Nervous Tissue: Neurons, Glia, and Signal Transmission

Detailed Notes

14.1 Organization of the Nervous System

The nervous system is divided anatomically and functionally into two major subdivisions:

Table 14.1 — Divisions of the Nervous System

The PNS is further subdivided functionally:

• Sensory (afferent) division — Carries impulses from sensory receptors toward the CNS.
• Motor (efferent) division — Carries impulses from the CNS to effector organs (muscles and glands). The motor division is further split into the somatic nervous system (voluntary control of skeletal muscle) and the autonomic nervous system (involuntary control of cardiac muscle, smooth muscle, and glands).

At the tissue level, the nervous system is composed of just two broad cell types: neurons (the excitable cells that transmit electrical signals) and neuroglia (the supporting cells that outnumber neurons and are essential for their survival and function).

14.2 Neuron Structure

Neurons are highly specialized, amitotic cells (most do not divide after maturation) that are structurally adapted to generate and conduct electrical signals called nerve impulses or action potentials. A typical neuron has four morphologically and functionally distinct regions:

1. Cell body (soma) — Contains the nucleus, nucleolus, and most cytoplasmic organelles (rough endoplasmic reticulum, Golgi apparatus, mitochondria). The extensive rough ER — visible under the light microscope as dark-staining clumps called Nissl bodies — reflects the neuron's enormous demand for protein synthesis. The soma is the biosynthetic and metabolic center of the neuron; it integrates incoming signals and, if threshold is reached at the axon hillock, initiates an action potential.

1. Dendrites — Short, highly branched, tapering processes that radiate from the soma. Their surface area is vastly expanded by tiny protrusions called dendritic spines, which serve as the primary postsynaptic sites for incoming signals. Dendrites contain the same cytoplasmic organelles as the soma (except the nucleus) and are specialized to receive chemical signals (neurotransmitters) from other neurons and convert them into graded electrical signals. A single neuron may have hundreds of dendrites, collectively receiving input from thousands of other neurons.

1. Axon — A single, long, cylindrical process that arises from a specialized region of the soma called the axon hillock. Unlike dendrites, the axon is uniform in diameter and may extend from less than a millimeter to over a meter in length (e.g., axons innervating the foot originate in the lumbar spinal cord). The axon hillock is the trigger zone — the site where graded potentials are summed and, if the membrane potential reaches threshold (approximately −55 mV), an action potential is initiated. The axon conducts this action potential rapidly away from the soma toward its terminal branches.

1. Axon terminals (synaptic knobs / boutons) — The distal branches of the axon that end as swollen bulbs. Each terminal contains synaptic vesicles filled with neurotransmitter molecules and numerous mitochondria to supply ATP for vesicle trafficking and transmitter synthesis. When an action potential arrives at the terminal, it triggers the release of neurotransmitter into the synaptic cleft, the narrow (20–40 nm) gap separating the presynaptic and postsynaptic membranes.

Table 14.2 — Structural Regions of a Neuron

14.3 Myelin Sheath and Nodes of Ranvier

Many axons in both the CNS and PNS are wrapped in an insulating layer called the myelin sheath, which dramatically increases the speed of action potential conduction. Myelin is not continuous; it is interrupted at regular intervals (approximately 1 mm apart) by gaps called nodes of Ranvier where the axonal membrane is exposed.

Myelin in the PNS is formed by Schwann cells. Each Schwann cell wraps its plasma membrane repeatedly around a single segment of one axon (like a jelly roll), squeezing out the cytoplasm so that the concentric layers consist mainly of tightly compacted phospholipid bilayers. The outermost layer of the Schwann cell, containing the nucleus and cytoplasm, is called the neurolemma (or neurilemma) and is critical for the regeneration of damaged peripheral axons.

Myelin in the CNS is formed by oligodendrocytes. A single oligodendrocyte extends multiple flat, tongue-like processes, each wrapping around a segment of a different axon. Thus, one oligodendrocyte can contribute myelin to several (potentially up to 50) axons simultaneously. Crucially, CNS oligodendrocytes lack a neurolemma — CNS axons generally do not regenerate effectively after injury.

