Neurons & Synapses

The neuron is the signaling cell of the nervous system — a specialized eukaryotic cell whose entire morphology and biochemistry are devoted to receiving, integrating, and transmitting electrical and chemical signals. There are about 86 billion neurons in the human brain, embedded in a vastly larger number of supporting glial cells and connected by approximately 100 trillion synapses. The diversity of neuron types is enormous: from the small granule cell of the cerebellum, with its tiny soma and short axon, to the giant Betz cell of the motor cortex, with an axon that may exceed a meter in length running from cortex to lumbosacral spinal cord. Despite this diversity, all neurons share a basic plan and a basic set of operating principles, and understanding them is the foundation of everything that follows in neuroanatomy and neurophysiology.

This page covers the parts of a neuron, the principles of synaptic transmission, the major neurotransmitter systems, and the clinical relevance of cellular neuroanatomy. The point is to give the trainee a working understanding of the cellular substrate of brain function — enough to read a textbook chapter on Alzheimer disease, multiple sclerosis, or stroke and recognize the cellular events being described.

Parts of a Neuron

The Soma (Cell Body)

The soma contains the nucleus and most of the protein synthetic machinery. It ranges from a few micrometers in diameter (granule cells) to over 100 micrometers (motor neurons, Purkinje cells). The cytoplasm is rich in rough endoplasmic reticulum — the “Nissl substance” visible on classical histology — because of the demand for protein synthesis to support the cell’s far-flung dendrites and axons. Damage to a neuron’s soma is irreversible; the cell cannot regenerate. This single fact underlies the relentless progression of neurodegenerative diseases.

Dendrites

Dendrites are tapered processes extending from the soma, branching extensively to form the dendritic tree. Their job is to receive synaptic inputs from other neurons. The total dendritic surface area of a typical cortical pyramidal neuron may exceed 10,000 square micrometers, accommodating tens of thousands of synapses. Dendrites are studded with small protrusions called dendritic spines — the postsynaptic sites of most excitatory synapses in the brain. Spine number, shape, and dynamics are highly plastic and are altered in essentially every neurological and psychiatric disease. Reduced spine density is a feature of intellectual disability, schizophrenia, depression, and Alzheimer disease.

The Axon

The axon is a single, usually long process extending from the axon hillock (a specialized region of the soma) to the synaptic terminals. Axons range from a few hundred micrometers (interneurons) to over a meter (corticospinal projection neurons). The axon’s role is to propagate action potentials away from the soma to the synapses. Several specialized regions:

Axon hillock and initial segment: the site where action potentials are initiated. Has a high density of voltage-gated sodium channels, which determine the threshold for firing.
Myelinated segments: insulated by the lipid-rich myelin sheath. Action potentials “jump” from one node of Ranvier to the next, vastly increasing conduction velocity (saltatory conduction).
Nodes of Ranvier: small unmyelinated gaps between myelin segments, with high densities of voltage-gated sodium channels. The sites of action potential regeneration during saltatory conduction.
Terminal arborization: the axon branches extensively at its terminal end, with each branch ending in a presynaptic terminal (bouton).

Axonal Transport

Materials synthesized in the soma must reach the distant axon terminals, and signals from terminals must reach the soma. This is accomplished by axonal transport:

Anterograde transport (fast): carries vesicles, mitochondria, and membrane proteins from soma to terminals at about 400 mm/day. Powered by kinesin motors moving along microtubules.
Anterograde transport (slow): carries cytoskeletal and soluble proteins at 1-5 mm/day.
Retrograde transport: carries cargo from terminals back to soma at about 200 mm/day. Powered by dynein motors. Used by certain viruses (rabies, herpes simplex) and toxins (tetanus) to invade the CNS.

The Resting Membrane Potential

A neuron at rest has a membrane potential of about −70 mV (inside negative compared to outside). This potential is maintained by two factors:

Ionic gradients: established by the Na⁺/K⁺ ATPase pump, which moves three Na⁺ ions out and two K⁺ ions in per ATP molecule consumed. The result: high external Na⁺ and Ca²⁺, high internal K⁺.
Selective permeability: the resting neuron is more permeable to K⁺ than to Na⁺, so the membrane potential approaches the K⁺ equilibrium potential (about −90 mV) but is pulled positive by smaller Na⁺ permeability and other ions.

