Neurons - Anatomy & Physiology

()Map NERVOUS AND SPECIAL SENSES (Map)

Introduction

• There are two major cell types within the CNS:

1. Neurons
   • These are the "functional" cells of the central nervous system.
2. Glial cells:
   • These play a supporting role within the CNS, and include:
     • Astrocytes
     • Oligodendrocytes
     • Microglial cells
     • Ependymal Cells
     • Choroid plexus epithelial cells

Neurons

• Neurons are the functional cells of both the CNS and PNS.
  • They are highly specialised to process and transmit signals.

Structure:

Soma

• The soma, or cell body is the central part of the neuron.
• The soma contains:
  • The nucleus
  • Smooth and rough endoplasmic reticulum
  • Ribosomes
  • Golgi apparatus
  • Due to the organelles it contains, the soma is where most protein synthesis occurs.

Dendrites

• The neuron's dendrites are branching extensions of the cell body.
  • Collectively, branching structure of the dendrites is known as the "dendritic tree".
• The dendritic tree is the site where input to the neuron occurs.
  

  Diagram of a neuron. Image courtesy of Wikimedia Commons
• Information outflow can also occur in the reverse direction, from the soma to the dendrites.
  • However, information is not transmitted from the dendrites in this way, because axons do not possess chemoreceptors and dendrites cannot secrete neurotransmitter chemicals.
    • Nerve impulses are therefore conducted in one direction only.

Axon

• The axon is a very fine projection that can measure up to thousands of time the soma diameter in length.
• The axon carries nerve signals away from the soma.
• Most neurons have only one axon.
  • However, this will usually undergo extensive branching to communicate with many target cells.
• The axon emerged from the soma at the axon hillock
  • The axon hillock has the highest density of voltage-dependent Na⁺channels, making it the most easily-excited part of the neuron.
  • The axon and axon hillock are generally involved in information outflow.
    • However, this region can also receive input from other neurons.
• At the end of the axon, there are synapses.
  • Neurotransmitter chemicals are released here in order to communicate with target neurons.
• The axon is dependent on the cell body for all its metabolic functions.
  • The axon has no Nissl substance: it cannot make its own protein, and so the soma must undertake this function.
  • The soma must also dispose of the axon's waste.
  • Death or damage to the cell body will therefore result in axon compromise or degeneration

Function:

• Neurons are the functional cells of both the CNS and PNS.
  • They are highly specialised to process and transmit signals.
• Neurons in different parts of the nervous system perform different functions.
  • There is therfore variation in the size, shape, structure, metabolism, function shape and electrochemical properties between locations.

Astrocytes

• Astrocytes, or astroglia, are star-shaped glial cells in the brain.
• Astrocytes have several functions:
  • Biochemical support of the endothelial cells forming the blood-brain barrier
  • Provision of nutrients to nervous tissue
  • Repair and scarring in the brain

Structure:

Astrocyte (immunofluorescence staining). Image courtesy of Alliance Européenne Dana pour le Cerveau (EDAB)

• Astrocytes are "star-shaped".
  • Their many processes envelope synapses made by neurons.
• Astrocyte expression of glial fibrillary acidic protein (GFAP) allows their identification histologically.

Function:

• Structural
  • Astrocytes are involved in the physical structuring of the brain:
    • Interplay between astrocytes and mesenchymal cells is important in sculpting sulci in development.
    • Astrocytes delineate the CNS by creating the CNS-PNS interface.
    • The cells cover the surface of the brain.
      • In this situation, the astrocytes' surface is coated by a basal lamina.
    • Astrocytes take over from fibroblasts to play an important role in abscess formation, as it is difficult to induce fibrosis in the CNS.
    • Astrocytes are the only differentiated CNS cell that retains the ability to divide.
• Metabolic
  • Astrocytes may control glucose levels and provide lactate for neurone for energy production
    • This is by the lactate shuttle mechanism.
  • Astrocytes have high levels of antioxidants, such as glutathione peroxidase.
    • This protects neurons from damage by reactive oxygen species.
• Blood brain barrier
  • It was originally thought that the astrocyte end-feet encircling endothelial cells aided in the maintenance of the blood-brain barrier.
    • The tight junctions and basal lamina of the endothelial cells are now considered to play a more substantial role in maintaining the barrier.
• Transmitter reuptake
  • Astrocytes:
    1. Isolate synapses
    2. Control potassium levels
    3. Take up transmitters
       • Astrocytes express transporters for several neurotransmitters, including glutamate, ATP and GABA.
         • Glutamate is particularly well taken up, and converted to glutamine using glutamine synthase.
• Regulation of ion concentration in the extracellular space
  • Astrocytes release K⁺ when neurons are active, increasing the local extracellular K⁺ concentration.
  • Astrocytes have a high density of K⁺ channels, allowing them to rapidly clear the excess accumulation in the extracellular space.
    • If this function fails extracellular K⁺ concentration rises. This leads neuronal depolarisation, and may be a cause of epilepsy.
• Vasomodulation
  • Astrocytes may serve as intermediaries in neuronal regulation of blood flow.
• Promotion of the myelinating activity of oligodendrocytes
  • Neuronal electrical activity releases ATP, which stimulates myelin formation.
  • This stimulation occurs via astrocytes, which secrete LIM in response to the ATP.
    • LIM is a regulatory protein that promotes the myelinating activity of oligodendrocytes.
• Control of inflammation
  • Astrocytes may play a crucial rule in controlling inflammation in the CNS, by:
    • Secreting chemokines
    • Playing an important role in the entry of inflammatory cells to the CNS.
  • When astrocytes are lost or destroyed, the neurons become very vulnerable in the face of inflammation.

