Comprehensive Neurophysiology Study Notes: Neurons, Action Potentials, Synapses, and Glial Cells

Cellular Anatomy of Neurons and Membrane Structure

• Functional Architecture of Neurons:

  • Soma (Perikaryon): Primary metabolic center containing the nucleus, rough endoplasmic reticulum (Nissl substance), Golgi apparatus, and mitochondria; synthesizes cellular proteins, neuroreceptors, and neurotransmitter metabolic enzymes.

  • Dendrites & Dendritic Spines: Highly arborized receptive processes containing postsynaptic density proteins (PSD-95); dendritic spines function as biochemical microdomains essential for synaptic plasticity, long-term potentiation (LTP), and long-term depression (LTD).

  • Axon Hillock & Axon Initial Segment (AIS): Cone-shaped transition zone rich in voltage-gated sodium channels ($\text{Na}_v1.6$); site of postsynaptic potential summation and action potential initiation.

  • Axon & Axoplasmic Transport: Conducts electrical spikes over long distances; supported by bidirectional axoplasmic transport along microtubules via anterograde motor proteins (kinesins) and retrograde motor proteins (dyneins).

  • Axon Terminals (Presynaptic Boutons): Specialized distal terminals packed with active zones, synaptic vesicles, voltage-gated calcium channels ($\text{Ca}_v2.1$, $\text{Ca}_v2.2$), and neurotransmitter reuptake transporters.

• Membrane Composition and Architecture:

  • Phospholipid Bilayer: Amphipathic lipid matrix restricting passive flux of polar molecules and hydrated inorganic ions; maintains high electrical resistance and dielectric capacitance.

  • Integral & Transmembrane Proteins: Spanning membrane proteins including voltage-gated/ligand-gated ion channels, primary/secondary active transporters ($\text{Na}^+/\text{K}^+-\text{ATPase}$, $\text{NCX}$), and seven-transmembrane G-protein coupled receptors (GPCRs).

  • Peripheral Proteins & Cytoskeletal Anchors: Intracellular and extracellular membrane-associated proteins providing structural scaffolding (spectrin-actin) and receptor clustering (PSD-95, gephyrin).

  • Glycocalyx (Glycoproteins & Glycolipids): Extracellular carbohydrate moieties governing synaptic cell adhesion (NCAMs), cell-cell recognition, and structural stabilization of synaptic clefts.

  • Membrane Cholesterol & Lipid Rafts: Interspersed sterols regulating membrane fluidity, phase transitions, and localization of signaling cascades, ion channels, and exocytotic machinery.

Ion Transport Mechanics and Membrane Permeability

• Passive Transport & Ion Channel Biophysics:

  • Passive ion flux driven down electrochemical gradients without direct metabolic energy expenditure.

  • Aqueous Pore Structure: Fluid-filled central pore lined with polar amino acids facilitating hydrated ion passage across the hydrophobic core.

  • Selectivity Filter: Structural domain lined with conserved amino acid motifs (e.g., TVGYG in $\text{K}^+$ channels) that dehydrates specific ion species based on ionic radius and charge density.

  • Gating Mechanisms: Conformational transitions between open, closed, and inactivated/desensitized states triggered by membrane voltage ($S_4$ domain displacement), ligand binding, or mechanical force.

• Active Transport Systems & Pumps:

  • $\text{Na}^+/\text{K}^+-\text{ATPase}$ (Electrogenic Pump): Primary active transporter hydrolyzing $1\,\text{ATP}$ to extrude $3\,\text{Na}^+$ and import $2\,\text{K}^+$ per cycle; maintains steep baseline ionic gradients and contributes an electrogenic hyperpolarizing current ($\sim 5-10\,\text{mV}$); target of cardiac glycosides (ouabain, digoxin).

  • $\text{Ca}^{2+}$ Extrusion Mechanisms:

  • $\text{PMCA}$ (Plasma Membrane $\text{Ca}^{2+}-\text{ATPase}$): High-affinity, low-capacity primary pump maintaining sub-micromolar baseline cytosolic free $\text{Ca}^{2+}$ ($\sim 100\,\text{nM}$).

  • $\text{NCX}$ ($\text{Na}^+/\text{Ca}^{2+}$ Exchanger): Low-affinity, high-capacity secondary active transporter utilizing the $\text{Na}^+$ gradient to exchange $3\,\text{Na}^+$ inward for $1\,\text{Ca}^{2+}$ outward; reversible under high intracellular $\text{Na}^+$ or severe depolarization.

• Membrane Permeability Values ($P$ in $\text{cm/s}$):

  • Water ($\text{H}_2\text{O}$): $1.2 \times 10^{-2}\,\text{cm/s}$

  • Chloride ($\text{Cl}^-$): $1.1 \times 10^{-10}\,\text{cm/s}$

  • Potassium ($\text{K}^+$): $6.0 \times 10^{-11}\,\text{cm/s}$

  • Sodium ($\text{Na}^+$): $1.0 \times 10^{-12}\,\text{cm/s}$

• Standard Metric Scale for Biological Permeability and Conductance:

  • deci- ($d$): $10^{-1} = 0.1$

  • centi- ($c$): $10^{-2} = 0.01$

  • milli- ($m$): $10^{-3} = 0.001$

  • micro- ($\mu$): $10^{-6} = 0.000001$

  • nano- ($n$): $10^{-9} = 0.000000001$

  • pico- ($p$): $10^{-12} = 0.000000000001$

  • femto- ($f$): $10^{-15} = 0.000000000000001$

  • atto- ($a$): $10^{-18} = 0.000000000000000001$

  • zepto- ($z$): $10^{-21} = 0.000000000000000000001$

  • yocto- ($y$): $10^{-24} = 0.000000000000000000000001$

Resting Membrane Potential and Ionic Equilibrium

• Resting Membrane Potential ($E_M$ / $V_m$):

  • Steady-state electrical potential across the cell membrane at rest ($-60\,\text{mV}$ to $-80\,\text{mV}$, classically recorded at $-70\,\text{mV}$ to $-75\,\text{mV}$).