About 20% of the brain’s energy consumption goes to maintaining ionic gradients. Anoxic interruption of energy supply (stroke, cardiac arrest) leads to pump failure within minutes, depolarization, calcium influx, and excitotoxic cell death — the cellular basis of acute ischemic injury.

The Action Potential

An action potential is a brief (about 1 millisecond) reversal of membrane polarity that propagates along the axon. The sequence:

A graded depolarization reaches threshold (about −55 mV) at the axon hillock.
Voltage-gated sodium channels open, sodium rushes in, the membrane depolarizes rapidly toward the Na⁺ equilibrium potential (about +60 mV).
Sodium channels inactivate after about 1 ms.
Voltage-gated potassium channels open more slowly, potassium flows out, the membrane repolarizes.
A brief hyperpolarization (afterhyperpolarization) follows before the membrane returns to rest.

The action potential is an all-or-none event — once threshold is reached, the full action potential occurs; below threshold, nothing happens. Information is encoded in the frequency of action potentials (rate code) and in the timing of action potentials across populations of neurons (temporal code).

Synaptic Transmission

At a chemical synapse, the arrival of an action potential at the presynaptic terminal triggers neurotransmitter release. The sequence:

Action potential reaches the presynaptic terminal, depolarizing it.
Voltage-gated calcium channels open, calcium flows into the terminal.
Calcium triggers fusion of synaptic vesicles with the presynaptic membrane, releasing neurotransmitter into the synaptic cleft.
Neurotransmitter diffuses across the cleft (about 20-30 nm) and binds receptors on the postsynaptic membrane.
Postsynaptic receptors open ion channels (ionotropic) or activate second-messenger cascades (metabotropic), producing a postsynaptic potential.
Neurotransmitter is removed from the cleft by reuptake into the presynaptic terminal or by enzymatic degradation.

The whole sequence takes 0.5-1 millisecond. Postsynaptic potentials can be excitatory (depolarizing, EPSP) or inhibitory (hyperpolarizing, IPSP) depending on the neurotransmitter and the postsynaptic receptor.

The Major Neurotransmitter Systems

Glutamate

The principal excitatory neurotransmitter of the CNS. Used by most projection neurons of the cerebral cortex, thalamus, and many other regions. Three main receptor families:

AMPA receptors: ionotropic, mediate fast excitatory transmission.
NMDA receptors: ionotropic, voltage-dependent, key for long-term potentiation and learning. Blocked by Mg²⁺ at resting potential, opening only when the membrane is depolarized — a “coincidence detector.”
Metabotropic glutamate receptors: G-protein-coupled, modulating excitability over slower timescales.

Excessive glutamate release — excitotoxicity — kills neurons through calcium overload. This is the cellular basis of injury in stroke, traumatic brain injury, status epilepticus, and other acute neurological insults. The NMDA receptor antagonist memantine is used in Alzheimer disease for its theoretical reduction of excitotoxic injury.

GABA

The principal inhibitory neurotransmitter of the CNS. Used by inhibitory interneurons throughout the brain and by projection neurons of the striatum, substantia nigra pars reticulata, and cerebellum. Two receptor families:

GABA_A receptors: ionotropic chloride channels. Targets of benzodiazepines (positive allosteric modulators), barbiturates, propofol, etomidate, alcohol, and gamma-hydroxybutyrate.
GABA_B receptors: G-protein-coupled, mediating slower inhibition. Target of baclofen.

Loss of GABAergic inhibition produces hyperexcitability — the cellular basis of many seizure types. Some genetic epilepsies involve mutations in GABA receptor subunits.

Glycine

The principal inhibitory neurotransmitter of the brainstem and spinal cord. Used by Renshaw cells (recurrent inhibition of motor neurons) and many interneurons. Strychnine blocks glycine receptors, producing the spectacular hyperexcitability of strychnine poisoning. Hyperekplexia (exaggerated startle response) results from mutations in glycine receptor subunits.

Acetylcholine

Used at all autonomic preganglionic neurons, all parasympathetic postganglionic neurons, some sympathetic postganglionic neurons (sweat glands), all neuromuscular junctions of skeletal muscle, and various CNS projections. Two receptor families:

Nicotinic receptors: ionotropic, found at the neuromuscular junction and autonomic ganglia. Blocked by curare and other muscle relaxants.
Muscarinic receptors: G-protein-coupled, at parasympathetic effector organs and in the CNS. Blocked by atropine.

