Study Notes on Synaptic Transmission

Essential Electrical Concepts: Understanding Synaptic Transmission

• Introduction

  • Prior knowledge of electrical concepts is foundational for understanding synaptic transmission.

  • Focus is on three key principles:

  • Neurons' maintenance of electrical readiness.

  • Generation of all-or-nothing signals.

  • Rapid signal conduction to synaptic terminals.

The Resting Potential: A Loaded Battery

• Neurons maintain a resting membrane potential of approximately −70 mV.

• This potential can be likened to a battery that is charged and ready to discharge.

• Mechanism of the Resting Potential:

  • The membrane is selectively permeable which affects ion flow:

  • Potassium (K⁺) tends to flow outwards.

  • Sodium (Na⁺) has restricted permeability and tends to flow inwards.

  • The Nernst equation predicts equilibrium potentials for each ion, whereas the Goldman–Hodgkin–Katz (GHK) equation explains how real neurons stabilize near −70 mV due to a dynamic balance between K⁺ and Na⁺ flows.

  • Every action potential begins from this resting potential, which subsequently triggers neurotransmitter release.

Action Potentials: The All-or-Nothing Signal

• Discovery

  • The action potential mechanism was elucidated by Hodgkin and Huxley, earning them a Nobel Prize.

• Process:

  • When a threshold is reached, voltage-gated sodium channels open rapidly leading to a membrane potential change from −70 mV to +40 mV in under a millisecond.

  • Following this, sodium channels become inactivated and potassium channels open, facilitating the restoration of the resting potential.

  • This creates an absolute refractory period, during which a new action potential cannot occur, ensuring unidirectional signal propagation.

  • Action potentials are characterized as identical in amplitude and duration, delivering a reliable digital signal that maintains integrity during transmission.

Conduction Velocity: Speed Matters for Synapses

• The speed at which action potentials travel is influenced by two factors:

  • Axon diameter.

  • Presence of myelination:

  • Unmyelinated fibers conduct signals slowly (approximately 1 m/s) because the action potential must regenerate at every point along the membrane.

  • Myelinated fibers exhibit saltatory conduction, allowing action potentials to jump between nodes and travel at speeds of up to 120 m/s.

• Fast-conducting axons facilitate precise timing with slower inputs, establishing temporal windows essential for synaptic plasticity.

Importance for Synaptic Function

• When an action potential reaches the synaptic terminal, timing and amplitude are critical:

  • Sufficient depolarization opens voltage-gated calcium channels, which trigger neurotransmitter release.

  • The all-or-nothing characteristic guarantees a reliable influx of calcium ions, while conduction velocity determines the timing of various inputs reaching their targets.

• Understanding these electrical fundamentals is crucial as synaptic transmission converts reliable electrical signals into flexible chemical communication via neurotransmitters.

Bridging to Chemistry

• The transition from electrical signals to neurotransmitter release involves the following mechanisms:

  • How calcium triggers vesicle fusion.

  • The role of SNARE proteins in executing membrane fusion.

  • The significance of low synaptic release probability in enabling neuroplasticity and learning.

• Big Picture:

  • Electrical signals ensure precise timing and reliable long-distance propagation, whereas chemical signals allow modulation, amplification, and integration of messages.

• The conversion between electrical signals and neurotransmitter release is mediated by:

  • Voltage-gated calcium channels reacting to action potentials.

  • Postsynaptic receptors translating chemical signals back into electrical currents, which trigger plasticity mechanisms.

• Small voltage fluctuations at axon terminals determine calcium influx and vesicle release probability, which tends to be probabilistic rather than deterministic with typical success rates ranging from 10% to 30%.

Tripartite Synapses and Astrocytic Role

• Tripartite synapse dynamics involve:

  • Astrocytes that:

  • Clear neurotransmitters through specific transporters (e.g., EAATs for glutamate, GATs for GABA).

  • Buffer extracellular potassium concentrations.

  • Release gliotransmitters that modulate synaptic strength.

• Unique characteristics of acetylcholine (ACh):

  • Unlike most neurotransmitters, ACh is cleared via enzymatic breakdown by acetylcholinesterase, as opposed to reuptake mechanisms.

Neuromuscular Junction: The First Chemical Proof

• Otto Loewi's 1921 experiment confirmed the chemical nature of neuron communication.

  • Loewi stimulated a frog's vagus nerve to slow one heart and transferred the solution to another heart, demonstrating that a diffusible chemical (later identified as acetylcholine) mediated the signal.

