Neurology III – Synaptic Activity & Information Processing

Synaptic Activity Overview

• Neural signaling cascade comprises five sequential electrical/chemical stages:
  • Resting potential: the baseline membrane charge difference (≈ -70\,\text{mV} for most neurons).
  • Local (graded) potentials: small, graded depolarizations or hyperpolarizations produced by incoming synaptic inputs.
  • Action potential (AP): the stereotyped, all-or-nothing spike that propagates along the axolemma once threshold (≈ -55\,\text{mV}) is reached at the trigger zone.
  • Synaptic activity: conversion of the electrical signal into a chemical message (neurotransmitter release) at the presynaptic terminal and reception/processing on the postsynaptic membrane.
  • Information processing: the integration of thousands of excitatory and inhibitory postsynaptic potentials (EPSPs & IPSPs) that ultimately decide whether the postsynaptic cell fires.
• In functional terms, “nerve impulse” generally refers to the propagating AP that carries the message to the end of the axon.

General Properties of Synapses

• Two fundamental channel types govern synaptic physiology:
  • Voltage-gated channels
  • \text{Na}^+ and \text{K}^+ channels along the axon and axon hillock set up and propagate the AP.
  • Voltage-gated \text{Ca}^{2+} channels at the presynaptic bouton open when the AP arrives, allowing \text{Ca}^{2+} influx that triggers exocytosis of synaptic vesicles.
  • Chemically-gated (ligand-gated) channels on the postsynaptic membrane open when neurotransmitter binds (e.g., nicotinic ACh receptor).
• Key physiological points:
  • A single AP may or may not release sufficient neurotransmitter to drive the postsynaptic cell to threshold—synaptic efficacy is probabilistic.
  • Excitatory neurotransmitters generate EPSPs (graded depolarizations); inhibitory neurotransmitters generate IPSPs (graded hyperpolarizations).
  • The final postsynaptic effect = algebraic sum of simultaneous EPSPs and IPSPs.

Cholinergic Synapse (Prototype Example)

• Releases acetylcholine (ACh).
• Major anatomical locations:
  • Neuromuscular junctions (NMJs) of skeletal muscle.
  • Neuron-to-neuron synapses in the CNS and PNS (e.g., all pre-ganglionic autonomic neurons, all parasympathetic post-ganglionic neurons).
• Termination mechanism: acetylcholinesterase (AChE) hydrolyzes ACh to acetate + choline, rapidly clearing the cleft and preventing continuous stimulation.
• Clinical/experimental relevance: drugs/toxins that inhibit AChE (e.g., organophosphates) lead to prolonged depolarization and spastic paralysis.

Other Neurotransmitters and Their Prototypical Actions

• Norepinephrine (NE)
  • Typically excitatory via \alpha and \beta adrenergic receptors.
  • Cardiovascular example: increases rate and force of cardiac muscle contraction.
• Dopamine
  • CNS modulatory transmitter; promotes reward & elevated mood.
  • Deficiency in substantia nigra → Parkinson disease; excess in mesolimbic pathway → psychosis.
• Serotonin (5-HT)
  • Pervasive effects: mood regulation, sleep–wake cycle, appetite.
  • Target for SSRIs in depression/anxiety treatment.
• GABA (gamma-aminobutyric acid)
  • Principal inhibitory transmitter in the CNS.
  • Opens \text{Cl}^- or \text{K}^+ channels → hyperpolarization.
• Cocaine
  • Blocks monoamine reuptake (dopamine, NE, 5-HT); net effect depends on receptor distribution & state of the user.

Drugs and Toxins Affecting Synaptic Transmission

• Local anesthetics (e.g., lidocaine)
  • Depress axolemma sensitivity by blocking voltage-gated \text{Na}^+ channels → prevent AP initiation/propagation.
• **Agents that *stimulate ACh release* (e.g., black widow spider venom)
  • Massive vesicular discharge → spastic paralysis followed by flaccid paralysis.
• Botulinum toxin (BoNT)
  • Blocks presynaptic release of ACh by cleaving SNARE proteins → flaccid paralysis; therapeutic use in dystonia, cosmetics.
• Nicotine
  • Agonist at nicotinic ACh receptors; stimulates postsynaptic membranes → increased heart rate, alertness, addiction potential.

Clinical Focus: Myasthenia Gravis (MG)

• Pathophysiology
  • Autoimmune antibodies bind to, block, and promote internalization of nicotinic ACh receptors at the NMJ.
  • Result: failure of efficient neuromuscular transmission → fatigable weakness.
  • Frequently associated with thymic hyperplasia or thymoma (thymus may provide aberrant immune education).
• Key symptoms (fluctuate, worsen with activity, improve with rest):
  • Facial muscle weakness & ptosis (drooping eyelids).
  • Diplopia (double vision) due to extra-ocular muscle fatigue.
  • Generalized fatigue; possible respiratory compromise requiring ventilatory support.
• Therapeutic strategies
  • AChE inhibitors (e.g., pyridostigmine) prolong ACh action in cleft.
  • Immunosuppression (glucocorticoids, azathioprine, monoclonal antibodies).
  • Thymectomy in select cases.

Information Processing in Neural Circuits

• A single postsynaptic neuron may receive hundreds to thousands of synapses on its dendrites and soma.
• Each input delivers either an EPSP or IPSP; the cell body integrates these to generate the net postsynaptic potential.
• If the net depolarization at the trigger zone (axon hillock) reaches threshold (≈ -55\,\text{mV}), an AP is initiated; else, the neuron remains quiescent.
• Conceptual parallel: neurons “vote,” and the trigger zone acts as the ballot counter.

Action Potentials & Stimulus Intensity Encoding

• AP obeys the all-or-none principle: once threshold is crossed, amplitude is constant; suprathreshold stimulus does not increase AP size.
• The CNS discriminates stimulus intensity via frequency coding:
  • Weak stimulus → low AP frequency.
  • Strong stimulus → higher AP frequency.
• Functional mapping:
  • Motor paths: low frequency may produce a twitch; higher frequency summates Ca²⁺ in muscle, yielding sustained contraction.
  • Sensory (afferent) paths: gentle touch evokes lower frequency vs. heavy pressure evoking higher frequency bursts.
• Frequency measured in Hz (spikes per second).

Refractory Period Dynamics

• Absolute refractory period: during depolarization & most of repolarization, \text{Na}^+ channels are inactivated; no new AP can begin.
• Relative refractory period: late repolarization & early hyperpolarization—\text{Na}^+ channels reset but \text{K}^+ conductance still elevated; larger-than-normal stimulus required.
• Net effect: ensures unidirectional AP propagation & caps maximal firing rate.
• Diagram reference: Fig. 7.17 (classic AP tracing with refractory windows).

Looking Ahead

• Chapter 12 closes with synaptic integration principles.
• Lecture note hints a brief detour to Chapter 14 before returning to Chapter 13—indicates upcoming material on higher-order neural functions or autonomic physiology.