Functions of myelination:

• Electrical insulation — prevents ion leakage and reduces membrane capacitance, enabling saltatory conduction (see Section 14.10).
• Increases conduction velocity by 10- to 100-fold compared with unmyelinated axons of the same diameter.
• Conserves metabolic energy because fewer ions cross the membrane per impulse, reducing the workload of the Na⁺/K⁺ pump.

14.4 Neuron Classification

Neurons are classified both structurally (by the number of processes extending from the soma) and functionally (by the direction of impulse conduction).

Table 14.3 — Structural Classification of Neurons

Table 14.4 — Functional Classification of Neurons

14.5 Neuroglial Cells

Neuroglia (glial cells) are the non-excitable supporting cells of nervous tissue. They outnumber neurons by roughly 10:1 in the CNS and perform diverse roles including structural scaffolding, metabolic support, immune surveillance, myelination, and the regulation of the extracellular environment. Unlike neurons, most glial cells retain the ability to divide throughout life — this is why most primary brain tumors (gliomas) arise from glial cells.

14.5.1 CNS Neuroglia

1. Astrocytes — The most abundant and versatile glial cells in the CNS. Their name derives from their star-shaped (stellate) morphology, with numerous radiating processes.
   • Blood-brain barrier (BBB) contribution: Astrocytic end-feet wrap around brain capillaries and induce tight junction formation between endothelial cells, restricting the passage of most substances from blood into brain tissue.
   • Microenvironment regulation: Absorb excess K⁺ from the extracellular fluid following intense neuronal activity, preventing pathological depolarization. Remove excess neurotransmitters (especially glutamate) from the synaptic cleft, terminating synaptic signaling and preventing excitotoxicity.
   • Structural framework: Provide a three-dimensional scaffold for neuronal migration during development and for synaptic organization in the mature brain.
   • Energy support: Store glycogen and can deliver lactate to neurons during periods of high metabolic demand.
   • Scar formation: After CNS injury, astrocytes proliferate and form a glial scar that walls off damaged tissue but also inhibits axonal regeneration.

1. Oligodendrocytes — Smaller cells with fewer processes than astrocytes. As described in Section 14.3, each oligodendrocyte myelinates segments of multiple CNS axons. Oligodendrocytes are the CNS equivalent of Schwann cells.

1. Microglia — The smallest and least numerous glial cells. They are the resident immune cells (macrophages) of the CNS, derived from embryonic mesoderm rather than neural ectoderm.
   • In their resting (ramified) state, they constantly survey the CNS parenchyma with motile processes.
   • Upon detecting injury, infection, or debris, they transform into an activated (amoeboid) form and migrate to the site to phagocytose pathogens, dead neurons, and myelin debris.
   • They also prune excess synapses during development (synaptic pruning) and contribute to neuroinflammation in neurodegenerative diseases.

1. Ependymal cells — Simple cuboidal or columnar epithelial cells that line the fluid-filled cavities of the CNS: the ventricles of the brain and the central canal of the spinal cord.
   • Many ependymal cells are ciliated; the beating of these cilia circulates cerebrospinal fluid (CSF) through the ventricular system.
   • Specialized ependymal cells of the choroid plexus, in combination with fenestrated capillaries, produce CSF by filtering blood plasma and secreting additional components.

14.5.2 PNS Neuroglia

1. Schwann cells (neurolemmocytes) — Form the myelin sheath around PNS axons. Each Schwann cell myelinates exactly one segment of one axon. The neurolemma (outer cytoplasmic layer) contains the nucleus and cytoplasm and is essential for guiding axonal regeneration after PNS injury. Non-myelinating Schwann cells also envelop multiple small-diameter unmyelinated axons, providing structural and metabolic support without forming concentric myelin lamellae.

