Cellular and Synaptic Basis of Neural Signaling – Key Vocabulary

Overview & Clinical Relevance

• Neuropsychiatric disorders stem from malfunctions in intercellular communication, synaptic transmission, and intrinsic neuronal excitability.
  • Maladaptations may manifest as abnormal oscillations, shifts in excitation–inhibition (E/I) balance, or defective plasticity.
  • Therapies now span pharmacology, neuromodulation (ECT, rTMS, DBS, tDCS, VNS), and psychotherapy—all ultimately reshape electrical signaling.
• Ion channels are the macromolecular basis for electrical signaling and are therefore prime therapeutic targets and common loci of genetic/auto-immune pathology (channelopathies).

Classes of Ion Channels and General Principles

• Nongated (leak) channels
  • Always open; set resting membrane potential (RMP).
• Gated channels
  • Voltage-gated (Na+, K+, Ca^{2+}, Cl^−, HCN).
  • Ligand-gated (neurotransmitter-operated; e.g., nicotinic ACh, GABAA, NMDA).
  • Second-messenger/GPCR-regulated (e.g., GIRK, KCNQ opened/closed by Gβγ, PIP_2, cAMP).
• Fundamental electrical quantities
  • I=g(Vm-E{rev}) (Ohm’s law for ionic current).
  • I{cap}=Cm\frac{dV}{dt} (capacitive current during voltage change).

Resting Membrane Potential (RMP)

• Dominated by high K+ permeability through leak channels.
• Typical ion:
  • [K+]i ≈100, [K+]o ≈2–6.
  • [Na+]i ≈10, [Na+]o ≈140.
  • [Cl^−]o > [Cl^−]i; [Ca^{2+}]o \gg [Ca^{2+}]i.
• Nernst Equation (equilibrium/“Nernst” potential):
  • EK=\frac{RT}{zF}\ln!\left(\frac{[K]o}{[K]_i}\right)\approx -96\;\text{mV at }37^{\circ}\text{C}
• Goldman–Hodgkin–Katz (GHK) Equation (true RMP weighted by relative permeabilities):
  • Em=\frac{RT}{F}\ln!\left(\frac{P{K}[K]o+P{Na}[Na]o+P{Cl}[Cl]i}{P{K}[K]i+P{Na}[Na]i+P{Cl}[Cl]_o}\right)
• Na+/K+ ATPase exchanges 3\,\text{Na}^+{out}/2\,\text{K}^+{in}; electrogenic; ~40 % of brain O_2 consumption.

Passive Membrane Properties

• Leak conductance + membrane capacitance (≈1 µF cm^{-2}) yield low-pass filtering.
• Equivalent-circuit representation: variable resistors (ion channels) in parallel with Cm and batteries (E{ion}).
• Voltage clamp / patch clamp isolate ionic vs capacitive currents.

Action Potentials (APs)

• Initiation at axon hillock; threshold ≈−45 to −30 mV.
• Phases
  • Rapid depolarization via voltage-gated Na+ activation.
  • Peak/overshoot (Vm > 0 mV but < E{Na}).
  • Repolarization by Na+ inactivation + delayed rectifier K+ activation.
  • Undershoot/AHP via lingering K+ conductance.
• Refractory periods
  • Absolute: Na+ channels inactivated.
  • Relative: K+ channels still open.

Axonal Conduction & Myelination

• Passive spread causes decremental conduction; remedied by AP regeneration.
• Myelin ↑Rm & ↓Cm → faster axial current.
• Saltatory conduction: AP “jumps” node-to-node; velocities: myelinated ≈100 m/s; unmyelinated ≈0.3 m/s.
• Demyelinating diseases (MS, Guillain–Barré) slow/ block conduction.

Voltage-Gated Na+ Channels (Nav)

• Structure: Single α-subunit (4 domains ×6 TM segments) + 2 β-subunits.
  • S4 = voltage sensor (positively charged), P-loop = selectivity filter.
  • Fast activation & inactivation loop between domains III–IV.
• Isoforms: Nav1.1–1.9, Nax; tissue-specific expression.
• Toxins/drugs & sites
  • TTX, STX: pore block (extracellular) → “TTX-sensitive” vs “-resistant” channels.
  • α/β-scorpion, sea anemone toxins: shift gating → hyper-excitability.
  • Batrachotoxin, aconitine, veratridine: keep channel open.
  • Local anesthetics & anticonvulsants (lidocaine, phenytoin, carbamazepine) bind intrapore; use-dependent block.
• Channelopathies: GEFS+, hyperkalemic periodic paralysis, pain disorders (SCN9A/Nav1.7 mutations).