Oligodendrocytes

Structure:

Oligodendrocyte (immunofluorescence staining). Image obtained from WikiMedia Commons Repository

• "Oligodendrocyte" literally means a "cell with many branches".
• Oligodendrocyte precursors are found throughout the CNS.
  • These precursors are post-mitotic, meaning oligodendrocytes can be replaced.

Function:

• Oligodendrocytes can myelinate up to 40 axons at a time.
  • The myelin sheath functions to:
    1. Decrease ion leakage and lower the capacitance of the cell membrane.
    2. Increase impulse speed by allowing saltatory conduction of action potentials between the nodes of Ranvier.
       • Nodes of Ranvier are spaces along the axon in between oligodendrocytes.

Microglial Cells

Structure:

• Microglia are the CNS representatives of mononuclear phagocyte system.
  • As such, they are derived from bone marrow, and are first seen in brain just before vascularistion.
• There are two populations of microglial cells:
  1. Extrinsic cells
     • Located perivascularly and in the meninges.
  2. Intrinsic cells
     • Located within the substance of the neural tissue.

Function:

Microglia (immunohistochemical staining). Image from WikiMedia Repository

• Microglia act as macrophages.
  • They rapidly respond to any type of injury.
• However, microglia differ from other representatives of mononuclear phagocyte system by their low expression of MHC-2.
  • MHC-2 is easily up-regulated though.
• The different types of microglia have different turnover rates.
  • Perivascular and meningeal microglia turnover fairly rapidly.
  • Intrinsic microglia have a very slow turnover.

Ependymal Cells

• Ependymal cells make up the is the epithelial membrane lining the ventricular system of the brain and the spinal cord.
• They are involved in the production of cerebrospinal fluid

Structure:

Forking aqueduct, showing ependymal cells. Image courtesy of BioMed Archive

• Ependymal cells line the CSF-filled ventricles in the brain and the central canal of the spinal cord, and form part of the choroid plexus.
• The cells are cuboidal/columnar.
• The apical surfaces of ependymal cells are covered with:
  • A layer of cilia.
  • Microvilli.

Function:

• Within the ventricles, modified ependymal cells and capillaries form a system called the choroid plexus.
  • The choroid plexus which produces the CSF.
• Ependymal cells beat thier cilia to circulate CSF around the central nervous system.
• The microvilli absorb CSF.

Endothelial Cells and the Blood Brain Barrier

• The walls of capillaries in the CNS are formed by endothelial cells, as for capillaries elsewhere in the body.
• However, in the CNS capillary endothelial cells are very tightly packed.
  • This density of cells restricts passage of substances out of the bloodstream much more than endothelial cells in capillaries elsewhere in the body.
    • This is the basis of the blood brain barrier

Structure and Function:

Peripheral Nerve Structure © Sophie Stenner

• Nerve fibres reside in a connective tissue matrix called the endoneurium and are gathered together into bundles or fascicles defined by a second connective tissue layer called the perineurium.
• Groups of fascicles are then gathered together in a third connective tissue layer called the epineurium.
• Thus, peripheral nerves have a three-tiered hierarchical arrangement of connective tissue.
• Renaut bodies are loose, cigar-shaped whorls of extracellular matrix within fascicles. They are common in horse nerves and may also occur in human and rat peripheral nerves at points of stress or compression.

Nerve Fibre

• The nerve fibre consists of the impulse-carrying axon, which is surrounded by an ensheathing cell, the Schwann cell, which in turn is surrounded by an acellular basal lamina that is continuous along the length of the nerve.
• Nerve fibres come in various discrete diameter groups, which are reflected in their conduction velocities.
• The larger the diameter the more rapid the rate of impulse conduction.
• Particular targets or receptors are associated with axons of a particular diameter, for example:
  • Those connected to muscles spindles have a large diameter (20 um) and conduct at 120 m/s
  • The smallest myelinated fibres are about 1um and conduct at around 6 m/s.
  • The smallest fibres of all are the unmyelinated fibres (the high-threshold sensory afferents, or C-fibres, and post-ganglionic autonomies) and have a diameter of between 1 and 0.1 um. These fibres do not conduct by saltatory conduction and have very slow conduction rates of around 0.5 m/s.

