Nervous Tissue Histology

~7 min read

Lesson 3 of 5

Notes

Nervous Tissue Histology

Introduction

The nervous system is the master regulator of the body, coordinating rapid communication between tissues and organs. At the histological level, nervous tissue is composed of two major cell populations: neurons (the signalling units) and glial cells (the supportive, metabolic, and homeostatic units). Understanding their microscopic architecture underpins clinical reasoning across neurology, neurosurgery, and pharmacology.

---

Neuron Classification

Neurons are classified by the number of processes extending from the cell body (soma):

Multipolar neurons possess one axon and multiple dendrites. They are by far the most common type in the CNS, including motor neurons of the anterior horn of the spinal cord and cortical pyramidal cells. On H&E staining, the large cell body shows a prominent nucleus with a conspicuous nucleolus, and abundant cytoplasm filled with Nissl substance.

Bipolar neurons have one axon and one dendrite. They are specialised for sensory reception and are found in the retina (ganglion and bipolar cell layers), the vestibulocochlear nerve (spiral and vestibular ganglia), and the olfactory epithelium.

Unipolar (pseudounipolar) neurons develop from a bipolar precursor; the two processes fuse near the soma, leaving a single process that bifurcates into a central branch (to the CNS) and a peripheral branch (to the receptor). Dorsal root ganglion neurons are the classic example. On H&E, they appear as large round cells with a centrally placed nucleus and surrounding satellite cells.

---

Nissl Substance

Nissl substance is the histological term for the abundant rough endoplasmic reticulum (rER) present in the neuronal soma and, to a lesser extent, in proximal dendrites. It stains intensely with basic dyes (e.g., cresyl violet, thionin) and is responsible for the basophilic appearance of neurons on routine staining.

Nissl substance:

Reflects the high demand for protein synthesis in neurons (synaptic proteins, neurotransmitter-synthesising enzymes, cytoskeletal components)
Is notably absent from the axon hillock and the axon proper — a diagnostically useful feature
Undergoes chromatolysis (dispersal and loss of basophilia) following axonal injury — a reactive response indicating the soma is shifting resources toward axonal regeneration

---

Axon Hillock

The axon hillock is the cone-shaped region of the soma from which the axon originates. It is the site of action potential initiation because it has the lowest threshold for depolarisation, owing to the highest density of voltage-gated Na⁺ channels. Histologically, it is identified by:

Absence of Nissl substance
Transition from the pale soma cytoplasm into the axon initial segment

The axon initial segment also contains ankyrin-G scaffolding protein, which anchors Nav1.6 channels and is a key target in certain channelopathies.

---

Myelin Sheath

Myelin is a spiral wrapping of lipid-rich plasma membrane around an axon. Its primary function is to increase conduction velocity via saltatory conduction (action potentials jump between nodes of Ranvier).

In the PNS: Each Schwann cell myelinates a single internode of a single axon. Unmyelinated fibres in the PNS are also ensheathed by Schwann cells but simply sit in invaginations (Remak bundles). Schwann cells are critical for peripheral nerve regeneration — after injury, Schwann cells dedifferentiate and form Büngner bands to guide regrowth.

In the CNS: A single oligodendrocyte extends processes to myelinate segments of up to 50 different axons. Because oligodendrocytes lack the regenerative capacity of Schwann cells, CNS remyelination is limited. This is the pathological basis of multiple sclerosis, where autoimmune demyelination leads to conduction block.

On histology, the myelin sheath appears as a pale halo around axons on routine staining; Luxol fast blue (LFB) stains myelin blue-green and is the standard method for demonstrating myelinated tracts.

---

Glial Cells

Glial cells (neuroglia) outnumber neurons and perform essential structural, metabolic, and immune functions.

Astrocytes are the most abundant CNS glial cell, identified by their star-shaped morphology and GFAP (glial fibrillary acidic protein) immunoreactivity. Subtypes include fibrous astrocytes (white matter) and protoplasmic astrocytes (grey matter). Key roles:

Form the blood-brain barrier (BBB) by ensheathing capillaries with end-feet and inducing tight junctions in endothelial cells
Regulate extracellular K⁺ and glutamate (via EAAT transporters)
Participate in the glymphatic system
Form gliotic scars after CNS injury (reactive astrogliosis)

Oligodendrocytes are small, round cells with few processes visible on routine staining. They produce and maintain CNS myelin. Loss of oligodendrocytes is central to the pathology of MS and leukodystrophies.