• Model System:

  • At the neuromuscular junction, motor neurons release ACh to bind to nicotinic receptors on muscle fibers, resulting in end-plate potentials that facilitate muscle contraction.

  • Curare blocks these nicotinic receptors, causing paralysis.

• Bernard Katz's Contribution:

  • Established neurotransmitter release occurs in discreet quantal packets linked to individual vesicles, forming the basis for understanding synaptic transmission.

Controversy Surrounding Dale's Principle

• Dale's principle proposed each neuron releases only one neurotransmitter. However, modern evidence supports the co-release hypothesis, indicating:

  • Neurons can release multiple transmitters simultaneously, such as ACh with ATP or glutamate with GABA in certain circuits, enriching complexity in signaling.

Mechanisms of Neurotransmitter Release

• Action potentials instigate the opening of voltage-gated calcium channels at axon terminals, which initiates vesicle fusion within microseconds.

• Components Involved:

  • Synaptotagmin functions as the calcium sensor that detects calcium levels to facilitate fusion.

  • SNARE Proteins:

  • Synaptobrevin on vesicles, binds with syntaxin and SNAP-25 on the presynaptic membrane, pulling membranes together for fusion.

• Clostridial Neurotoxins:

  • Provide insights into SNARE function:

  • Botulinum toxin cleaves SNAREs, resulting in flaccid paralysis.

  • Tetanus toxin obstructs inhibitory neurotransmitter release, creating a state of rigid paralysis.

• Electron Microscopy:

  • Captures vesicles undergoing various states of fusion and provides insights into the dynamics of neurotransmitter release.

• Release Probability:

  • Varies among synapses, typically ranging from 0.1 – 0.3 per docked vesicle per action potential and is influenced by the readily releasable pool of vesicles.

• Calcium creates nanodomains around release sites which allow for precise timing of neurotransmitter release.

• In paired stimuli, facilitation occurs when residual calcium from the first spike augments the second release, while high-frequency stimulation can lead to depression as vesicles deplete quicker than replenished.

  • Vesicles may undergo kiss-and-run fusion or full fusion, depending on calcium levels and vesicle pool status.

• Endocannabinoids:

  • Released postsynaptically to activate presynaptic CB1 receptors, effectively diminishing neurotransmitter release and providing rapid feedback control for synaptic strength.

Fast Synaptic Transmission: Ion Channels

• Nicotinic Acetylcholine Receptors:

  • Comprise five ligand-gated ion channels allowing sodium influx when ACh binds, culminating in muscle fiber depolarization.

• Glutamate Receptor Types:

  • AMPA receptors: Generate rapid excitatory currents.

  • NMDA receptors: Blocked by magnesium at resting membrane potential, only becoming active when:

  • Presynaptic glutamate is present.

  • Postsynaptic depolarization occurs, creating conditions favorable for Hebbian plasticity.

• GABA and Glycine Receptors:

  • Conduct chloride to induce hyperpolarization of neurons.

  • Benzodiazepines enhance GABA function, while ketamine inhibits NMDA** receptors.

• Current magnitude adheres to Ohm's law:

  • $I = g(V - E_{rev})$, where excitatory currents reverse near 0 mV and inhibitory currents reverse at chloride equilibrium potential.

• NMDA receptor functionality necessitates both glutamate and a co-agonist (glycine or D-serine).

Differentiation Between Neural and Electronic Circuits

• Key distinctions include:

  • Neurons perform analog integration of synaptic currents.

  • Nonlinear dendritic processing creates variability in response dynamics.

  • Action potentials are discrete events encoding information by firing rates and timing.

  • Synapses inherently exhibit probabilistic release with short- and long-term plasticity that affects synaptic connection strength.

  • Neuromodulators can adjust intrinsic neuronal properties and synaptic rules.

  • Astrocytes and ion concentrations affect circuit dynamics.

• Unlike deterministic electric circuits that are synchronized, neural networks operate:

  • Asynchronously, history-dependent, and with inherent noise, using variability to enhance computational robustness while conserving energy.

Historical Context

• In the 1950s, there was contention over whether all synapses were electrical.

• While electrical synapses exist, providing quick, direct communication, chemical synapses offer modulation, amplification, and the plasticity mechanisms essential for learning and memory formation.

Acetylcholine Beyond Muscle: Its Broad Functions

• ACh acts through two receptor types with distinct functionalities:

  • Nicotinic receptors: Quick ligand-gated channels supporting thalamocortical transmission and enhancing attention.

  • Muscarinic receptors: G-protein coupled and involved in modulating neural states related to learning and sleep-wake cycles.

