Glial Cell Biology

Question 1

Glial cell General Characteristics

Answer 1

– non-neuronal brain cells; 10-50x more abundant in the brain than neurons
o Majority of CNS cells
o Fraction of glia cells is proportional to the size of the animal (fruit fly has less than humans)
o DON’T directly propagate action potentials
o Do not retain ability to divide
o Derived from mesoderm or neuroectoderm
o 5 Types in CNS – astrocytes, oligodendrocytes, microglia, NG2 cells, ependymal cells
o 2 Types in PNS – satellite cells, Schwann cells

Question 2

Astrocyte Characteristics

Answer 2

o “star-shaped”; most abundant and largest glial cell (20-50% of brain volume)
o Present in both gray and white matter
o Highly branched  single astrocyte can contact 100,000 synapses
o Processes can contact neuronal cell bodies, dendrites, and axonal surfaces; blood vessels and capillaries
 Varicose projection astrocytes – found in human and primate brains but NOT rodents
• Contain a lot of mitochondria indicating that they require a lot of energy and have function beyond interconnecting matrix
 Varicose projections – “bumps/beads” along astrocytes

Question 3

Astrocyte Derivation

Answer 3

o Derived from radial glial cells
 Radial glial cell processes retract during CNS maturation and become progenitors of adult astrocytes
 Bergmann glial (adult cerebellum) and Muller cells (adult retina) are radial glial cells remaining in adult brain

Question 4

Astrocyte Structural Organization

Answer 4

 Bidirectional communication with neurons through contact and chemical transmission
 Form tripartite synapse – presynaptic neuronal element, postsynaptic neuronal element, and astrocyte
 Gliotransmitters (glutamate, D-serine, ATP, TNFalpha) are released from astrocytes
o NOT all astrocytes are the same (depends on environment in portion of the brain)
 Regional Heterogeneity exists but not understood
• Example: brain tumors occur in temporal lobe – something specific about the cells in this area makes it susceptible to tumor formation

Question 5

Glial Fibrillary Acidic Protein (GFAP)

Answer 5

– intermediate filament that differentiates astrocytes from other CNS cells
• Protoplasmic – thick, short, and highly branches processes
o Found in gray matter; associated with neurons
o End in expansions called “end-feet” that form glia limitans (glia-limiting membrane)
 Wrap around blood vessels and capillaries and release vasoactive substances that control blood flow
 Surround epithelial cells of BBB – serve as “passageways” for the transfer of nutrients from the blood to neurons
 Surround neuronal cell bodies, dendrites, and some axons
• Fibrous – thin, long, smooth, and less branched processes
o Found in white matter between nerve fibers; associated with axons
• Muller cells – unique to the retina

Question 6

Astrocyte Function

Answer 6

o Neuronal migration and guidance – radial glia cells assist in migrating neurons during development
o Produce and secrete growth factors – regulate morphology, proliferation, differentiation, and survival of neurons
o Major source of extracellular matrix proteins and adhesion molecules
o Act as physical barrier (Protoplasmic astrocytes)
o Response to injury: Reactive Astrogliosis (fibrous astrocytes)
o Maintain brain homeostasis
o Formation and Modulation of Synapse

Question 7

Astrocytes as Physical Barrier

Answer 7

 End feet and Glial limitans
• Glia-limiting membrane (glia limitans) is a thick layer of joined end-feet at the surface of the brain covered by an outer basal lamina making contact with pia mater
o Passageways for the transfer of nutrients from blood to neurons
• End feet wrap around blood vessels and capillaries releasing vasoactive substances that control local blood flow
• Perivascular lining membrane - surrounds endothelial cells of blood brain barrier
o Also surround neuronal cell bodies, dendrites, and some axons

Question 8

Astrocytes Response to Injury

Answer 8

 Perform a defensive brain reaction by complex astrocyte remodeling
• Isolate damaged area by a local response to fill space left by lesion and a distal response to facilitate neuronal remodeling
 Source of innate inflammatory mediators (microglia also perform this function)
• Astrocyte-microglia communication is key for innate immune respone

Question 9

Astrocytes Maintaining Brain Homeostasis

Answer 9

 Control blood flow by signaling blood vessels about need for oxygen and glucose
 Buffer extracellular space by rapidly removing neurotransmitters and ions from the synaptic cleft after neurotransmission
• Provide energy and substrates for neurotransmission
• Ex: Glutamate-Glutamine Cycle

Question 10

Astrocytes and Formation/Modulation of Synapse

Answer 10

 Astrocytes release TNFalpha for “synaptic scaling”- form of neuronal plasticity
 Bidirectional communication with neurons
 Release chemical messengers

Question 11

Astrocyte Clinical Diseases

Answer 11

o Glial scar – forms during spinal cord injuries
o Amyotrophic Lateral Sclerosis (ALS; Lou Gehrig’s Disease) – astrocyte release toxic factors that kill motor neurons
o Gliomas – astrocyte tumors (most common type of glial cancer)
o Tuberous Sclerosis & Epilepsy – from GFAP and astrocyte in tubers with impairment of astrocyte buffering of glutamate and potassium

