Medical School · Year 2 · Neuroscience · includes a quiz and discussion video

Lecture 2: Neurons and Synaptic Transmission

Unit 2.5: Neuroscience

Learning Objectives

By the end of this lecture, students will be able to:

1. Describe the structure and classification of neurons including cytoskeletal elements and axonal transport
2. Explain the ionic basis of the resting membrane potential and equilibrium potentials
3. Describe the mechanism, phases, and propagation of action potentials
4. Explain the structure and function of chemical and electrical synapses
5. Describe neurotransmitter synthesis, vesicle release mechanisms, and receptor types
6. Explain the major neurotransmitter systems and synaptic plasticity mechanisms

1. Neuron Structure

Neurons exhibit highly specialized morphology optimized for receiving, integrating, and transmitting electrochemical signals across considerable distances. The cell body or soma, ranging from 5 to 100 micrometers in diameter, contains the nucleus with genetic material and perinuclear cytoplasm rich in rough endoplasmic reticulum visible as Nissl substance on histological staining. This protein synthesis machinery produces the neurotransmitters, receptors, ion channels, and structural proteins essential for neuronal function.

Dendrites extend from the soma as branching processes that receive synaptic inputs from other neurons. Their extensive arborization pattern creates a receptive field capable of integrating thousands of simultaneous inputs. Dendritic spines, small protrusions studding many dendrite surfaces, represent principal sites of excitatory synapses and demonstrate remarkable structural plasticity in response to activity. Spine morphology correlates with synaptic strength, with larger spines containing more receptors and exhibiting stronger transmission.

The axon hillock emerges from the soma as the trigger zone where action potentials initiate. This region has the lowest threshold for firing due to its high density of voltage-gated sodium channels. The axon extends as a single process that may travel millimeters in the CNS or over a meter to reach peripheral targets. Axon collaterals branch to contact multiple targets. The axon terminal or synaptic bouton contains mitochondria for energy and synaptic vesicles filled with neurotransmitter awaiting calcium-triggered release.

The neuronal cytoskeleton provides structural support and intracellular transport infrastructure. Microtubules form the tracks along which motor proteins transport cargo between soma and terminals. Kinesin motors carry vesicles, mitochondria, and membrane proteins anterogradely at fast rates up to 400 millimeters per day, while dynein motors transport endosomes and growth factors retrogradely. Slow anterograde transport moves cytoskeletal elements themselves. Neurofilaments determine axon caliber, correlating with conduction velocity. Actin microfilaments concentrate in growth cones and dendritic spines where dynamic remodeling occurs.

<image>Panel A: A multipolar neuron with all components labeled showing soma (cell body) containing a large nucleus with prominent nucleolus and Nissl substance (rough ER) in the cytoplasm, multiple branching dendrites with dendritic spines shown in magnified inset revealing mushroom, thin, and stubby spine morphologies. Panel B: The axon hillock transitioning to the initial segment, then the myelinated axon with nodes of Ranvier between myelin segments, and the axon terminal showing synaptic vesicles clustered at the active zone with mitochondria nearby. Panel C: Axonal transport showing microtubule tracks with kinesin motors (depicted as two-headed molecules walking toward plus end/terminal) carrying vesicles anterogradely, and dynein motors carrying endosomes retrogradely toward the minus end/soma, with speed indicators showing fast transport (200-400 mm/day) versus slow transport (1-5 mm/day). Panel D: Comparison of CNS myelination (one oligodendrocyte with processes to multiple axons) versus PNS (one Schwann cell per internode).</image>

2. Resting Membrane Potential

The resting membrane potential represents the voltage difference across the neuronal membrane when the cell is not actively signaling, typically measuring approximately negative 70 millivolts with the inside negative relative to outside. This potential arises from asymmetric ion distributions maintained by ATP-dependent pumps combined with selective membrane permeability primarily to potassium at rest.

Ion concentration gradients establish the driving forces for electrical signaling. Potassium concentration is high intracellularly (approximately 150 millimolar) and low extracellularly (approximately 5 millimolar), creating an outward driving force. Sodium shows the opposite pattern, with high extracellular (145 millimolar) and low intracellular (15 millimolar) concentrations creating an inward driving force. Chloride distributes with higher extracellular concentration, while calcium is maintained at extremely low intracellular levels (0.0001 millimolar) compared to extracellular (2 millimolar), creating a steep inward gradient essential for signaling.

