the equation, influencing the outcome.  9. Understanding Logs in the Equation: ○ Negative Sign in the Equation: The negative sign arises when the log of a fraction (concentration outside < concentration inside) is calculated, resulting in a negative value. Slide Notes: Slide with Ion Concentrations: Important to understand the general ranges rather than memorize exact values. Slide with Nernst Equation: Critical for understanding how to calculate ion equilibrium potentials. Conclusion: Understanding the fundamental features of cell membranes and the forces acting on ions is crucial for grasping how neurons transmit signals. The Nernst potential is a key concept that illustrates the balance of these forces, and temperature plays a significant role in determining this balance. Lecture Notes on Neuronal Membrane Potentials and Conductance Temperature Effects on Neuronal Properties Temperature Impact: Lower temperatures, such as room temperature, will decrease the equilibrium potential (E_k) slightly compared to physiological temperature. This should be considered during experiments, such as slice recordings, as properties of neurons may differ based on the recording temperature. Sodium Ion Concentration and Membrane Potential Important Numbers: The lecturer emphasized the importance of memorizing key ion concentrations, especially sodium (Na⁺), as they are crucial for understanding neuronal function. The concentration of Na⁺ is high outside the cell and low inside, contributing to a positive reversal potential when calculated. Slide Reference: This point was highlighted as important, with a reminder to review the slides for accurate values. Potassium Ion and Reversal Potential  Ion Valence: The valence of ions is crucial when calculating potentials. The example given showed a high concentration of potassium (K⁺) inside the cell and low outside, leading to a negative reversal potential. Comparison to Last Year’s Class: This class was noted to have a better grasp of ion valence compared to the previous year, which struggled with calculating the correct values. Driving Force and Conductance Driving Force: Defined as the difference between the current membrane potential and the reversal potential for a specific ion. For instance: ○ Potassium (K⁺): If membrane potential is -70 mV and E_k is -85 mV, the driving force is +15 mV, pushing K⁺ out of the cell. ○ Sodium (Na⁺): If membrane potential is -70 mV and E_Na is around +60 mV, the driving force is -130 mV, pulling Na⁺ into the cell. Conductance: This refers to the number of available pathways (e.g., ion channels) for ions to cross the membrane. The analogy of "holes in a hose" was used, where driving force is the water pressure, and conductance is the number of holes. Note that ion channels are selective, allowing specific ions (like K⁺ or Na⁺) to pass. Resting Membrane Potential Resting Potential Dynamics: ○ If a neuron has only potassium leak channels, the resting membrane potential will align with the potassium reversal potential (E_k), approximately -85 mV. ○ Adding sodium leak channels introduces a depolarizing effect, raising the membrane potential closer to Na⁺'s reversal potential (+60 mV), but due to the smaller number of sodium channels, the membrane potential typically stabilizes around -70 mV. Goldman-Hodgkin-Katz Equation: This equation was mentioned as key for calculating the resting membrane potential, considering the permeability of different ions and their respective concentrations. Membrane Potential Variability Neuronal Leakiness: The lecturer noted that not all neurons have uniform leakiness throughout the membrane. This variability can affect where and how the resting membrane potential stabilizes, with soma being a focus in the discussion.  Chloride and Calcium: Chloride leak conductance plays a minor role in setting the resting potential, and calcium conductance is not typically considered in this context. Important Slide References The lecturer mentioned that certain equations and concepts would be on the slides available online. Specifically, the Goldman-Hodgkin-Katz equation was noted as being placed towards the end of the presentation and was highlighted as essential for understanding the weighted average of ion contributions to the membrane potential. Note: These notes summarize key points from the lecture, including references to specific slides for further study. Make sure to review the slides and equations mentioned, as they are critical for understanding the material. Detailed Notes on Ion Channels, Membrane Potential, and Neuronal Activity 1. Ion Leakage and Membrane Potential Stabilization Sodium (Na+) and Potassium (K+) Leakage: ○ Sodium ions (Na+) slowly leak into the cell while potassium ions (K+) leak out. ○ This leakage occurs continuously and is balanced by the sodium-potassium pump, which actively uses ATP to restore the ion concentration across the membrane. ○ This process is crucial for maintaining the resting membrane potential of the neuron. ○ Important Note: The leak is relatively small but significant enough to require continuous correction by the sodium-potassium pump to maintain stability. 2. Ion Channels and Conductance Glial Cells vs. Neurons: ○ Glial cells have potassium (K+) conductance but minimal sodium (Na+) conductance, which prevents them from firing action potentials.  ○ Neurons, on the other hand, possess a variety of ion channels, allowing them to become excitable and generate action potentials. ○ The resting membrane potential of glial cells is close to the equilibrium potential of potassium (EK_KK​) because of their high potassium conductance. Channel Types and Structure: ○ Ion channels can open through various mechanisms, including structural changes or the presence of blocking particles that control ion flow. ○ Ligand-Gated Ion Channels: Open in response to the binding of a specific molecule (ligand). Example: AMPA receptors, a type of glutamate receptor, which are ligand-gated ion channels. ○ Voltage-Gated Ion Channels: Open or close in response to changes in the membrane's electrical potential. These channels are selective for specific ions, such as sodium (Na+), potassium (K+), or chloride (Cl-). Voltage-gated channels have positively charged regions that move in response to depolarization, triggering a conformational change that opens the channel. 3. Functional and Structural Aspects of Ion Channels Key Points on Ion Channels: ○ Channels are selective, and their structure determines which ions can pass through. ○ Some channels, such as leak channels, are always open, while others require specific stimuli to open. ○ Potassium (K+) Channels: Potassium channels are selective and have a structural filter that allows K+ ions to pass while excluding others like Na+, which typically enters the cell with water molecules attached. ○ Voltage-Gated Potassium (Kv) Channels: Kv Channels are tetrameric (composed of four subunits). The mutation in the KV 6.4 subunit affects potassium conductance and neuronal excitability (discussed in detail later). 4. Effects of Mutations on Neuronal Function  Study on Women with a KV 6.4 Mutation: ○ A specific single nucleotide polymorphism (SNP) in the KV 6.4 channel was found in a subset of women who experienced less pain during labor. ○ This mutation results in KV 6.4 not being trafficked to the membrane, leading to a lack of incorporation into the KV 2.1 channel. ○ Normally, the inclusion of KV 6.4 in the KV 2.1 heteromeric channel reduces potassium conductance. ○ In women with the mutation, increased potassium conductance leads to a membrane potential closer to EK_KK​, resulting in hyperpolarization and decreased neuronal excitability. ○ Discussion Point: The mutation leads to less depolarization, affecting the neuron's sensitivity to stimuli and potentially contributing to reduced pain perception during labor. 5. Neurotransmitter Receptors Overview Types of Neurotransmitter Receptors: ○ Ionotropic Receptors: Directly allow ions to flow through the membrane upon ligand binding. Examples: AMPA receptors (glutamate receptors), GABA receptors. ○ Metabotropic Receptors: G-protein coupled receptors (GPCRs) that activate intracellular signaling cascades, potentially leading to changes in membrane potential. Example: GPCRs that modulate ion channels indirectly. Receptor Permeability and Reversal Potential: ○ Ionotropic Receptors have varying permeability to ions, leading to different reversal potentials. ○ Glutamate Receptors and Acetylcholine Receptors have a reversal potential around 0 mV due to their mixed permeability to Na+ and K+. ○ GABA and Glycine Receptors are mainly permeable to chloride (Cl-), resulting in different effects on the membrane potential. 6. Important Slides and Summary Tables Slide Summary Tables:  ○ These tables categorize ion channels by type, structure, and function. ○ Key points to focus on: Terminology: Understanding the different types of ion channels (e.g., KV channels for voltage-gated potassium channels). Channel Structure: Although detailed structural knowledge isn't required, recognizing that channels are made up of different subunits and that these subunits can vary. Pharmacological Blockers: Tetrodotoxin (TTX): Selectively blocks voltage-gated sodium channels. Tetraethylammonium (TEA): Selectively blocks voltage-gated potassium channels. Cadmium: Acts as an open-channel blocker for calcium channels. ○ Clinical Relevance: Understanding these concepts helps in interpreting research and clinical data, such as the impact of specific ion channel mutations on neuronal function. Conclusion Membrane Potential Dynamics: ○ The balance between sodium and potassium conductance plays a critical role in determining the resting membrane potential and the excitability of neurons. ○ Mutations that alter ion channel conductance can have significant effects on neuronal behavior and physiological responses. Neurotransmitter Receptor Function: ○ The type and permeability of neurotransmitter receptors influence their role in synaptic transmission and neuronal communication. Future Lectures: ○ More detailed discussions on voltage-gated channels and their role in action potential generation and propagation. ○ Further exploration of neurotransmitter receptors and their role in synaptic transmission. Note: Pay close attention to the slides that categorize ion channels and their pharmacological blockers, as this information is vital for understanding the broader context of neuronal signaling. Detailed Notes on Potassium Reversal Potentials, Neurotransmitter Receptors, and Recording Techniques 1. Potassium Reversal Potentials and Neurotransmitter Receptors Potassium Reversal Potential: ○ Potassium (K+^++) reversal potentials are significant because they allow both sodium (Na+^++) and potassium ions to pass through the membrane. ○ The exact reversal potential is closer to the