CNS cholinergic projections from the basal forebrain (especially the nucleus basalis of Meynert) to the cortex are critical for arousal, attention, and memory. Their loss is a major feature of Alzheimer disease, and cholinesterase inhibitors (donepezil, rivastigmine, galantamine) are the principal pharmacological treatment.

Dopamine

Used by three major CNS projection systems:

Nigrostriatal: from substantia nigra pars compacta to the striatum. Critical for motor function. Loss produces Parkinson disease.
Mesolimbic and mesocortical: from ventral tegmental area to limbic structures (mesolimbic) and prefrontal cortex (mesocortical). Involved in reward, motivation, and executive function. Implicated in schizophrenia, addiction.
Tuberoinfundibular: from hypothalamus to pituitary. Regulates prolactin secretion.

Receptor subtypes D1-D5 mediate distinct functions. D2 receptor antagonism is the principal mechanism of all antipsychotic drugs. Levodopa (a dopamine precursor) is the principal treatment for Parkinson disease.

Norepinephrine

Used by sympathetic postganglionic neurons and by CNS projections from the locus coeruleus to widespread cortical, brainstem, and spinal targets. The locus coeruleus system mediates arousal, attention, and stress responses. Alpha and beta adrenergic receptors mediate diverse autonomic effects. The locus coeruleus is among the earliest sites of Alzheimer pathology.

Serotonin

Used by neurons of the raphe nuclei in the brainstem, projecting widely throughout the CNS. Involved in mood, sleep, appetite, and pain modulation. Seven receptor families (5-HT₁ through 5-HT₇) with multiple subtypes. SSRIs and SNRIs target reuptake at serotonergic terminals; their efficacy in depression underlines the importance of this system in mood regulation. Sumatriptan and other triptans are 5-HT_1B/D agonists used in migraine.

Histamine

Used by neurons of the tuberomammillary nucleus of the hypothalamus, projecting widely to maintain wakefulness. Antihistamines that cross the blood-brain barrier (older sedating antihistamines) produce sleepiness; newer non-sedating antihistamines do not cross. Orexin-deficient narcolepsy is associated with abnormal histaminergic regulation.

Neuropeptides

Many small peptides function as neurotransmitters or neuromodulators: substance P, calcitonin gene-related peptide (CGRP, important in migraine pathophysiology), opioid peptides (enkephalins, endorphins, dynorphins), oxytocin, vasopressin, orexin/hypocretin (deficient in narcolepsy), and many others. They typically act through G-protein-coupled receptors and produce slow modulatory effects.

Synaptic Plasticity

Synapses are not static. Their strength changes with experience, providing the substrate for learning and memory. Two principal forms:

Long-term potentiation (LTP): a long-lasting increase in synaptic strength following high-frequency stimulation. The principal molecular event is activation of NMDA receptors with calcium influx, leading to insertion of additional AMPA receptors in the postsynaptic membrane. LTP is the leading candidate cellular mechanism of memory.
Long-term depression (LTD): a long-lasting decrease in synaptic strength following low-frequency stimulation. Important for unlearning and for motor learning in the cerebellum.

Both LTP and LTD require NMDA receptor activation, calcium signaling, and changes in postsynaptic receptor density. Pharmacological agents that affect these processes — including alcohol, ketamine, anticonvulsants — have effects on memory and cognition that are partially understood in these terms.

Neuronal Diversity

Neurons come in many varieties, classified by morphology, neurotransmitter, and projection target:

Pyramidal neurons: the principal projection neurons of the cerebral cortex and hippocampus. Pyramidal soma, prominent apical dendrite, and a long axon projecting to other cortical or subcortical targets. Glutamatergic.
Granule cells: small, numerous neurons in the cerebellum, dentate gyrus, and elsewhere. The cerebellum’s granule cells outnumber all other neurons in the brain combined.
Purkinje cells: large neurons of the cerebellar cortex with extensive flat dendritic trees and GABAergic axons projecting to the deep cerebellar nuclei.
Motor neurons: lower motor neurons in the ventral horn of the spinal cord, projecting to skeletal muscle. Cholinergic. Large somas.
Interneurons: local circuit neurons that synapse within the same nucleus or cortical region. Most are inhibitory (GABAergic), though some are excitatory.
Stellate cells, basket cells, chandelier cells: various types of cortical interneurons with characteristic morphologies and connectivities.