The Nernst equation calculates the equilibrium potential for any single ion based on its concentration gradient. At equilibrium, the electrical force exactly balances the concentration gradient force, producing zero net ion flux. Potassium's equilibrium potential is approximately negative 90 millivolts, sodium's approximately positive 60 millivolts, and calcium's approximately positive 130 millivolts. The Goldman-Hodgkin-Katz equation extends this concept to multiple ions, weighting each equilibrium potential by relative membrane permeability.

The resting potential lies close to but not exactly at the potassium equilibrium potential because the membrane is primarily permeable to potassium through leak channels, with minor contributions from other ion conductances. The sodium-potassium ATPase maintains concentration gradients by pumping three sodium ions out for every two potassium ions in, consuming ATP and generating a small electrogenic contribution to the resting potential. This pump activity is essential for long-term neuronal viability; its failure during ischemia leads to rapid membrane depolarization and cell death.

<image>Panel A: A neuron membrane cross-section with ion channels and pumps showing potassium leak channels (open, allowing K+ efflux), closed sodium channels, and the Na+/K+-ATPase pump (depicted with 3 Na+ arrows pointing out, 2 K+ arrows pointing in, ATP to ADP conversion indicated). Panel B: Ion concentrations displayed in boxes showing intracellular (K+ 150 mM, Na+ 15 mM, Cl- 10 mM, Ca2+ 0.0001 mM) versus extracellular (K+ 5 mM, Na+ 145 mM, Cl- 110 mM, Ca2+ 2 mM), with a voltage scale showing the membrane potential at -70 mV. Panel C: Equilibrium potentials on a vertical voltage axis showing E_Ca at +130 mV (top), E_Na at +60 mV, 0 mV reference line, E_Cl at -70 mV, resting potential marked at -70 mV, and E_K at -90 mV (bottom). Panel D: The Nernst equation shown as E = (61.5/z) x log([ion]_out/[ion]_in) at 37 degrees Celsius.</image>

3. Action Potential Phases

The action potential represents a rapid, all-or-none electrical signal that propagates along the axon without decrement. This regenerative process begins when membrane depolarization reaches threshold, approximately negative 55 millivolts, triggering a characteristic sequence of voltage changes mediated by voltage-gated ion channels with distinct kinetics.

At rest, voltage-gated sodium channels exist in their closed state with the activation gate shut. When threshold is reached, conformational changes rapidly open the activation gate, allowing sodium influx down its steep electrochemical gradient. This positive feedback loop, where sodium entry causes further depolarization which opens more sodium channels, produces the rapid rising phase. Within approximately one millisecond, the membrane potential approaches sodium's equilibrium potential, peaking around positive 30 millivolts.

Repolarization involves two concurrent processes: sodium channel inactivation and potassium channel opening. The sodium channel inactivation gate, slower than activation, swings closed within milliseconds of opening, blocking further sodium conductance regardless of membrane potential. Simultaneously, voltage-gated potassium channels, with slower activation kinetics, open during the rising phase and reach maximal conductance during repolarization. Potassium efflux driven by both concentration gradient and electrical gradient rapidly returns the membrane toward rest.

The action potential typically undershoots the resting potential briefly, creating an afterhyperpolarization. This results from potassium channels remaining open after the membrane returns to resting voltage, transiently increasing potassium conductance above resting levels. Two refractory periods follow each action potential: the absolute refractory period during which another action potential cannot be generated regardless of stimulus strength because sodium channels remain inactivated, and the relative refractory period during which a stronger than normal stimulus is required because some sodium channels remain inactivated and potassium conductance remains elevated.

<image>Panel A: A graph showing membrane potential (y-axis, -90 to +40 mV) versus time (x-axis, milliseconds) with the classic action potential waveform, showing resting state at -70 mV with closed Na+ channels and open K+ leak channels, threshold at -55 mV marked with dotted line, and rising phase/depolarization with Na+ channel activation gates opening and Na+ influx arrows. Panel B: Peak at +30 mV with Na+ channels inactivating and K+ channels opening, falling phase with Na+ channels inactivated and K+ efflux, and undershoot/afterhyperpolarization below -70 mV with K+ channels still open. Panel C: Voltage-gated Na+ channel states showing closed (activation gate closed, inactivation gate open), open (both gates open, brief), inactivated (activation gate open, inactivation gate closed), and recovery back to closed. Panel D: Timeline indicating absolute refractory period (during inactivation) and relative refractory period (during recovery).</image>

4. Action Potential Propagation

Action potential propagation transmits electrical signals along axons through local circuit currents that depolarize adjacent membrane regions. The mechanism differs fundamentally between unmyelinated and myelinated axons, with important consequences for conduction velocity and energy efficiency.