  • Primary determinants: asymmetric ion concentrations, selective resting membrane permeability ($P_{\text{K}} \gg P_{\text{Na}}$), intracellular impermeable anions ($\text{Pr}^-$), and electrogenic $\text{Na}^+/\text{K}^+-\text{ATPase}$ pump activity.

• Physiological Concentrations of Inorganic Ions:

  • Sodium ($\text{Na}^+$): Extracellular = $150\,\text{mmol/L}$, Intracellular = $15\,\text{mmol/L}$

  • Chloride ($\text{Cl}^-$): Extracellular = $110\,\text{mmol/L}$, Intracellular = $10\,\text{mmol/L}$

  • Potassium ($\text{K}^+$): Extracellular = $5\,\text{mmol/L}$, Intracellular = $150\,\text{mmol/L}$

• Equilibrium Potential and the Nernst Equation:

  • The membrane potential ($E_{\text{ion}}$) where electrical driving force precisely counterbalances the chemical concentration gradient, yielding zero net flux.

  • Calculated via the Nernst Equation:     $E_{\text{ion}} = \frac{RT}{zF} \ln\left(\frac{[\text{ion}]_o}{[\text{ion}]_i}\right)$

  • Physiological Nernst Reversal Potentials ($E_{\text{ion}}$):

  • Potassium ($E_{\text{K}^+}$): $-80\,\text{mV}$

  • Chloride ($E_{\text{Cl}^-}$): $-70\,\text{mV}$

  • Sodium ($E_{\text{Na}^+}$): $+50\,\text{mV}$

  • The Goldman-Hodgkin-Katz (GHK) voltage equation accounts for relative permeabilities ($P_{\text{K}} : P_{\text{Na}} : P_{\text{Cl}} \approx 1 : 0.04 : 0.45$), demonstrating why baseline $E_M$ resides close to $E_{\text{K}^+}$.

Action Potential Generation and Voltage-Gated Channels

• Electrophysiological Principles of the Action Potential:

  • Threshold Requirement: Membrane potential must depolarize by $\sim +15\,\text{mV}$ (reaching $\sim -55\,\text{mV}$) to initiate positive feedback activation of voltage-gated sodium channels.

  • All-or-None Law: Spike amplitude and duration are independent of stimulus strength once threshold is breached; stimulus intensity is encoded by firing frequency.

  • Refractory Periods:

  • Absolute Refractory Period: Window during depolarization and early repolarization where $\text{Na}_v$ channels are open or fully inactivated by the intracellular isoleucine-phenylalanine-methionine (IFM) motif; no secondary spike can occur. Site of action for use-dependent channel blockers (lidocaine, phenytoin, carbamazepine).

  • Relative Refractory Period: Window during hyperpolarization where $\text{Na}_v$ channels have reset to closed states, but high delayed-rectifier $\text{K}^+$ conductance persists; requires stronger depolarizing current to fire.

• Action Potential Phases & Channel Kinetics:

  • Resting State ($-70\,\text{mV}$): $\text{Na}_v$ activation gate closed, inactivation gate open; $\text{K}_v$ channels closed.

  • Depolarization Phase: Voltage sensor ($S_4$ alpha-helix) shifts outward, opening $\text{Na}_v$ activation gates. Rapid inward $\text{Na}^+$ influx (up to $5000\times$ increase in $\text{Na}^+$ conductance) depolarizes membrane toward $E_{\text{Na}^+}$ ($+30\,\text{mV}$ to $+50\,\text{mV}$). Blocked by neurotoxins tetrodotoxin (TTX) and saxitoxin (STX).

  • Repolarization Phase: $\text{Na}_v$ channels undergo rapid inactivation while delayed rectifier voltage-gated $\text{K}^+$ channels ($\text{K}_v1.1$, $\text{K}_v2.1$) open fully, producing strong outward $\text{K}^+$ efflux. Blocked by tetraethylammonium (TEA) and 4-aminopyridine (4-AP).

  • Hyperpolarization Phase (Undershoot): Slow closing kinetics of $\text{K}_v$ channels drive $\text{V}_m$ transiently toward $E_{\text{K}^+}$ ($\sim -80\,\text{mV}$) before returning to resting state via leak channels and $\text{Na}^+/\text{K}^+-\text{ATPase}$ action.

Action Potential Propagation and Conduction Velocity

• Continuous Conduction in Unmyelinated Axons:

  • Inward $\text{Na}^+$ current depolarizes the local axon membrane, generating intracellular local current circuits.

  • Positive charge spreads passively down the axoplasm, depolarizing adjacent inactive segments to threshold.

  • Unidirectional propagation is enforced by trailing membrane remaining in the absolute refractory period with inactivated $\text{Na}_v$ channels.

• Saltatory Conduction in Myelinated Axons:

  • Myelin Sheath: Multi-layered lipid membrane rich in sphingomyelin, produced by Schwann cells in the PNS and Oligodendrocytes in the CNS; acts as an electrical insulator by increasing membrane resistance ($R_m$) and decreasing membrane capacitance ($C_m$).

  • **Nodes of Ranvier