HBF-III LEC 24 Neuroscience Electrochemical Basis Neural Signaling Notes PDF 2025

Maria Bykhovskaia Neurology Department, OVAS Department Electrochemical Basis of Neural Signaling Learning Objectives: At the conclusion of this session, students will demonstrate that they can effectively: 1. Explain sending and receiving parts of a neuron. 2. Explain the mechanisms driving the n...

Maria Bykhovskaia Neurology Department, OVAS Department Electrochemical Basis of Neural Signaling Learning Objectives: At the conclusion of this session, students will demonstrate that they can effectively: 1. Explain sending and receiving parts of a neuron. 2. Explain the mechanisms driving the neuronal membrane potential. 3. Analyze the determinants of the neuronal membrane potential. 4. Describe the role of the graded potential in neuronal signaling. 5. Explain the propagation of graded potentials. 6. Explain the involvement of ion channels in the generation of action potentials. 7. Analyze the determinants of the action potential and explain how action potentials can be manipulated. 8. Explain the contribution of ion channel inactivation to the action potential. 9. Explain the propagation of the action potential. 10. Explain the role of axon myelination. 11. Explain determinants of the velocity of the action potential propagation and the associated pathologies. 12. Compare electrical and chemical synaptic transmission. 13. Summarize the steps underlying chemical synaptic transmission. 14. Explain the organization of the presynaptic active zone. 15. Explain the probabilistic nature of synaptic transmission. 16. Compare excitatory and inhibitory synapses. 17. Explain the formation of neuronal networks and provide examples. Outline: 1. Neuronal structure and information transfer 2. Membrane potential 3. Grading potential 4. Action potential 5. Synapses 6. Neuronal networks 1 1. Neuronal structure and the information transfer The signaling within a neuron is electrical. It represents the ion flux across the membrane, which propagates from dendrites to axonal terminals. 2. Membrane potential Ion channels are transmembrane proteins, which a pore in the lipid bilayers. Opening the pore (gating) enables ion flux (electric current) across the membrane. Different gating mechanisms underly components of neuronal signaling. The membrane potential is largely define by the activity of leak channels. 2 The membrane is polarized due to the functioning of the Na+/K+ pump and leak ion channels. The negative charge accumulates at the cytoplasmic side, and the positive charge accumulates at the extracellular side. The voltage difference across the membrane (intracellular minus extracellular) is called the membrane potential. The Na+/K+ pump produces the K+/Na+ concentration gradient. Due to the concentration gradient, K+, Na+ and Cl- ions leak through the leak ion channels and produce the membrane polarization. The membrane potential can be described by the Nernst equation. The Nernst equation assumes (for simplicity) that only the K+ current defines the membrane potential. This is a reasonable assumption, since the leak K+ current is the major determinant of the membrane potential, while the contribution of other ion channels is minor. More accurate description of the membrane potential is provided by Goldman equation, which allows us to compute the membrane potentials taking all the ionic currents into consideration. The Goldman equation integrates Nernst equations for each ion in their general forms, which incorporate ion charges (z). The simplification of the Goldman equation eliminates the Cl- current as being negligibly small compared to K+ and Na+ currents. 3 These examples illustrate that the membrane potential is largely driven by the leak K+ current, while Na+ current acts to reduce the membrane potential. 4 3. Graded potential Neurons receive their inputs as graded electric potentials. Graded potentials propagate passively through dendrites and soma. The passive propagation is described by the cable properties of the membrane. Graded potentials decay exponentially with the distance and their shape becomes distorted (filtered via the RC circuit). Graded potentials can add up, and they integrate in the soma, propagating to the axon hillock. 5 4. Action potential Once the graded potential reaches the axon hillock, it may (or may not) produce the action potential. To produce the action potential, the graded potential needs to reach the threshold for opening voltage-gated ions channels. The voltage-gated Na+ and K+ channels define the properties of action potentials (amplitude, decay, etc.) 6  Voltage gated K+ Two possibilities: Inactivation of channels are voltage gated Na+ 1) Extracellular Na+ channels is blocked is reduced inhibited 2) Voltage gated Na+ channels are partially blocked Action potential can be manipulated pharmacologically 7 Inactivation of voltage gated Na+ channels underlies two important properties of the action potential: 1) unidirectional propagation and 2) refractory period. 8 Because of the refractory period, a prolonged depolarizing signal can produce repetitive action potentials – firing. Firing depends on the ionic composition of a neuron and can be neuron specific. Firing patters can encode sensory signals, such as smell. Axonal myelination accelerates the propagation of the action potential. Myelinated sheaths insulate the axon. The signal propagates passively via myelinated stretches and retriggers at the nodes of Ranvier, which have high density of voltage gated channels. 9 Two factors define the conduction velocities: myelination and the axon diameter. Deficiencies in myelination can produce severe disease, such as CMT or MS 5. Synapses Neurons communicate through neuronal connections – synapses. Synapses can be electrical or chemical. Chemical synaptic transmission is more common. At electrical synapses, the electrical current is transmitted through gap junctions –ion channels spanning through both presynaptic and postsynaptic membranes. At chemical synapses, action potentials trigger the opening of voltage gated Ca2+ channels, which enable Ca2+ influx into nerve terminals. Ca2+ triggers a cascade of molecular events, which lead to the fusion of synaptic vesicles with the presynaptic membrane and release of neuronal transmitters into the synaptic cleft. Transmitters then diffuse through the synaptic cleft and activate postsynaptic ligand-gated ion channels, which generate the postsynaptic depolarization. Release of transmitters occurs at morphological specializations termed active zones. Active zones cluster Ca2+ channels and synaptic vesicles. Synaptic vesicles attach to the membrane via a coil-coiled four-helical SNARE protein complex. Vesicle protein Synaptotagmin serves as a Ca2+ sensor. 10 Presynaptic active zones can be defined as morphological specializations incorporating electron dense material (seen in electron microscope) surrounded by clusters of synaptic vesicles. The include clusters of Ca2+ channels and synaptic proteins regulating fusion. Vesicles are attached to the plasma membrane by the four-helical coil- coiled SNARE complex, and the vesicle protein Synaptotagmin serves as a Ca2+ sensor. Deficiencies in the proteins mediating the release of neuronal transmitters can produce severe neurological and mental disorders. 11 Neuropeptide transmitters are usually packed in large dense-core vesicles. 12 Synaptic transmission is probabilistic in nature. The response to an action potential varies from trial to trial. In addition, vesicles also fuse in a spontaneous or asynchronous (delayed) mode. This property of synaptic transmission is important for the information transfer in the brain Excitatory synapses typically (but not always) synapse onto dendritic spines or dendritic shafts (axodendritic synapses). Inhibitory synapses often synapse onto the cell body (axosomatic synapses), which enables them to shunt the excitatory depolarizing signal more efficiently. The ending points of neuronal networks are neuromuscular junctions, which mediate muscle contraction, or neurosecretory cell, which release hormone molecules, such as adrenaline, into the blood flow. 13 6. Neuronal networks Neurons form neuronal networks via neuronal connections, synapses. One of the simplest neuronal networks, mediating the knee jerk reflex, involves free forward excitation: sensory neuron ->extensor motor neuron, as well as free forward inhibition: sensory neuron ->inhibitory interneuron- >flexor motor neuron. More complex networks involve convergence, divergence, and feedback loops. 14