In unmyelinated axons, action potentials propagate continuously. Sodium influx at the active region creates positive charges intracellularly that spread passively to adjacent inactive regions, depolarizing them toward threshold. The refractory period at recently active regions ensures unidirectional propagation. This continuous regeneration at every point along the membrane results in relatively slow conduction velocities of 0.5 to 2 meters per second. Unmyelinated C fibers carrying pain and temperature information, as well as postganglionic autonomic fibers, conduct in this manner.

Myelinated axons achieve dramatically faster conduction through saltatory propagation. Myelin, produced by oligodendrocytes in the CNS and Schwann cells in the PNS, wraps axons in lipid-rich insulating layers that prevent ion flux across the covered membrane. Nodes of Ranvier, small gaps between myelin segments, contain extremely high densities of voltage-gated sodium channels. Current spreads rapidly through the myelinated internode and regenerates the action potential at each successive node, effectively jumping between nodes.

Saltatory conduction provides multiple advantages: velocities up to 120 meters per second, reduced metabolic demand because ion flux occurs only at nodes rather than along the entire axon length, and space efficiency allowing more axons to be packed into a given nerve or tract. Conduction velocity correlates positively with axon diameter (larger axons conduct faster due to lower internal resistance) and with myelination thickness. Demyelinating diseases including multiple sclerosis in the CNS and Guillain-Barré syndrome in the PNS disrupt saltatory conduction, causing slowed or blocked signal transmission that manifests as weakness, sensory loss, and visual disturbances.

<image>Panel A: Continuous conduction in an unmyelinated axon showing sequential snapshots depicting the action potential zone (with Na+ influx shown) moving along the membrane, local circuit currents flowing ahead, recently active region in refractory state behind, with conduction velocity indicated as 0.5-2 m/s. Panel B: Saltatory conduction in a myelinated axon showing myelin segments (shown as wrapped membrane layers) with nodes of Ranvier between them, action potential regenerating only at nodes (high Na+ channel density indicated), with current spreading rapidly through internodes and arrows showing current flow jumping between nodes, velocity indicated as up to 120 m/s. Panel C: Comparison of CNS (oligodendrocyte with processes to multiple axons) versus PNS (single Schwann cell per internode) myelination. Panel D: Demyelination effects showing bare axon segment with current leak and conduction block indicated.</image>

5. Synapse Structure and Types

Synapses are specialized junctions where neurons communicate with other neurons, muscle cells, or gland cells. The vast majority are chemical synapses utilizing neurotransmitter release, though electrical synapses play important roles in specific circuits requiring synchronization or metabolic coupling.

Chemical synapses comprise three elements: the presynaptic terminal, the synaptic cleft, and the postsynaptic membrane. The presynaptic terminal or bouton contains mitochondria providing ATP for neurotransmitter synthesis and vesicle recycling, and clusters of synaptic vesicles at the active zone where release machinery concentrates. The synaptic cleft, measuring 20 to 40 nanometers across, separates pre- and postsynaptic membranes and contains extracellular matrix proteins that maintain synaptic structure. The postsynaptic membrane contains neurotransmitter receptors, scaffolding proteins, and signaling machinery organized into the postsynaptic density in excitatory synapses.

Synaptic arrangements vary based on the neuronal compartments involved. Axodendritic synapses, the most common type, form between axon terminals and dendrites or dendritic spines. Axosomatic synapses contact the cell body directly, often exerting powerful inhibitory control. Axoaxonic synapses terminate on other axon terminals, enabling presynaptic modulation of neurotransmitter release. Dendrodendritic synapses between dendrites allow local circuit processing without involving axons, found in olfactory bulb and retina.

Electrical synapses consist of gap junctions directly connecting the cytoplasm of adjacent neurons through connexin channels. These allow bidirectional flow of ions and small molecules, transmitting signals with virtually no delay. Electrical synapses synchronize neuronal populations in cardiac and smooth muscle, inferior olive, retina, and cortical interneuron networks. They cannot amplify signals or change polarity like chemical synapses but provide speed, reliability, and metabolic coupling advantages in appropriate contexts.

