Unit 06 — Nervous Tissue · Question Bank

The multipolar neuron is the workhorse design of the central nervous system — it is what you should draw when an examiner asks for a “typical neuron” without further specification. Examples include the alpha motor neuron of the spinal cord ventral horn, the pyramidal cell of the cerebral cortex and the Purkinje cell of the cerebellum. Three structural parts must appear in your answer: the cell body, the dendrites and the single axon. Each part has both a light-microscopic and an ultrastructural signature that the examiner expects you to know.

Cell body (soma / perikaryon)

The soma houses the nucleus and the bulk of the synthetic machinery. The nucleus is large, round and pale-staining — the classic “vesicular” or “open-faced” nucleus — with one prominent nucleolus, reflecting how aggressively the neuron must transcribe to keep its long processes supplied. The cytoplasm contains the diagnostic Nissl bodies: basophilic tigroid clumps that on EM resolve into stacks of rough endoplasmic reticulum with free polyribosomes between them. They manufacture every protein the cell will use, including the enzymes for neurotransmitter synthesis. Running through the perikaryon and out into the processes are the neurofibrils — bundles of microtubules, microfilaments and neurofilaments that form the cytoskeleton and the tracks for axonal transport. Golgi apparatus and abundant mitochondria sit nearby, and with age lipofuscin pigment accumulates as undigested lipid residue.

Dendrites

Dendrites are usually multiple, short and tapering, and they branch like a tree to maximise the surface area available for receiving signals. Their cytoplasm is essentially extended perikaryon — it still contains Nissl substance, mitochondria and Golgi — and so on a stained slide the dendrites continue the basophilia of the soma. Their distal segments are studded with small swellings called dendritic spines, the preferred landing site for excitatory synapses. The job of the dendritic tree is to receive and integrate inputs from many upstream neurons before passing the summed signal toward the soma.

Axon and axon hillock

Every multipolar neuron has exactly one axon, which arises from a specialised cone of cytoplasm on the soma called the axon hillock. The axon is long, thin, of uniform diameter and branches only sparsely until it reaches its target. Its plasma membrane is the axolemma and its cytoplasm is the axoplasm, which contains neurofilaments, microtubules and mitochondria but conspicuously lacks Nissl substance — the reason the hillock and the axon look pale on a stained section. The axon hillock and the unmyelinated initial segment carry the highest density of voltage-gated Na⁺ channels of any region of the cell, which is why this is the trigger zone for the action potential. Every protein the axon needs must be made in the soma and shipped down by axonal transport: anterograde (kinesin) to the terminal, retrograde (dynein) back to the soma.

Myelin sheath and nodes (when present)

Most CNS axons of any length are myelinated. In the CNS the sheath is built by oligodendrocytes — one cell wrapping several different axons — while in the PNS it is built by Schwann cells in a 1:1 fashion. Either way the lipid insulation is broken at regular intervals by the nodes of Ranvier, where the axolemma is exposed and the impulse regenerates, producing fast saltatory conduction. The axon ends in fine branches, each ending in a swollen terminal button packed with synaptic vesicles for the next chemical synapse.

Clinical anchor

Two clinical pictures hinge on this structural plan. After axotomy the soma swells, the nucleus moves peripherally and Nissl disperses — this is chromatolysis, and it is the pathologist’s sign that the neuron has lost the integrity of its axon. Rabies, by contrast, exploits the axon’s own retrograde transport to climb from a peripheral bite wound into the CNS, depositing Negri bodies in the soma of hippocampal and Purkinje cells.

The neuroglia outnumber the neurons of the central nervous system roughly ten to one. They are not excitable, but without them the neurons could not survive a day — glia hold the wiring in place, insulate it, feed it, protect it and replace nothing when it dies. The CNS uses four types, conveniently remembered as A.O.M.E.: Astrocyte, Oligodendrocyte, Microglia, Ependymal cell. All four arise from neuroectoderm except the microglia, which alone are mesodermal — a single fact that is heavily tested.