1. Satellite cells — Flattened cells that surround and encapsulate the neuronal cell bodies within PNS ganglia (clusters of neuron cell bodies outside the CNS).
   • Regulate the microenvironment around the neuron cell body (ion concentrations, metabolite exchange), analogous in function to the role astrocytes play in the CNS.
   • Provide structural support and may modulate signal transmission within the ganglion.

Table 14.5 — Summary of Neuroglial Cells

14.6 Resting Membrane Potential

All living cells maintain an electrical potential difference across their plasma membrane — the interior is negative relative to the exterior. In a typical neuron at rest, the resting membrane potential (RMP) is approximately −70 mV. This potential is the foundation upon which all neuronal signaling is built.

14.6.1 Ionic Basis of the RMP

Two forces govern the movement of ions across the membrane:

1. Chemical (concentration) gradient — Ions diffuse from regions of higher concentration to lower concentration.
2. Electrical gradient — Ions are attracted to regions of opposite charge and repelled from regions of the same charge.

Together, these forces constitute the electrochemical gradient for each ion.

Table 14.6 — Approximate Ion Concentrations Across a Resting Neuronal Membrane (mM)

Key observations:

• K⁺ is high inside, low outside — its equilibrium potential (the voltage at which its chemical and electrical driving forces balance) is approximately −90 mV.
• Na⁺ is low inside, high outside — its equilibrium potential is approximately +60 mV.
• Resting membrane potential (−70 mV) is close to but not identical to the K⁺ equilibrium potential (−90 mV), because the resting membrane is about 25–30 times more permeable to K⁺ than to Na⁺ — but this small Na⁺ permeability pulls the RMP slightly away from E_K toward E_Na.

14.6.2 The Na⁺/K⁺ Pump (Na⁺/K⁺-ATPase)

The Na⁺/K⁺ pump is an integral membrane protein that actively transports 3 Na⁺ out of the cell and 2 K⁺ into the cell for every molecule of ATP hydrolyzed. This pump:

1. Maintains the concentration gradients — Without it, the gradients would slowly decay as ions leak through resting channels.
2. Is electrogenic — Because it moves 3 positive charges out for every 2 positive charges in, it directly contributes a small (approximately −3 to −5 mV) hyperpolarizing component to the resting potential.
3. Prevents osmotic swelling — By extruding Na⁺, it keeps intracellular osmolarity balanced.

14.6.3 Leak Channels

The resting membrane potential is established primarily by leak channels — ion channels that are open at rest. Neurons have many more K⁺ leak channels than Na⁺ leak channels, which is why the resting membrane is predominantly permeable to K⁺. At rest:

• K⁺ diffuses out of the cell through K⁺ leak channels, driven by its concentration gradient.
• As K⁺ exits, it leaves behind unbalanced negative charges (large anions, A⁻), creating a negative interior.
• The growing negative charge increasingly pulls K⁺ back in (electrical gradient opposing the chemical gradient).
• At −70 mV, the net driving force on the most permeable ion (K⁺) plus the small contributions of other ions and the electrogenic pump produce a steady state.

14.7 Graded Potentials

A graded potential is a local, non-propagated change in membrane potential whose amplitude is proportional to the strength of the stimulus. Graded potentials occur primarily in the dendrites and soma (the receptive regions) when neurotransmitter molecules bind to ligand-gated ion channels, or when sensory receptors respond to physical stimuli.

14.7.1 Characteristics of Graded Potentials

• Graded in amplitude — a stronger stimulus produces a larger change in membrane potential (not all-or-none like action potentials).
• Decremental — the signal decays with distance from the site of origin because ions leak across the membrane and the cytoplasm offers resistance (this is why graded potentials are local, not long-distance signals).
• Can be depolarizing or hyperpolarizing — depending on which ion channels open.

14.7.2 EPSPs and IPSPs

At synapses, graded potentials take two forms:

1. Excitatory Postsynaptic Potential (EPSP) — A depolarization of the postsynaptic membrane. Neurotransmitter (typically glutamate in the CNS) binds to ligand-gated channels that open and allow Na⁺ (and sometimes Ca²⁺) to enter the cell. The influx of positive charge drives the membrane potential closer to threshold, making the neuron more likely to fire an action potential.