<image>Panel A: A chemical synapse in cross-section showing presynaptic terminal with clustered synaptic vesicles (shown as small spheres with neurotransmitter molecules inside), active zone where vesicles dock at the membrane, mitochondria providing ATP, and the presynaptic membrane with voltage-gated Ca2+ channels. Panel B: The synaptic cleft (20-40 nm labeled) containing extracellular matrix, the postsynaptic membrane showing receptors (ionotropic and metabotropic) with the postsynaptic density beneath. Panel C: Synapse types with simple neuron diagrams showing axodendritic (terminal to dendrite/spine), axosomatic (terminal to cell body), axoaxonic (terminal to terminal), and dendrodendritic (dendrite to dendrite). Panel D: An electrical synapse showing two neurons with gap junction connecting their membranes, connexin channels spanning both membranes with their central pore allowing ion and small molecule passage, and bidirectional current flow indicated by arrows.</image>

6. Synaptic Transmission Mechanism

Synaptic transmission converts electrical signals in the presynaptic neuron to chemical signals across the synapse and back to electrical signals in the postsynaptic cell. This transduction process, occurring within milliseconds, enables signal modification, amplification, and integration that underlie all neural computation.

The sequence begins when an action potential invades the presynaptic terminal, depolarizing the membrane and opening voltage-gated calcium channels concentrated at active zones. Calcium ions rush inward driven by a steep electrochemical gradient. The local calcium concentration rise, reaching hundreds of micromolar near channel mouths, triggers vesicle fusion through interaction with calcium sensor proteins.

Synaptotagmin, the principal calcium sensor, binds calcium through its C2 domains and undergoes conformational changes that drive membrane fusion. SNARE proteins provide the fusion machinery: synaptobrevin (v-SNARE) on vesicle membranes and syntaxin plus SNAP-25 (t-SNAREs) on target membranes assemble into a tight complex that brings membranes together. Calcium-bound synaptotagmin accelerates this process, producing fusion within 200 microseconds of calcium entry. Vesicle contents release into the cleft through the fusion pore.

Neurotransmitter diffuses across the narrow synaptic cleft to bind postsynaptic receptors, initiating signal transduction. Termination of transmission requires neurotransmitter removal through three mechanisms: enzymatic degradation in the cleft (acetylcholine by acetylcholinesterase), reuptake into the presynaptic terminal or glia by specific transporters (monoamines, glutamate, GABA), or simple diffusion away from the synapse. Understanding these mechanisms informs pharmacotherapy: drugs targeting reuptake transporters (SSRIs) or degradation enzymes (cholinesterase inhibitors) prolong neurotransmitter action.

<image>Panel A: An action potential arriving at the presynaptic terminal (voltage waveform indicated), followed by voltage-gated Ca2+ channels opening with Ca2+ influx arrows and local Ca2+ concentration indicated. Panel B: The SNARE complex and vesicle fusion machinery showing synaptobrevin on vesicle, syntaxin and SNAP-25 on membrane, assembled into zipper-like complex with synaptotagmin (depicted bound to Ca2+) engaging the complex, with vesicle fusion and neurotransmitter release into the cleft with molecules dispersing. Panel C: Neurotransmitter binding postsynaptic receptors (ionotropic receptor opening its channel, metabotropic receptor activating G-protein), and neurotransmitter removal mechanisms showing enzymatic degradation (enzyme breaking down NT shown), reuptake transporter (NT entering presynaptic terminal), and diffusion away. Panel D: Clinical targets showing botulinum toxin cleaving SNAREs, SSRIs blocking serotonin reuptake transporter, and AChE inhibitors blocking acetylcholine degradation.</image>

7. Postsynaptic Potentials and Integration

Neurotransmitter binding to postsynaptic receptors generates graded potentials whose summation determines whether the postsynaptic neuron fires. These postsynaptic potentials differ fundamentally from action potentials in being graded, decremental, and capable of summation.