Astrocytes

Astrocytes are the most numerous of the CNS glia and the most versatile. They are star-shaped cells whose cytoplasm contains the intermediate filament GFAP, which is the immunohistochemical marker you use to identify them. Two morphological types are recognised: protoplasmic astrocytes in grey matter, with short, leafy processes that wrap around synapses; and fibrous astrocytes in white matter, with long slender processes that thread between axon tracts. Their many jobs include structural support of neurons, perivascular foot processes that contribute to the blood-brain barrier, buffering of extracellular K⁺ and recycling of glutamate and GABA back to neurons, and formation of the glial scar after CNS injury. Most primary CNS tumours (astrocytoma, glioblastoma) arise from this lineage.

Oligodendrocytes

The oligodendrocyte is the myelin-maker of the CNS. A single oligodendrocyte sends out several flat extensions; each extension wraps tightly around an internode on a different neighbouring axon, so one cell can myelinate up to fifty axon segments. Compact CNS myelin has no neurolemma and no basal lamina, and is laced with growth-inhibitory proteins (Nogo, MAG, OMgp) — which is part of the reason CNS axons largely fail to regenerate. Oligodendrocytes are the target of demyelination in multiple sclerosis.

Microglia

Microglia are the resident immune cells of the CNS — the brain’s macrophages. Embryologically they derive from yolk-sac progenitors and are therefore mesodermal, the only glial outsider in an otherwise ectodermal family. They are small cells with fine ramified processes that constantly surveil the parenchyma; on encountering injury or infection they retract their processes, become amoeboid, and phagocytose debris and pathogens. They also present antigen and release cytokines. Their chronic activation is now recognised as a central player in Alzheimer’s disease and other neurodegenerations.

Ependymal cells

Ependymal cells form a cuboidal-to-columnar epithelium that lines every CSF-filled cavity of the CNS — the cerebral ventricles and the central canal of the spinal cord. Many bear cilia, which keep CSF moving, and microvilli, which sense the composition of the fluid. Specialised ependymal cells covering the choroid plexus participate in the production of CSF itself. Unlike other epithelia they have no basal lamina, sitting directly on the neural parenchyma.

Clinical anchor

Each glial cell has its own headline disease. Astrocytoma / glioblastoma is the commonest primary CNS tumour. Multiple sclerosis is the autoimmune demyelinating disease of the oligodendrocyte. Microglial activation sits at the heart of Alzheimer’s pathology. Ependymoma arises from ventricular lining, and disturbance of the ependymal cilia can produce communicating hydrocephalus by impaired CSF circulation.

This is the most repeated essay in the entire histology paper, so it deserves to be written as a clear narrative. A peripheral myelinated nerve fibre is built around a single axon, but the histologically interesting part is the partnership between that axon and the Schwann cells that wrap it. Read the structure from the centre outwards, then describe the way the myelin is laid down, and finish with the functional payoff — saltatory conduction — and a brief clinical anchor.

The axon at the centre

At the core of the fibre lies the axon itself, bounded by its plasma membrane (the axolemma) and containing axoplasm rich in neurofilaments, microtubules and mitochondria but without any rough ER — no protein synthesis ever happens here. Everything the axon needs is manufactured in the soma and trucked along the microtubules by anterograde transport.

The myelin sheath and the Schwann cell

Surrounding the axon is the myelin sheath, formed from the spirally wrapped plasma membrane of a single Schwann cell. Each Schwann cell is responsible for exactly one internode of one axon — the 1:1 relationship that distinguishes the PNS from the CNS. Outside the spiral lies the thin layer of Schwann cytoplasm and nucleus, called the neurolemma (sheath of Schwann), and outside that a continuous basal lamina. The outermost connection between the Schwann surface and the start of the myelin spiral is the mesaxon. Inside the compact myelin you sometimes see oblique pale clefts — these are the Schmidt-Lanterman incisures, small pockets of trapped Schwann cytoplasm that keep the sheath flexible and supplied.

How the myelin is actually laid down

The story of myelin formation is a classic histology vignette. A premyelinating Schwann cell first engulfs the axon so that the axon sits in a deep groove on its surface. The lips of the groove then meet behind the axon to form the inner mesaxon. The Schwann cell now begins to rotate around the axon (or, equivalently, slides its inner tongue around it), and with each turn another double layer of plasma membrane is added to the spiral. The cytoplasm is gradually squeezed out of every loop except the innermost and outermost rims, so the final product is dozens of concentric, tightly apposed lipid bilayers — compact myelin — with the Schwann cell’s body and nucleus pushed to the outside.