Question 12

Oligodendrocyte Structure and Function

Answer 12

o Smaller than astrocytes and only few branches
o Found in both gray and white matter
o 2 types
 Interfascicular oligodendrocytes – in white matter
• Myelinate axons-1 oligodendrocyte can construct/maintain several myelin sheaths
 Perinueral oligodendrocytes – in gray matter
• Lie next to neurons; unknown function

Question 13

Oligodendrocyte Clinical Diseases

Answer 13

o Multiple Sclerosis (MS) – inflammatory demyelinating disease with oligodendrocytes and myelin sheath degeneration  autoimmunity plays a role
o Progressive Multifocal Leukoencephalopathy (PML) – degeneration of oligodendrocytes and myelin sheaths
o Changes in myelination associated with cerebral infarcts, infections, premature infants with hypoxia/ischemia, leukodystrophies
o Clinical Depression – loss of oligodendrocytes and myelin
o Oligodendrogliomas (tumors) – usually slow growing and arise from perineural oligodendrocytes

Question 14

Microglia Structure

Answer 14

o Smallest glial cells scattered throughout CNS
o Second most abundant glial cell (make up 20% of total brain glia); in both gray and white matter
o Derived from hematopoietic cells of monocyte-macrophage lineage (mesoderm) and yolk-sac-derived myeloid cells
o Few short branching processes with thorn-like endings
o Resting microglia – small rod-shaped with symmetrical processes; ramified processed
o Active microglia – thicker processes and larger, rounder cell bodies; can form more ameboid shape for easy movement

Question 15

Microglia Function

Answer 15

o Resident immune cells of the brain – hallmark is their ability to become quickly activated and respond to pathological changes
o Survey the brain for damage and infection – once activated they phagocytose debris
o Mediate CNS inflammatory response – produce and secrete cytokines/chemokines and proinflammatory molecules (TNFalpha; IL1b; nitric oxide)
o Important during CNS development – phagocytose degenerating cells during normal developmental programmed cell death
o Synaptic Health – “Quad-partite Synapse” – may be involved in strengthening of synapse

Question 16

Microglia Clinical Disease

Answer 16

o Stroke – leads to secondary cell death and some of the molecules secreted by activated microglia are neurotoxic (TNFalpha, IL1b)
o Bacterial Meningitis – blood brain barrier opened by excessive TNFalpha and IL1b which worsens infection as leukocytes infiltrate
o HIV – microglia are targeted by the virus, causes proinflammation
o Neurodegenerative disease – increased microglial activation
o Others: MS, autism, environmental toxins

Question 17

Satellite Cell Structure and Function

Answer 17

o Surround cell bodies of sensory and autonomic ganglia
o Regulate the external environment; respond to ATP
o Connected by gap junctions
o Respond to injury and produce proinflammatory molecules

Question 18

Schwann Cells Structure and Function

Answer 18

o Derived from the neural crest
o Provide myelin sheaths around peripheral axons; surround some unmyelinated axons too
o Other Roles: Developmental and Regenerative Role
 Phagocytose damaged axons
 Guide regeneration by forming a “tunnel” toward the target neuron
 Produce neurotrophins
 Needed for preservation of healthy axons

Question 19

Schwann Cells Clinical Diseases

Answer 19

o Guillain-Barre syndrome – acute inflammatory demyelinating polyneuropathy where inflammation results in conduction block and muscle paralysis
 Unknown etiology; ½ cases are triggered by acute infection
 Autoimmune disease that destroys Schwann cells
 Progresses from lower limbs upwards
o Chronic inflammatory demyelinating polyneuropathy
o Tumors – Schwannoma are encapsulated and easily removed
o Charcot-Marie-Tooth disease – NONfatal autosomal dominant demyelinating peripheral neuropathy causing weakness of foot and lower leg muscles (foot drop)
 Most common inherited neurological disorder
 Adolescent onset with varying severity

Question 20

Distinguishing between CNS and PNS Myelination

Answer 20

CNS – white matter – made by interfascicular oligodendrocytes
 Produce flattened process of plasma membrane that wrap tightly around the axon repeatedly; cytoplasm is removed as layers accumulate  mature myelin sheath
 Single oligodendrocyte can construct and maintain several myelin sheaths

PNS – made by Schwann cells
 Wrap around axon and cytoplasm is excluded as the inner layers fuse; forms around peripheral axons; slightly more cytoplasm than in oligodendrocytes
 1 schwann cell = 1 internode/axon

Question 21

Myelination

Answer 21

o Myelin sheaths – electrochemically-insulating sheaths that conduct action potential quicker
 Good insulators due to high lipid-protein ratio (80:20)
o Internodes – myelinated sections of axons
o Nodes of Ranvier – unmyelinated section of axon following each internode
o Salutatory conduction – process by which actin potential leap from node to node; facilitated by low resistance and high presence of sodium channels in Nodes of Ranvier