Excitatory postsynaptic potentials depolarize the postsynaptic membrane toward threshold, increasing the probability of action potential generation. Most EPSPs result from cation channel opening that allows sodium and potassium flux, with net inward current due to sodium's stronger driving force at rest. The prototypical excitatory neurotransmitter glutamate activates AMPA receptors producing fast EPSPs. Individual EPSPs are small, typically 0.5 to 1 millivolt at the soma, insufficient alone to reach threshold.

Inhibitory postsynaptic potentials hyperpolarize the membrane or stabilize it at resting potential, decreasing firing probability. IPSPs typically result from chloride channel opening, which clamps membrane potential near chloride's equilibrium potential (approximately negative 70 millivolts), or from potassium channel opening, which hyperpolarizes toward potassium's equilibrium potential. GABA acting on GABA-A receptors produces fast IPSPs in the brain, while glycine serves this role in the spinal cord.

Synaptic integration at the axon hillock determines neuronal output. Spatial summation combines simultaneous inputs from different synapses: multiple EPSPs from various dendrites can sum to reach threshold even when individual EPSPs cannot. Temporal summation combines inputs arriving in rapid succession: if a second EPSP arrives before the first decays completely, their depolarizations add. The axon hillock serves as the trigger zone because it has the lowest threshold, highest sodium channel density, and receives the summed result of all dendritic inputs. Inhibitory synapses strategically positioned on the soma or proximal dendrites exert powerful veto control over excitatory inputs on distal dendrites.

<image>Panel A: Comparison of EPSP and IPSP showing voltage traces with EPSP (depolarizing toward threshold) and IPSP (hyperpolarizing or stabilizing at rest), with corresponding receptor mechanisms showing EPSP from cation channel opening (Na+ influx dominating) and IPSP from Cl- influx (GABA-A) or K+ efflux. Panel B: Spatial summation showing a neuron receiving multiple inputs, with individual small EPSPs from each synapse summing to reach threshold when occurring together. Panel C: Temporal summation showing two EPSPs in rapid succession with overlapping time courses summing to larger amplitude than either alone, versus two EPSPs widely separated remaining subthreshold. Panel D: Synaptic integration showing a neuron with excitatory synapses on distal dendrites and inhibitory synapses on soma/proximal dendrites, demonstrating how inhibition can veto excitation, with the axon hillock (highest Na+ channel density indicated) serving as the integration/trigger zone.</image>

8. Major Neurotransmitters

Neurotransmitters fall into several chemical classes with distinct synthesis, storage, release, and receptor mechanisms. Understanding these systems provides the foundation for neuropsychopharmacology and explains how drugs modify brain function.

Amino acid neurotransmitters mediate the majority of fast synaptic transmission. Glutamate serves as the primary excitatory neurotransmitter throughout the CNS, acting on ionotropic AMPA, NMDA, and kainate receptors plus metabotropic glutamate receptors. Its ubiquity makes glutamatergic transmission essential yet potentially dangerous in excess, as excitotoxicity contributes to stroke, epilepsy, and neurodegeneration. GABA serves as the primary inhibitory neurotransmitter in the brain, synthesized from glutamate by glutamic acid decarboxylase. GABA-A receptors are ligand-gated chloride channels modulated by benzodiazepines and barbiturates, while GABA-B receptors are metabotropic. Glycine mediates inhibition in the spinal cord and brainstem.

Monoamine neurotransmitters arise from amino acid precursors through enzymatic modification. Dopamine, synthesized from tyrosine, functions in reward, motivation, and motor control through distinct pathways: nigrostriatal (movement), mesolimbic (reward), mesocortical (cognition), and tuberoinfundibular (prolactin). Norepinephrine, derived from dopamine, projects from locus coeruleus throughout the brain, mediating arousal and attention. Serotonin, synthesized from tryptophan in raphe nuclei, influences mood, sleep, appetite, and numerous other functions through its remarkable diversity of receptor subtypes.

Acetylcholine functions both peripherally at neuromuscular junctions and autonomic ganglia, and centrally in cognitive circuits. Nicotinic receptors are ionotropic cation channels producing fast excitation, while muscarinic receptors couple to G proteins mediating slower modulatory effects. Cholinergic degeneration in the basal forebrain contributes to Alzheimer disease cognitive decline.