Nodes of Ranvier and saltatory conduction

The myelin sheath does not run continuously down the axon. Where one Schwann cell ends and the next begins, the axolemma is exposed for a micron or so — this is the node of Ranvier. The nodal membrane is densely packed with voltage-gated Na⁺ channels, while the internodal membrane underneath the myelin has very few. As a result the action potential cannot decay through the lipid-insulated internode, but at every node it can be regenerated. Functionally the impulse appears to jump from node to node — saltatory conduction — many times faster than continuous conduction would allow, and at far lower metabolic cost. The fibre also acquires three connective-tissue wrappings — endoneurium around each fibre, perineurium around each fascicle (with tight junctions forming the blood-nerve barrier), and epineurium around the whole nerve carrying the vasa nervorum.

Clinical anchor

Two disorders make this anatomy unforgettable. In Guillain-Barré syndrome the immune system attacks Schwann-cell myelin, internodes lose their insulation and conduction blocks — producing rapidly ascending paralysis. In Charcot-Marie-Tooth disease hereditary defects in PMP22 give chronic peripheral demyelination with distal weakness and pes cavus. After a clean PNS injury the distal axon dies (Wallerian degeneration) but the Schwann cells remain, form a hollow endoneurial tube, and guide regenerating sprouts back to the target at roughly 1 mm a day — a regenerative trick CNS axons cannot copy.

A neuron in isolation is useless. What turns a population of neurons into a nervous system is the synapse — the specialised junction at which one cell hands its signal to the next. The overwhelming majority of synapses in the body are chemical synapses, and the histology paper expects you to be able to describe their structure, their transmission sequence, their varieties and their clinical relevance. A chemical synapse, in essence, is a tightly engineered gap of 15–30 nm across which a packet of neurotransmitter is launched in one direction only, from presynaptic to postsynaptic membrane.

Presynaptic element

The presynaptic element is usually a swollen ending of an axon called the terminal button or bouton. On EM its membrane is thickened on the cytoplasmic side at specialised active zones — the only places where vesicles are licensed to fuse. The cytoplasm is packed with small, clear or dense-cored synaptic vesicles, each holding a quantum of neurotransmitter, and with plenty of mitochondria to fuel the cycle of release and recycling. Voltage-gated Ca²⁺ channels are clustered at the active zone, ready to translate an arriving action potential into a flash of calcium influx.

Synaptic cleft

Separating the two cells is the synaptic cleft, a precise 15–30 nm gap that is far too wide for ions to bridge directly. It is occupied by adhesion molecules (cadherins, neurexin-neuroligin pairs) that hold the two membranes in register, and by extracellular enzymes (such as acetylcholinesterase at the neuromuscular junction) that terminate transmission by cleaving the transmitter.

Postsynaptic element

On the other side lies the postsynaptic membrane, whose cytoplasmic face is marked by an EM-dark postsynaptic density. This density anchors a vast array of neurotransmitter receptors — ionotropic (ligand-gated channels for fast transmission) and metabotropic (G-protein-coupled receptors for slower modulatory effects) — together with the scaffolding proteins that hold them in place. The postsynaptic cell is most often another neuron but may equally be a skeletal muscle fibre, a smooth-muscle cell or a gland cell.

The transmission sequence

The sequence of events is worth memorising as a chain. The action potential arrives at the terminal → voltage-gated Ca²⁺ channels open and calcium enters → SNARE proteins on the vesicle and the active zone snap together, fusing the vesicle membrane with the presynaptic membrane → transmitter is released by exocytosis into the cleft → transmitter diffuses across and binds postsynaptic receptors → ion channels open (or a second-messenger cascade fires) → a new excitatory (EPSP) or inhibitory (IPSP) potential is generated. The transmitter is then cleared by enzymatic breakdown, reuptake into the presynaptic terminal, or diffusion away. Vesicle membrane is retrieved and recycled by endocytosis.