Voltage-Gated K+ Channels (Kv, Kir, BK, SK, HCN, K2P)

• Structural diversity (2-, 4-, 6-, 7-TM; 1 or 2 P-loops).
• Delayed rectifier (Kv2, Kv3): main AP repolarizers.
• A-type (Shaker/Kv4): rapid inactivation; set interspike interval.
• M-current (KCNQ2/3; Kv7): slow, subthreshold; inhibited by muscarinic ACh; opened by retigabine → anticonvulsant.
• Ca^{2+}-activated
  • BK (big conductance): fast AHP; mutations → autism/intellectual disability.
  • SK (small conductance): medium/slow AHP; variants linked to schizophrenia.
• Inward rectifiers (Kir)
  • GIRK opened by GPCRs (GABAB, 5-HT1A, adenosine A1).
  • K_{ATP} (Kir6 + SUR); pancreatic insulin release; CNS energy sensing.
• HCN (I_h): mixed Na⁺/K⁺; hyperpolarization-activated pacemaker; modulated by cAMP; target of lamotrigine (activator) & ketamine (blocker).
• K2P (tandem-pore/TWIK, TASK, TRAAK): background “leak”; sensitive to pH, temperature, stretch, anesthetics.

Voltage-Gated Ca^{2+} Channels (Cav)

• Families
  • LVA/T-type (Cav3.1–3.3): activate −80 to −50 mV; burst firing, oscillations, absence epilepsy.
  • HVA
  • L-type (Cav1.1–1.4): slow inactivation; gene = CACNA1C etc.; dihydropyridine-sensitive.
  • N-type (Cav2.2): presynaptic release; blocked by ω-conotoxin GVIA; MVIIA = ziconotide (analgesic).
  • P/Q-type (Cav2.1): Purkinje & cortical terminals; blocked by ω-Aga-IVA; mutations → familial hemiplegic migraine, episodic ataxia type 2, SCA6.
  • R-type (Cav2.3): SNX-482 sensitive; auxiliary in release & dendritic Ca^{2+}.
• Subunit composition: α1 (pore) + α2δ + β + γ (1:1:1:1).
• Selectivity: high-affinity Ca^{2+} binding within pore excludes monovalent cations.

Chloride & Other Anion Channels

• ClC family: 10–12 TM per subunit; double-barrel dimer; ClC-1 defect → myotonia congenita.
• CFTR (ABC family): phosphorylation + ATP-gated; ΔF508 mutation → cystic fibrosis; triple therapy (elexacaftor/tezacaftor/ivacaftor) restores folding & function.
• Ca^{2+}-activated Cl^−: contribute to firing frequency.
• VDAC (mitochondria): component of permeability transition pore; involved in apoptosis.

Neurotransmitters & Receptors

• Low-molecular-weight amines: glutamate, GABA, glycine, ACh, dopamine, NE, Epi, 5-HT, histamine, purines.
• Neuropeptides: vasopressin, CCK, etc.; often co-released.
• Fast vs slow transmission
  • Fast (≤100 ms): ligand-gated channels.
  • Slow (sec–min): GPCR cascades.
• Excitatory vs inhibitory determined by ion gradients (e.g., developmental switch of GABA from excitatory to inhibitory as [Cl^−]_i ↓ via KCC2).
• Receptor superfamilies
  • Cys-loop pentamers: nicotinic, GABAA, glycine, 5-HT_3 (cation vs anion selectivity via pore charges).
  • Ionotropic glutamate tetramers (AMPA, NMDA, kainate); P-loop enters from cytoplasmic side; “venus-flytrap” ligand-binding domain.
  • P2X trimers: ATP-gated, Ca^{2+} permeant.
  • GPCR heptahelical dimers: metabotropic glutamate, monoamine, peptide receptors; engage Gs, Gi/o, G_q/11 pathways; may form heteromers.

Network Oscillations & Pacemakers

• Rhythms (
• Pacemaker mechanisms: interplay LVA Ca^{2+}, HCN, Ca^{2+}-activated K+, GIRK etc.
• Cerebellar inferior olive: LVA Ca^{2+} –► Ca^{2+} influx –► BK activation –► hyperpolarization –► de-inactivate LVA.
• Thalamocortical oscillations: sleep spindles, δ waves, absence seizures (3 Hz spike-wave; ethosuximide targets Cav3; lamotrigine targets HCN).
• Ketamine dissociation: induces 1–3 Hz rhythms in retrosplenial cortex via HCN1 block; γ-power ↑ correlates with antidepressant actions.