<image>Panel A: Amino acid transmitters showing glutamate synthesis from glutamine with vesicular glutamate transporter, acting on ionotropic (AMPA with Na+/K+ channel, NMDA with Ca2+ permeability and Mg2+ block shown) and metabotropic receptors, and GABA synthesis from glutamate via GAD enzyme, acting on GABA-A (Cl- channel with benzodiazepine binding site) and GABA-B (GPCR), and glycine with its Cl- channel. Panel B: Monoamine pathways on a sagittal brain section showing dopamine pathways from substantia nigra (nigrostriatal to striatum) and VTA (mesolimbic to nucleus accumbens, mesocortical to prefrontal cortex), norepinephrine from locus coeruleus with widespread projections, and serotonin from raphe nuclei similarly projecting broadly. Panel C: Acetylcholine with central cholinergic neurons in basal forebrain and receptors showing nicotinic (ion channel with multiple subunits) and muscarinic (GPCR types M1-M5 with G protein coupling indicated). Panel D: A table summarizing functions including glutamate (excitation), GABA (inhibition), dopamine (reward, motor), NE (arousal), 5-HT (mood, sleep), and ACh (cognition, NMJ).</image>

9. Neurotransmitter Receptors

Neurotransmitter receptors transduce chemical signals into cellular responses through two fundamentally different mechanisms: ionotropic receptors providing fast, direct ion flux, and metabotropic receptors producing slower, modulatory effects through second messenger cascades.

Ionotropic receptors, also called ligand-gated ion channels, open a transmembrane pore upon neurotransmitter binding. This direct coupling produces responses within milliseconds, ideal for rapid point-to-point signaling. Nicotinic acetylcholine receptors, composed of five subunits surrounding a cation-permeable pore, mediate fast excitation at neuromuscular junctions and autonomic ganglia. AMPA and kainate glutamate receptors pass sodium and potassium, generating fast EPSPs. GABA-A and glycine receptors pass chloride, generating fast IPSPs.

The NMDA receptor exhibits unique properties making it critical for synaptic plasticity. It requires both glutamate binding and membrane depolarization to conduct because magnesium ions block its pore at resting potential. This coincidence detection property means the receptor opens only when presynaptic activity (glutamate release) coincides with postsynaptic depolarization. The NMDA receptor passes calcium in addition to sodium and potassium, and this calcium influx triggers molecular cascades underlying learning and memory.

Metabotropic receptors couple to heterotrimeric G proteins that modulate intracellular second messenger pathways. Activated G proteins regulate adenylyl cyclase (affecting cAMP levels), phospholipase C (producing IP3 and DAG), or ion channels directly. These cascades amplify and prolong receptor activation effects. Muscarinic acetylcholine receptors exemplify this family: M1, M3, and M5 couple to Gq proteins activating phospholipase C, while M2 and M4 couple to Gi proteins inhibiting adenylyl cyclase and activating potassium channels. Dopamine D1/D5 receptors stimulate cAMP through Gs, while D2/D3/D4 receptors inhibit cAMP through Gi. The diversity of metabotropic receptor signaling enables nuanced modulation of neuronal function.

<image>Panel A: Ionotropic receptor structure and function showing a ligand-gated ion channel depicted as five subunits forming a central pore, with neurotransmitter binding causing conformational change that opens the pore, and specific examples including nicotinic receptor (Na+/K+ permeable, fast EPSP), GABA-A receptor (Cl- permeable, fast IPSP with benzodiazepine and barbiturate binding sites indicated), AMPA receptor (Na+/K+, fast glutamate EPSP). Panel B: NMDA receptor (Na+/K+/Ca2+ with Mg2+ block at resting potential, block removed upon depolarization) showing its unique coincidence detection properties. Panel C: Metabotropic receptor signaling showing GPCR structure with seven transmembrane domains, G protein (alpha, beta, gamma subunits) coupling, and downstream pathways including Gs stimulating adenylyl cyclase increasing cAMP, Gi inhibiting adenylyl cyclase decreasing cAMP, and Gq activating PLC producing IP3 (Ca2+ release from ER) and DAG (PKC activation). Panel D: Examples listed showing M1/M3/M5 muscarinic (Gq), M2/M4 muscarinic (Gi), D1/D5 dopamine (Gs), D2/D3/D4 dopamine (Gi), and GABA-B (Gi increasing K+ conductance).</image>

10. Synaptic Plasticity

Synaptic plasticity, the activity-dependent modification of synaptic strength, provides the cellular basis for learning and memory. Changes range from short-term facilitation lasting seconds to long-term modifications persisting years, enabling the nervous system to adapt to experience.