Microglia are the resident immune cells of the CNS, derived from yolk sac progenitors (not from neural tube). They are the CNS equivalent of tissue macrophages. In their resting (ramified) state they are inconspicuous; on activation they adopt an amoeboid morphology and upregulate MHC II and phagocytic activity. IBA-1 and CD68 immunostaining highlights microglia.

Ependymal cells line the ventricular system and the central canal of the spinal cord. They are ciliated cuboidal-to-columnar epithelial-like cells that contribute to CSF circulation. Specialised ependymal cells of the choroid plexus (choroid epithelium) produce CSF via active secretion. Tanycytes are specialised ependymal cells in the hypothalamic third ventricle with roles in neuroendocrine signalling.

---

Peripheral Nerve Architecture

A peripheral nerve is organised into three connective tissue sheaths, best appreciated on cross-section with Masson trichrome or toluidine blue staining:

Endoneurium — loose connective tissue surrounding individual nerve fibres within a fascicle; contains collagen III and fibronectin; forms the tube within which Schwann cells and axons reside.

Perineurium — a multi-layered sheath of flattened epithelioid cells (perineurial cells) connected by tight junctions surrounding each fascicle; forms the blood-nerve barrier by restricting diffusion of large molecules into the endoneurial space.

Epineurium — dense irregular connective tissue encasing the entire nerve trunk and extending between fascicles (interfascicular epineurium); contains the vasa nervorum (blood supply), adipose tissue, and fibroblasts.

Myelinated vs unmyelinated fibres: Myelinated fibres appear as large, rounded profiles with a thick pale myelin ring; each has a 1:1 relationship with a Schwann cell. Unmyelinated fibres appear as small, irregular axon profiles clustered within a single Schwann cell (Remak bundle), identifiable on electron microscopy. On toluidine blue–stained semithin sections, unmyelinated fibres are distinguished from myelinated ones by the absence of a dark-staining myelin ring.

---

Synapse Types

Synapses are specialised junctions for interneuronal communication. The three morphological types described by Gray are:

Type I (asymmetric, Gray's type I): Prominent postsynaptic density; found on dendritic spines; typically excitatory (glutamatergic); large, round synaptic vesicles
Type II (symmetric, Gray's type II): Thin postsynaptic density similar to presynaptic density; found on soma and axon initial segment; typically inhibitory (GABAergic/glycinergic); flattened or pleomorphic vesicles

Chemical synapses transmit via neurotransmitter release into the synaptic cleft (20–50 nm wide). On electron microscopy: presynaptic terminal with mitochondria and vesicles, active zone, synaptic cleft with extracellular matrix, postsynaptic density.

Electrical synapses (gap junctions) allow direct ionic coupling between cells via connexin hemichannels. They are fast, bidirectional, and found in areas requiring synchronised activity (e.g., inferior olive, cardiac muscle, smooth muscle).

---

Neuromuscular Junction (NMJ)

The NMJ is a specialised synapse between a lower motor neuron and a skeletal muscle fibre. Histological and ultrastructural features:

Presynaptic terminal (motor end plate bouton): ACh-filled synaptic vesicles, mitochondria, active zones aligned opposite junctional folds
Primary synaptic cleft: ~50 nm wide, contains AChE (acetylcholinesterase) anchored by ColQ protein to the basal lamina
Postsynaptic junctional folds: Amplify membrane surface area; high density of nAChRs (nicotinic ACh receptors) at the crests; Nav1.4 channels in the troughs
Terminal Schwann cells: Cap the presynaptic bouton and participate in maintenance and repair

Clinical correlations: myasthenia gravis (autoantibodies against nAChR); Lambert-Eaton myasthenic syndrome (autoantibodies against VGCC — voltage-gated Ca²⁺ channels on presynaptic terminal); botulinum toxin (cleaves SNARE proteins, blocking vesicle fusion).

---