1. Inhibitory Postsynaptic Potential (IPSP) — A hyperpolarization of the postsynaptic membrane. Neurotransmitter (typically GABA or glycine) binds to ligand-gated channels that open and allow Cl⁻ to enter the cell or K⁺ to exit. Either way, the inside becomes more negative (or the membrane potential is stabilized near the Cl⁻ equilibrium potential), driving the membrane potential further from threshold and making the neuron less likely to fire.

14.7.3 Summation

A single EPSP is rarely sufficient to bring the neuron to threshold. Instead, the postsynaptic neuron integrates hundreds or thousands of synaptic inputs through summation:

1. Temporal summation — A single presynaptic neuron fires multiple action potentials in rapid succession. If the second EPSP arrives before the first has fully decayed, they add together, producing a larger depolarization. This is the same synapse firing repeatedly in a short time window.

1. Spatial summation — Multiple presynaptic neurons fire simultaneously, each producing an EPSP at a different synapse on the same postsynaptic neuron. The EPSPs overlap and summate, potentially reaching threshold. This is many synapses firing at approximately the same time.

In reality, the axon hillock continuously integrates both EPSPs and IPSPs arriving from hundreds or thousands of synapses across the dendritic tree and soma. The net sum of all synaptic activity at any given moment determines whether threshold is reached and an action potential is fired.

14.8 The Action Potential

If the summed depolarization at the axon hillock reaches threshold (approximately −55 mV), voltage-gated Na⁺ channels open, and a self-sustaining, all-or-none action potential is triggered. The action potential is a rapid, transient reversal of membrane potential that propagates along the entire length of the axon without decay.

14.8.1 Phases of the Action Potential

1. Resting state (RMP, ~−70 mV):

• Voltage-gated Na⁺ channels closed (activation gates closed).
• Voltage-gated K⁺ channels closed.
• Only leak channels are open; membrane is at steady-state resting potential.

2. Depolarization phase:

• Graded potentials summate and bring the membrane to threshold (−55 mV) at the axon hillock.
• At threshold, voltage-gated Na⁺ channels open rapidly (activation gates swing open). Na⁺ rushes into the cell down its steep electrochemical gradient.
• The massive Na⁺ influx causes the membrane potential to shoot upward, overshooting 0 mV and peaking near +30 to +40 mV (approaching E_Na).
• The interior becomes transiently positive — this is the rising phase (upstroke) of the action potential.

3. Repolarization phase:

• Within approximately 0.5–1 ms after opening, the voltage-gated Na⁺ channels inactivate (inactivation gates close). Na⁺ conductance drops sharply.
• At the same time, the depolarization has caused voltage-gated K⁺ channels to open — but K⁺ channel opening is significantly slower than Na⁺ channel opening (delayed rectifier behavior). K⁺ flows rapidly out of the cell, carrying positive charge away.
• The efflux of K⁺ drives the membrane potential back toward the negative direction — this is the falling phase of the action potential.

4. Hyperpolarization (undershoot) phase:

• Voltage-gated K⁺ channels are slow to close (they remain open for several milliseconds after repolarization is achieved).
• The continued outflow of K⁺ drives the membrane potential more negative than resting, dipping to approximately −80 to −90 mV.
• Eventually, the voltage-gated K⁺ channels close, and the RMP is restored by the Na⁺/K⁺ pump and leak channels.

Table 14.7 — Ion Channel States During the Action Potential

14.8.2 Refractory Periods

During and immediately after an action potential, the axon is less responsive to additional stimulation. There are two distinct refractory periods:

1. Absolute refractory period — No action potential can be initiated, regardless of stimulus strength. This period spans the depolarization and most of the repolarization phases. During this time, voltage-gated Na⁺ channels are either already open or inactivated; since inactivated channels cannot reopen until they recover, a second action potential is physically impossible. The absolute refractory period:
   • Ensures unidirectional propagation (an action potential cannot travel backward into the refractory membrane it just depolarized).
   • Sets an upper limit on firing frequency (typically ~500–1000 Hz for most neurons).