Short-term plasticity includes facilitation, depression, and augmentation occurring over seconds to minutes. Facilitation results from residual calcium in the presynaptic terminal following prior activity, enhancing release probability for subsequent action potentials. Depression reflects vesicle depletion when release rate exceeds replenishment. These mechanisms enable synapses to filter different temporal patterns of input.

Long-term potentiation represents a persistent increase in synaptic strength following specific patterns of activity, most extensively studied in hippocampal synapses where it likely contributes to spatial and declarative memory. The canonical mechanism involves NMDA receptor activation: coincident presynaptic glutamate release and postsynaptic depolarization relieve magnesium block, permitting calcium influx. This calcium activates calcium/calmodulin-dependent protein kinase II, which phosphorylates AMPA receptors, increasing their conductance, and promotes insertion of additional AMPA receptors into the postsynaptic membrane.

Long-term depression, the persistent weakening of synaptic strength, occurs with different activity patterns, typically low-frequency stimulation. LTD involves NMDA receptor activation but with lower calcium elevations that preferentially activate phosphatases rather than kinases. This leads to AMPA receptor dephosphorylation and internalization, reducing synaptic response. The bidirectional capability of LTP and LTD enables synapses to both strengthen and weaken, allowing memory formation without saturating all synapses at maximum strength. Together, these plasticity mechanisms implement Hebbian learning rules: synapses that contribute to postsynaptic firing strengthen, while those that do not weaken.

<image>Panel A: Short-term plasticity showing paired-pulse facilitation with two EPSPs where the second is larger due to residual Ca2+, and synaptic depression showing progressively smaller EPSPs during high-frequency stimulation due to vesicle depletion. Panel B: LTP mechanism in sequential steps showing high-frequency stimulation producing strong postsynaptic depolarization, NMDA receptor with Mg2+ block removed by depolarization allowing Ca2+ influx, Ca2+ activating CaMKII depicted as a protein with phosphorylation activity, CaMKII phosphorylating AMPA receptors (increased conductance) and promoting AMPA receptor insertion from intracellular vesicles, and strengthened synapse with more AMPA receptors in membrane. Panel C: LTD mechanism showing low-frequency stimulation producing modest depolarization, lower Ca2+ influx preferentially activating phosphatases, and AMPA receptor dephosphorylation and internalization. Panel D: A graph showing synaptic strength over time with baseline, LTP induction (step up maintained), or LTD induction (step down maintained), with a summary box stating Hebb's rule that cells that fire together wire together.</image>

Summary

Neurons are specialized cells with distinct compartments for receiving (dendrites), integrating (soma), and transmitting (axon) information. The cytoskeleton provides structure and transport infrastructure with microtubule-based anterograde (kinesin) and retrograde (dynein) motor systems.

The resting membrane potential of approximately -70 mV results from potassium leak channel conductance and sodium-potassium ATPase activity maintaining ion gradients (high intracellular K+, high extracellular Na+, Ca2+, Cl-). Equilibrium potentials calculated by the Nernst equation reflect each ion's gradient.

Action potentials are all-or-none signals initiated at threshold (-55 mV) through positive feedback sodium channel activation. Phases include depolarization (Na+ influx), repolarization (Na+ inactivation, K+ efflux), and afterhyperpolarization. Absolute and relative refractory periods ensure unidirectional propagation.

Propagation occurs continuously in unmyelinated axons (slow) or by saltatory conduction in myelinated axons (fast), jumping between nodes of Ranvier. Demyelinating diseases impair conduction.

Chemical synapses use calcium-triggered vesicle fusion via SNARE proteins, releasing neurotransmitter into the cleft. Electrical synapses use gap junctions for fast, bidirectional signaling.

Postsynaptic potentials (EPSPs and IPSPs) are graded and summate spatially and temporally at the axon hillock. Major neurotransmitters include glutamate (excitatory), GABA/glycine (inhibitory), monoamines (modulatory), and acetylcholine.

Ionotropic receptors produce fast responses through direct ion flux; metabotropic receptors produce slower modulation through G protein signaling. The NMDA receptor requires coincident activity for activation.

Synaptic plasticity mechanisms including LTP (strengthening via AMPA receptor insertion) and LTD (weakening via AMPA receptor internalization) underlie learning and memory.

Key Terms

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