• Alzheimer’s Disease:

  • Linked to degeneration of cholinergic neurons in the basal forebrain, treated with acetylcholinesterase inhibitors to mitigate cognitive decline by maintaining available ACh.

• Nicotine Addiction:

  • Associated with upregulation of nicotinic receptors.

• Atropine:

  • Blocks muscarinic receptors, leading to symptoms like pupil dilation and elevated heart rate.

• Organophosphate Compounds:

  • Inhibit acetylcholinesterase irreversibly, resulting in ACh accumulation and potentially fatal respiratory paralysis  treatment involves atropine plus pralidoxime to reactive the enzyme.

Biogenic Amines: The Mood, Drive, and Arousal Triad

• Dopamine:

  • Initial studies linked to Parkinson’s disease; L-DOPA used to replenish dopamine levels, restoring movement.

  • Wolfram Schultz's Findings: Dopamine neurons signal prediction errors, firing when rewards surpass expectations but not for fully predicted rewards, shaping behavioral contingencies.

  • Antipsychotic Medications: Block dopamine D2 receptors to alleviate psychotic symptoms but could provoke movement disorders.

• Norepinephrine:

  • Released from the locus coeruleus and modulates attention and arousal; responsible for pupil dilation and shifts network processing modes.

  • Beta-adrenergic blockers mitigate norepinephrine’s effects, alleviating anxiety and tremors.

  • SNRIs (Serotonin-Norepinephrine Reuptake Inhibitors): Used in treating depression through increased synaptic norepinephrine.

• Serotonin:

  • Considered an ancient signaling molecule; its surge occurs in organisms without nervous systems.

  • SSRIs (Selective Serotonin Reuptake Inhibitors): Elevate synaptic serotonin levels rapidly, but therapeutic effects manifest over a longer term, indicating that neuroplastic changes rather than immediate neurotransmitter availability promote recovery.

  • Psychedelic Drugs: Activate 5-HT2A receptors, potentially disrupting rigid neural circuits; ongoing research is exploring psychedelic-assisted therapy for treatment-resistant conditions.

Amino Acid Transmitters: The Brain’s Workhorses

• Glutamate:

  • The primary excitatory neurotransmitter; excessive release can lead to excitotoxicity due to calcium overload, often in stroke or brain injury contexts.

  • AMPA receptors: Facilitate rapid excitatory transmission.

  • NMDA receptors: Allow calcium entry, implicated in plasticity.

• GABA:

  • Principal inhibitory neurotransmitter formed from glutamate via glutamic acid decarboxylase (GAD).

  • GABAA receptors: Facilitate fast inhibition via chlorine conductance.

  • GABAB receptors: Function metabotropically, yielding slower, longer-lasting effects.

• Glycine: Provides inhibitory effects within spinal and brainstem circuits; blockage of glycine receptors via strychnine can lead to fatal convulsions, exemplifying inhibition's critical role.

• Neurotransmitter Receptors as Drug Targets:

  • Benzodiazepines, barbiturates, and zolpidem enhance GABAA function.

  • Ketamine and dextromethorphan block NMDA receptors, while memantine provides partial NMDA blockade in dementia management.

• Shunting Inhibition:

  • Produced by GABAA receptors by increasing chloride conductance, which keeps the membrane potential near chloride equilibrium and diminishes excitation effects without significant hyperpolarization.

• Chloride Homeostasis: Determines GABA's action; early development stages see NKCC1 maintaining high intracellular chloride making GABA depolarizing, while mature neurons deploy KCC2 to extrude chloride, thus rendering GABA hyperpolarizing.

  • Pathological shifts in chloride gradients can switch GABA's role from inhibitory to excitatory, contributing to conditions like epilepsy and chronic pain.

Clinical Considerations: When Synapses Go Sideways

• Myasthenia Gravis:

  • Autoantibodies attack nicotinic ACh receptors, leading to muscle weakness that improves with rest; treatments include acetylcholinesterase inhibitors and immunotherapy.

• Botulism:

  • Often from contaminated food; prevents ACh release by cleaving SNAREs leading to silence in communication and requiring ventilatory support in intensive care.

• Tetanus:

  • Toxin travels retrograde to disrupt inhibitory interneurons, causing unopposed motor neuron activity—characterized by lockjaw resulting from disinhibition.

• Excitotoxic Stroke:

  • Excessive glutamate release floods the synapse, excessively activating NMDA receptors, leading to calcium cascades; therapeutic hypothermia is sometimes employed to mitigate neuronal damage.