1. Relative refractory period — An action potential can be initiated, but only by a stimulus that is larger than the usual threshold. This period begins during late repolarization and continues through the hyperpolarization phase. During this time:
   • Some Na⁺ channels have recovered from inactivation, but not all (reduced Na⁺ availability).
   • K⁺ channels are still open (the membrane is hyperpolarized or returning from hyperpolarization), so a stronger depolarizing stimulus is needed to overcome the elevated K⁺ conductance and reach the threshold for the remaining available Na⁺ channels.

14.9 Action Potential Propagation

Once an action potential is generated at the axon hillock, it must travel the length of the axon to the terminals. Propagation occurs by two distinct mechanisms depending on whether the axon is myelinated.

14.9.1 Continuous Conduction

In unmyelinated axons, action potentials propagate as a continuous wave of depolarization. The sequence is:

1. An action potential at one patch of membrane reverses the polarity (inside becomes positive).
2. This creates local current loops: positive charge flows from the depolarized region along the inside of the membrane to the adjacent, still-polarized region (where the inside is negative).
3. This local current flow depolarizes the adjacent membrane patch to threshold, opening its voltage-gated Na⁺ channels.
4. An action potential is generated at the new site, and the process repeats sequentially along the entire length of the axon.

Continuous conduction is slow (0.5–10 m/s) and energetically costly because every segment of axonal membrane must generate an action potential, with associated Na⁺ influx and subsequent Na⁺/K⁺ pump activity.

14.9.2 Saltatory Conduction

In myelinated axons, action potentials appear to "jump" from one node of Ranvier to the next. The mechanism:

1. Myelin acts as an insulator — it prevents ion flow across the membrane in the internodal regions.
2. The only sites where the axonal membrane is exposed to the extracellular fluid and where voltage-gated Na⁺ channels are concentrated are the nodes of Ranvier.
3. When an action potential fires at one node, the local current flows rapidly through the axoplasm (low-resistance cytoplasmic path) to the next node — the myelin prevents the current from leaking out prematurely.
4. This inward current depolarizes the next node to threshold, opening its voltage-gated Na⁺ channels and generating a fresh action potential.
5. The action potential effectively "leaps" from node to node — hence the term saltatory (from Latin saltare, to jump).

Advantages of saltatory conduction:

• Speed — Conduction velocity of up to 120 m/s (vs. ~10 m/s for the same-diameter unmyelinated axon).
• Energy efficiency — Action potentials are regenerated only at the nodes (which cover roughly 0.2% of the axon's surface area), drastically reducing the amount of Na⁺ that must be pumped back out. For a given conduction velocity, a myelinated axon can be much smaller in diameter than an unmyelinated one, allowing the nervous system to pack more fibers into a limited space.

14.10 The Synapse

A synapse is the functional junction between a neuron and another cell (another neuron, a muscle fiber, or a gland cell). Transmission across the synapse converts the electrical signal of the presynaptic action potential into a chemical signal (neurotransmitter release) and back into an electrical signal (postsynaptic potential) in the target cell.

14.10.1 Synapse Classification by Site of Contact

14.10.2 Structure of a Chemical Synapse

The chemical synapse comprises three elements:

1. Presynaptic terminal — Contains synaptic vesicles (each packed with thousands of neurotransmitter molecules), mitochondria, and a specialized region of the membrane called the active zone where vesicles dock, fuse, and release their contents.

1. Synaptic cleft — A 20–40 nm gap filled with extracellular fluid, glycoproteins, and enzymes (e.g., acetylcholinesterase) that degrade or recycle neurotransmitter.