sodium reversal potential due to the permeability of Na+^++, though it is influenced by the presence of potassium. ○ Most reversal potentials for excitatory neurotransmitter receptors are around 0 mV. ○ GABA and glycine receptors reverse at the chloride equilibrium potential (ECl_\text{Cl}Cl​) because of their chloride (Cl−^-−) conductance. Neurotransmitter Receptor Function: ○ Neurotransmitter receptors can be categorized into two functional types: 1. Excitatory (Depolarizing): Pull the membrane potential towards 0 mV, making the neuron more likely to fire. 2. Inhibitory (Hyperpolarizing): Pull the membrane potential back towards the resting potential (around -70 mV), making the neuron less likely to fire. ○ Excitatory receptors typically involve glutamate (e.g., AMPA, NMDA receptors), while inhibitory receptors involve GABA and glycine. Reversal Potentials and Excitatory/Inhibitory Actions: ○ The reversal potential of a receptor determines its excitatory or inhibitory action. ○ Example: Even if the reversal potential of GABA is close to the resting membrane potential, opening GABA receptors can still inhibit neuron firing by increasing the membrane's leakiness and reducing its excitability. 2. Electrical vs. Chemical Synaptic Transmission Electrical Synaptic Transmission: ○ Involves direct ion flow between neurons through gap junctions (connexons). ○ Gap junctions act like small pipes allowing ions to pass directly between connected neurons, leading to near-synchronous activity.  ○ Common in certain types of inhibitory neurons, allowing them to synchronize their inhibitory effects. ○ Key Slide: Electrical synapses, while less common than chemical synapses, play a crucial role in synchronizing neuronal networks, particularly in certain brain regions. Chemical Synaptic Transmission: ○ Involves neurotransmitter release from vesicles, binding to receptors on the post-synaptic neuron, and initiating ion channel opening. ○ Chemical transmission is more common and complex, involving various types of receptors (e.g., ionotropic, metabotropic). 3. Types of Physiological Recordings Importance of Recording Techniques: ○ Different physiological recording techniques are used to study neuronal activity and ion channel function. ○ These techniques help determine the causes of changes in neuronal firing rates, such as reduced excitation, increased inhibition, or changes in input resistance. Extracellular Recordings: ○ Tetrodes, Arrays, and MEAs: Used to record spikes (action potentials) from multiple neurons simultaneously. ○ These methods are crucial for studying network-level activity in the brain. Intracellular Recordings: ○ Patch-Clamp Technique: Allows recording of membrane potential and current from a single neuron. ○ Can also be used to drive changes in current or voltage (stimulation). Current-Clamp vs. Voltage-Clamp: ○ Current-Clamp Recording: Measures membrane potential (voltage) while injecting a known current. Example: Injecting a negative current can stop a neuron from spiking, demonstrating the effect of inhibitory inputs. ○ Voltage-Clamp Recording: Measures the current required to maintain a specific membrane potential (voltage). Voltage clamp operates in a closed-loop system, similar to cruise control in a car. It adjusts the current to keep the membrane potential constant, despite any incoming synaptic activity.  Key Concept: The reported data in voltage-clamp experiments is the amount of current needed to maintain the membrane potential at a set value (e.g., -65 mV). Practical Application of Recording Techniques: ○ Understanding these techniques is vital for interpreting experimental data on neuronal function, particularly when studying the impact of ion channel mutations or synaptic inputs on neuron behavior. 4. Voltage Clamp and Feedback Mechanisms Voltage Clamp Mechanics: ○ The voltage clamp technique uses a feedback loop to maintain a constant membrane potential. ○ When the neuron’s potential deviates due to synaptic inputs, the amplifier injects the necessary current to bring it back to the set potential (e.g., -65 mV). ○ Analogy: Similar to a car’s cruise control adjusting gas injection to maintain a constant speed. Challenges with Voltage Clamp: ○ Voltage clamp is not perfect; it involves fast switching between measuring voltage and injecting current, which can cause slight imperfections in the recorded membrane potential. ○ The primary interest in voltage clamp experiments is how much current is needed to maintain the set potential, as this reflects the underlying ionic conductances. Future Lectures: ○ More in-depth discussions on voltage clamp, particularly focusing on its applications in studying ion channel function and synaptic transmission. 5. Additional Resources Meta Neuron Simulation: ○ Optional download from metaneuron.org for hands-on experience with the concepts discussed. ○ Example questions available for practice and self-assessment. Important Slides:  1. Electrical vs. Chemical Synapses: Key slide highlighting the roles of gap junctions and their impact on neuronal synchronization. 2. Voltage-Clamp Technique: Detailed explanation of the feedback loop mechanism, crucial for understanding future discussions on ion channel behavior. Note: Review the slides that categorize different types of synaptic transmission and recording techniques, as they are essential for grasping the broader context of neuronal physiology and research methodologies.