The Axon

• An outer membrane called the axolemma,
• Within this there is the axoplasm which is continuous with the cytoplasm of the neuron.
• There are no ribosomes, either free or attached to endoplasmic reticulum in axons and therefore, no protein synthesis.
• Protein synthesis takes place within the cell body and some dendrites.
  • All protein replacement required for the maintenance of the axon depends on proteins being imported from the cell body.
• A critical feature of the axon is its cytoskeleton, which consists of two key elements:

1. The Neurofilaments
   • Neurofilaments are intermediate filaments of about 10 nm diameter, and belong to the same class as other cytoskeletal proteins such as keratin, desmin, vimentin, or GFAP of astrocytes.
   • Neurofilaments are formed from a triplet of polypeptide subunits of heavy (~ 200 kD), medium (~ 150 kD) and low (~ 60 kD) molecular weights.
   • Typically, these subunits are heavily phosphorylated and are more numerous than microtubules, especially in large diameter axons, having a pivotal role in determining axon diameter.
   • They are formed in the cell body, transported down the axon by axoplasmic transport and degraded in the terminals by Ca²⁺ activated proteases.
   • In other words, there is a constant turnover of neurofllament within the healthy axon.
2. The microtubules
   • Micro tubules within axons are similar to microtubules elsewhere, consisting of polymerised dimers of alpha and beta tubulin arranged as a hollow tube of about 28 nm.
   • They are relatively abundant in smaller diameter axons, and are also synthesised in the cell body.
   • An important component of the cytoskeleton are the microtubule associated proteins or MAP's and the tau protein.
     • These proteins are important in microtubule assembly and stability.
     • Different classes of MAP's occur in the dendrites and the axons, and to some extent account for the different ultrastructural features that distinguish these two types of neuronal process.
     • They form cross links between adjacent microtubules but also connect to neurofilaments and actin microfilaments, implying complex interactions between the various components of the axon skeleton.

The Schwann Cell

• Myelination in the PNS is achieved by the Schwann cell, a derivative of neural crest cells, which bud off from the neuroepithelium at a very early stage of neurogenesis.
• During development, Schwann cells engage many small axons.
• As axonal diameter increases, Schwann cells eventually relate with only a single axon c.f oligodendrocytes.
  • This single axon is enveloped in a trough by the Schwann cell processes that engulf it.
  • As the processes come together, an inner mesaxon is formed.
  • The leading-edge process continues to move over the axon forming a spiral.
• Myelination, an extremely complex molecular process, occurs when the cytoplasm within the process is extruded allowing the internal surfaces of the membrane to come together as the major dense line, the outer membrane apposition constituting the intraperiod line.
• The alternating pattern of these two form the lamellae of compacted myelin.
• The myelin sheath is attached to, and is an integral part of, the Schwann cell on which it is dependent for its maintenance.

• A single Schwann cell forms a single myelin sheath or internode.
• There is a reasonably constant relationship between the myelin thickness and the internodal length, which in turn is associated with axon calibre.
• Large axons have long, thick myelin sheaths, and therefore also conduct more rapidly.
• The internodes do not abut one another but are separated by an exposed area of axon called the node of Ranvier.
• If the axons remain of small diameter, then a Schwann cell will continue to associate with many axons, although none of them are myelinated.
  • Thus, even unmyelinated axons retain a Schwann cell ensheathment.
  • These non-myelinating Schwann cells are sometimes referred to as Remak cells.

Axoplasmic Transport

• Neurons are very large cells and most of a neurons cytoplasm is present in its processes while most of the cells RNA is located in cell body (Nissl substance).
• These cells have therefore evolved mechanisms to transport large macromolecules and organelles up and down processes.

Anterograde Transport

• Two basic forms of anterograde transport can be recognised:

Fast anterograde transport

• Transports all membranous organelles such as synaptic vesicles
• Occurs at a rate of around 400mm/day (recent evidence suggests that there are many form of fast anterograde transport, mediated by different kinesins).
• Fast anterograde transport depends critically on oxidative metabolism, and is, in fact, independent of the cell body.
• The "motor" molecule is an ATPase called kinesin

Slow anterograde transport

• Deals with cytoskeletal elements and large soluble proteins.
• Slow anterograde transport can be further sub-divided into:
  • A slow component, which occurs at about 2mm/day (neurofilament, rubulin, actin)
  • A fast component, which occurs at around 4 mm/day, transporting all other proteins (eg myosin, clathrin).

Retrograde Transport

• Retrograde transport returns materials from the axon terminal to the cell body, either for degradation or restoration and reuse.
• As with fast anterograde transport, particles move along microtubules.
• The motor molecule for retrograde transport is dynein which is a microtubule-associated ATPase.
• The retrograde transport system is important not only for returning material to the cell body, but also provides the means whereby target-derived trophic factors, such as nerve growth factor (NGF) for dorsal root ganglion neurons, are conveyed to the cell body where they promote cell survival.