Excitation–Inhibition (E/I) Balance

• Hypothesis: psychiatric disorders = regional E/I imbalance.
• Evidence: ↑γ oscillations, hyper-connectivity, optogenetic studies (PV+ interneuron deficits → autism/schizophrenia-like phenotypes).
• Restoring inhibition (PV activation, GABA agonists, GIRK modulation) normalizes circuit activity.

Channelopathies & Genetic Associations

• Epilepsies: BFNC (KCNQ2/3), GEFS+ (SCN1A/Nav1.1), absence (Cav3.2).
• Pain: PEPD vs congenital analgesia (SCN9A/Nav1.7 gain vs loss).
• Migraine/Ataxia: CACNA1A variants (Cav2.1) → familial hemiplegic migraine, EA2, SCA6.
• Psychiatric links
  • SK (KCNN3) polymorphisms → psychosis.
  • KCNH2 (Kv11.1/HERG) variant → schizophrenia, cognitive deficits.
  • BK (KCNMA1) → autism/ID.
  • CACNA1C (L-type) GWAS hit in bipolar & schizophrenia.
• Autoimmune: anti-NMDA (GluN1) encephalitis; anti-AMPAR, anti-GABAB; treat with immunotherapy ± NMDAR positive modulators.

Plasticity Mechanisms

• Hebbian (LTP/LTD): NMDA-dependent coincident activity; information storage.
• Homeostatic scaling: global synaptic or intrinsic adjustments to stabilize firing (e.g., ketamine up-scales excitatory synapses; lithium down-scales).
• Metaplasticity: modulation of plasticity thresholds (stress, ethanol, ketamine can dampen LTP capacity).

Brain Stimulation Therapies & Electrophysiological Principles

• ECT
  • Optimal: brief rectangular pulses (0.1–2 ms) @30–40 Hz; dose ~1.5× threshold (bilateral) or 5–6× (unilateral).
• rTMS
  • 10–20 Hz (excite), 1 Hz (inhibit). Theta-burst (intermittent 50 Hz bursts @5 Hz) emulates physiological rhythms.
• DBS
  • 0.06 ms pulses, >100 Hz; suppresses local somatic firing but drives axonal outputs; moving toward closed-loop, rhythm-matching protocols.
• VNS/tDCS: chronic sub-threshold modulation; delayed but durable antidepressant/antiepileptic effects; may engage homeostatic plasticity.
• Future: optogenetics & chemogenetics for circuit-specific human therapies (gene delivery & safety hurdles remain).

Key Equations & Constants (quick reference)

• Nernst: E{ion}=\frac{RT}{zF}\ln!\left(\frac{[ion]o}{[ion]_i}\right)
• Typical E{ion} at 37 °C: EK≈−96\,\text{mV},\;E{Na}≈+67\,\text{mV},\;E{Cl}≈−81\,\text{mV},\;E_{Ca}>+97\,\text{mV}
• Ohm’s law (ionic): I=g(Vm−E{rev})
• Capacitive current: I{cap}=Cm\frac{dV}{dt}

Drug & Toxin Cheat-Sheet

• Blockers: TTX/STX (Nav), ω-conotoxins (Cav2.2), ω-Aga-IVA (Cav2.1), SNX-482 (Cav2.3), lidocaine/phenytoin (use-dependent Nav), quinidine (Kv).
• Openers/Modulators: retigabine (KCNQ), diazoxide (K{ATP}), lamotrigine (HCN activator + Nav blocker), ketamine (HCN blocker + NMDA antagonist), baclofen (GABAB → GIRK opening).
• Anesthetics: volatile agents↑K2P (TASK/TRAAK); propofol/barbiturates↑GABAA.
• CF therapy: elexacaftor/tezacaftor/ivacaftor rescues ΔF508 CFTR folding.

Take-Home Messages

• Neural computation relies on an interplay of voltage-gated, ligand-gated, and second-messenger–gated ion channels.
• Channel diversity enables nuanced control of RMP, AP shape, firing patterns, synaptic integration, and network oscillations.
• Channelopathies, whether genetic, autoimmune, or pharmacologic, underlie many neurologic and psychiatric conditions and provide tailored therapeutic entry points.
• Modern neuromodulation and pharmacotherapy increasingly exploit knowledge of ion channel kinetics, selectivity, and plasticity to restore healthy circuit function.