Varieties

Classify chemical synapses morphologically by the cells they connect: axodendritic (the commonest, usually excitatory and often onto dendritic spines), axosomatic (often inhibitory), axoaxonic (where one terminal modulates another — presynaptic inhibition), and the specialised neuromuscular junction and neuroglandular synapses onto effector cells. Compare them with the electrical synapse, which is simply a gap junction with no cleft, no vesicles and no delay.

Clinical anchor

The synapse is where many famous diseases and most psychiatric drugs play out. Myasthenia gravis attacks the post-synaptic ACh receptor at the neuromuscular junction; Lambert-Eaton attacks the presynaptic voltage-gated Ca²⁺ channel. Botulinum toxin cleaves SNARE proteins to block vesicle fusion, causing flaccid paralysis; tetanus toxin targets inhibitory synapses in the cord, producing unrelenting spasm. SSRIs, antipsychotics, benzodiazepines and most opioids all act at this 30-nm gap.

The blood-brain barrier (BBB) is the single most important reason the central nervous system can keep its neurons firing in a stable ionic and chemical environment. Every other organ tolerates moment-to-moment swings in plasma composition; the brain cannot. So evolution has built a selective wall around the CNS capillary, and on a histology paper you are expected to describe what that wall is made of, how it is reinforced, what it lets through, and what happens when it fails.

Structural components

The barrier has three structural tiers. The first and most important is the continuous capillary endothelium: the endothelial cells of CNS capillaries are flat, non-fenestrated and joined by elaborate tight junctions of claudin and occludin, plus adherens junctions of VE-cadherin. There are essentially no transcellular pores. The second tier is a thick, continuous basement membrane that surrounds the capillary, shared with the surrounding parenchyma and reinforced by laminin, type IV collagen and proteoglycans. The third tier is the carpet of perivascular astrocyte foot processes that almost entirely ensheath the capillary; these foot processes do not themselves form the barrier, but they release signals (Sonic hedgehog, angiopoietin-1) that induce and maintain the endothelial tight junctions. Pericytes sit within the basement membrane and contribute further regulation.

Selectivity — what crosses, what does not

The BBB allows free passage of small, lipid-soluble molecules — oxygen, carbon dioxide, ethanol, anaesthetic gases, many antidepressants. Water-soluble nutrients have to use specific carriers: glucose enters by GLUT-1, amino acids by L- and y+ systems, and ions by tightly regulated transporters. Plasma proteins, large peptides, polar drugs and most antibiotics are excluded. The barrier also runs efflux pumps (notably P-glycoprotein) that actively expel xenobiotics back into the blood, which is one reason getting drugs into the CNS is so difficult.

Significance

The BBB matters in three ways. First, it protects neurons from circulating toxins, neurotransmitters released elsewhere in the body, fluctuations in plasma K⁺ and Ca²⁺, and from most blood-borne pathogens. Second, it maintains a stable micro-environment within which neurons can fire reproducibly — ion concentrations are clamped, glucose supply is steady, ammonia is excluded. Third, it acts as a pharmacological gate: CNS drugs must either be lipophilic, mimic a natural substrate of a carrier, or be small enough to slip through. Levodopa enters via the large-neutral-amino-acid carrier; dopamine itself does not cross at all. The barrier is deliberately incomplete at the circumventricular organs (area postrema, posterior pituitary, OVLT, subfornical organ), where the brain needs to sample or release into the blood — which is exactly why the area postrema can detect circulating emetics and trigger vomiting.

Clinical anchor

The BBB breaks down in many clinical settings, and the breakdown is itself a piece of pathology. Stroke, traumatic brain injury and CNS infection all disrupt tight junctions and produce vasogenic oedema, with plasma proteins leaking into the parenchyma and worsening pressure. Glioblastoma neovessels are leaky — that is why contrast enhancement marks tumour on MRI. Multiple sclerosis lesions show focal BBB breakdown that lights up on gadolinium-enhanced sequences. Bacterial meningitis exploits the BBB’s relative weakness at the choroid plexus to seed the CSF. And many systemic drugs are deliberately designed to be too polar to cross, sparing the brain — while CNS-acting drugs are deliberately designed to be lipophilic enough to enter.