Neuronal Death and Survival

Neurons can die by apoptosis (programmed cell death, often through caspase-mediated pathways) or by necrosis (uncontrolled cell death from injury). In neurodegenerative diseases, the predominant pathway is debated but appears to involve programmed mechanisms that go awry. Protective signals — neurotrophic factors such as BDNF, NGF, GDNF — support neuronal survival and synaptic maintenance. Loss of these signals contributes to neuronal vulnerability in disease.

Throughout most of the adult brain, neurons cannot be replaced once lost. The two principal sites of adult neurogenesis are:

Subventricular zone of the lateral ventricles, producing new neurons that migrate to the olfactory bulb (in rodents; the existence and significance of this pathway in adult humans remains debated).
Subgranular zone of the dentate gyrus of the hippocampus, producing new granule neurons. There is evidence that this neurogenesis persists into adulthood in humans, though the magnitude and functional role are debated.

The general rule remains: neurons lost to disease or injury are not replaced.

🔍 Did You Know?

The largest neuron in the human body, a corticospinal motor neuron projecting from the motor cortex to the lumbosacral spinal cord, has an axon that may exceed one meter in length. The soma of this neuron — which must synthesize, package, and ship enough proteins to maintain that entire length — is correspondingly large, up to 100 micrometers in diameter. The energy requirements and the cell-biological challenge of maintaining such an enormous structure may be one reason these neurons are particularly vulnerable in amyotrophic lateral sclerosis and in many other “dying-back” neurodegenerative processes.

Pitfalls and Pearls

Neurons cannot be replaced once destroyed (with limited exceptions). The relentless progression of neurodegenerative disease reflects this single cellular fact.
The NMDA receptor is a coincidence detector: it requires both presynaptic glutamate release and postsynaptic depolarization to open. This dual requirement underlies its role in Hebbian learning.
Glutamate excitotoxicity is the proposed cellular mechanism of injury in stroke, traumatic brain injury, and many other acute neurological insults.
Most CNS inhibition is GABAergic, mediated through GABA_A chloride channels. Many sedatives, anesthetics, and anticonvulsants potentiate GABA_A receptors.
Dopaminergic projections fall into three main systems: nigrostriatal (motor, lost in PD), mesolimbic/mesocortical (reward and cognition, implicated in schizophrenia), and tuberoinfundibular (prolactin regulation).
The brain stores no significant energy and depends on continuous oxygen and glucose delivery. Ionic gradient maintenance consumes about 20% of the brain’s energy.
Axonal transport mediates the spread of certain pathogens and toxins: rabies, herpes, and tetanus toxin use retrograde transport to reach the CNS.
Spine density correlates with cognitive function. Reduced spine density is a feature of intellectual disability, depression, schizophrenia, and Alzheimer disease.
The NMDA receptor antagonist ketamine produces rapid antidepressant effects in some patients with treatment-resistant depression — a finding that has reshaped thinking about depression’s molecular basis.
Long-term potentiation (LTP) is the leading candidate cellular mechanism of memory. The requirement for NMDA receptor activation explains why anesthetics that block NMDA receptors (ketamine) interfere with explicit memory formation.

References

Kandel ER, Schwartz JH, Jessell TM, et al, eds. Principles of Neural Science. 5th ed. McGraw-Hill; 2013.
Purves D, Augustine GJ, Fitzpatrick D, et al, eds. Neuroscience. 6th ed. Sinauer/Oxford University Press; 2018.
Bear MF, Connors BW, Paradiso MA. Neuroscience: Exploring the Brain. 4th ed. Wolters Kluwer; 2016.
Lodish H, Berk A, Kaiser CA, et al. Molecular Cell Biology. 8th ed. WH Freeman; 2016.
Hyman SE. Neurotransmitters. Curr Biol. 2005;15(5):R154-R158.
Malenka RC, Bear MF. LTP and LTD: an embarrassment of riches. Neuron. 2004;44(1):5-21.