1. Postsynaptic membrane — Contains receptors (ligand-gated ion channels or G protein-coupled receptors) that bind the released neurotransmitter. The postsynaptic density is a protein-rich region that anchors receptors and signaling molecules directly opposite the active zone.

14.10.3 Sequence of Synaptic Transmission

Step-by-step at a typical chemical synapse (e.g., a CNS glutamatergic synapse or the neuromuscular junction):

1. Action potential arrives at the presynaptic terminal.
2. Depolarization opens voltage-gated Ca²⁺ channels in the presynaptic membrane. Ca²⁺ flows into the terminal down its steep electrochemical gradient (ECF [Ca²⁺] >> ICF [Ca²⁺]).
3. Ca²⁺ influx triggers exocytosis. The rise in intracellular Ca²⁺ activates synaptotagmin, a Ca²⁺-sensing protein that mediates the fusion of docked synaptic vesicles with the presynaptic membrane via SNARE proteins (synaptobrevin, syntaxin, SNAP-25).
4. Neurotransmitter is released into the synaptic cleft by exocytosis. Each vesicle releases a discrete packet (quantum) of transmitter molecules.
5. Neurotransmitter diffuses across the cleft and binds to receptors on the postsynaptic membrane. This binding is reversible and highly specific — receptors recognize particular transmitters (like a lock and key).
6. Postsynaptic ion channels open. The receptor may itself be a ligand-gated ion channel (ionotropic receptor) that opens directly upon transmitter binding, or it may be a G protein-coupled receptor (metabotropic receptor) that opens channels indirectly via second messenger cascades.
7. Postsynaptic potential is generated. Depending on which ions flow through the opened channels, the result is either an EPSP (depolarization — Na⁺ or Ca²⁺ entry) or an IPSP (hyperpolarization — Cl⁻ entry or K⁺ exit).
8. Neurotransmitter is cleared from the cleft to terminate the signal. Mechanisms include:
   • Reuptake by the presynaptic terminal or nearby astrocytes (e.g., glutamate, serotonin).
   • Enzymatic degradation in the cleft (e.g., acetylcholinesterase breaks down acetylcholine).
   • Diffusion away from the synaptic cleft.

14.11 EPSPs vs. IPSPs: Determinants of Postsynaptic Response

The type of postsynaptic potential produced depends on which ion channel the neurotransmitter receptor opens, not on the transmitter molecule itself.

Table 14.8 — Comparison of EPSPs and IPSPs

Importantly, a neuron's response to a neurotransmitter is determined by its receptors, not by any intrinsic property of the transmitter. For example, acetylcholine is excitatory at the neuromuscular junction (nicotinic receptors open Na⁺ channels) but can be inhibitory in the heart (muscarinic receptors open K⁺ channels, hyperpolarizing cardiac pacemaker cells).

14.12 Clinical Connections

Multiple Sclerosis (MS) — An autoimmune demyelinating disease in which the immune system attacks and destroys oligodendrocytes and the myelin sheaths of CNS axons. The resulting plaques (sclerotic scars) disrupt or block saltatory conduction, causing slowed or failed action potential propagation. Symptoms depend on the location of plaques and include visual disturbances, muscle weakness, numbness, coordination deficits, and cognitive changes. The pathophysiology illustrates the critical importance of myelin for normal neuronal signaling.

Tetrodotoxin (TTX) — A potent neurotoxin produced by pufferfish that blocks voltage-gated Na⁺ channels. By preventing the Na⁺ influx required for the depolarization phase of the action potential, TTX paralyzes neurons and skeletal muscle, leading to respiratory failure. TTX is a classic tool for demonstrating that the action potential depends specifically on voltage-gated Na⁺ channels.

Lambert-Eaton Myasthenic Syndrome (LEMS) — An autoimmune disorder in which antibodies target voltage-gated Ca²⁺ channels at the presynaptic terminal of the neuromuscular junction. The reduced Ca²⁺ entry impairs acetylcholine release, producing muscle weakness — a direct illustration of calcium's essential role in synaptic transmission (Step 2–3 of the sequence above).