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Neuronal Microenvironment
Block 3
2012
• Reading Assignment: Textbook of Medical
Physiology, 12th edition, Guyton & Hall
• Chapter 61, pp. 743-752
BECF & CSF
• Neuronal microenvironment includes the extracellular fluid
(ECF), capillaries, glial cells, and adjacent neurons
• The concentration of solutes in brain ECF (BECF) fluctuate
with neural activity. Similarly, changes in BECF can influence
nerve cell behavior
– Blood-brain-barrier (BBB) protects BECF from fluctuations in
blood composition
– The cerebrospinal fluid (CSF) strongly influences the BECF
composition
– The surrounding glial cells “condition” the BECF
Cerebrospinal Fluid
 CSF is a colorless, watery liquid which fills the
ventricles of the brain and forms a thin layer around
the outside of the brain and spinal cord in the
subarachnoid space
 CSF is secreted by a highly vascularized epithelial structure,
choroid plexus
 The ventricles of the brain are four small
compartments
 Each contains a choroid plexus and is filled with CSF
Ventricles and Subarachnoid Space
 The two lateral ventricles are the largest and each
communicate with the third ventricle via the two
interventricular foramina of Monro
 The third ventricle communicates with the fourth ventricle by the
cerebral aqueduct of Sylvius
 The fourth ventricle is continuous with the central canal of the
spinal cord
 CSF escapes from the fourth ventricle and flows into the
subarachnoid space via three foramina
 Two laterally placed foramina of Luschka
 Midline opening in the roof of the fourth ventricle, foramen
of Magendie
The Brain Ventricles & The CSF
Blumenfeld, Neuroanatomy
VENTRICULAR SYSTEM
Blumenfeld 131
Blumenfeld, Neuroanatomy
VENTRICULAR SYSTEM
The
Cerebrospinal
Fluid
Circulation
Blumenfeld, Neuroanatomy
The
Meninges
 The brain and spinal cord are covered by three membranes:
 The innermost layer is pia mater
 The middle is arachnoid mater (membrane)
* between the arachnoid mater and pia mater is the subarachnoid space (filled
with CSF)
 The outermost layer is dura mater
Blumenfeld, Neuroanatomy
Pia mater
• The pia mater is a thin layer of connective tissue cells
• Very closely applied to the surface of the brain and covers blood
vessels
• The glia limitans adjoins the pia from the brain side and is
separated from the pia by a basement membrane
– Pia adheres associated glia limitans very tightly; this combined
structure called the pial-glial membrane
Arachnoid Membrane & Dura Mater
 The cells of the arachnoid membrane are linked
together by tight junctions
 The arachnoid isolates the CSF in the subarachnoid space
from blood in the overlying vessels of the dura mater
 The dura mater is a thick, inelastic membrane that
forms an outer protective envelope around the brain
 The dura has two layers that split to form the intracranial
venous sinuses
The Meninges & Ependymal Cells
Arachnoid granulations
Choroid Plexuses Secrete CSF
 Most of the CSF is produced by the choroid plexuses which
are located in ventricles
 Capillaries also form a small amount of CSF
 CSF production is 500 ml/day and CSF volume of 150 ml is
replaced three times a day
 CSF percolates throughout the subarachnoid space, then
absorbed into venous blood from the superior sagittal sinus
Secretion of CSF
 Choroid epithelial cells are
bound to one another by tight
junctions, which makes the
epithelium an effective barrier
to free diffusion
 Ion concentration of CSF is
rigidly maintained
 Micronutrients are selectively
transported
Composition of Cerebrospinal Fluid
SOLUTE
PLASMA (mM OF PROTEINREE PLASMA)
CSF (mM)
CSF/PLASMA RATIO
Na+
153
147
0.96
K+
4.7
2.9
0.62
Ca2+
1.3 (ionized)
1.1 (ionized)
0.85
Mg2+
0.6 (ionized)
1.1 (ionized)
1.8
110
113
1.03
24
22
0.92
0.75 (ionized)
0.9
1.2
7.40
7.33
2.6
0.7
0.27
7 g/dl
0.03 g/dl
0.004
290
290
1.00
Cl-
PH
Aminoacids
acids
Amino
Proteins
Osmolality
(mOsm)
Absorption of
CSF
 the sites of absorption are specialized
evaginations of the arachnoid membrane
into the venous sinus “arachnoid
granulations/villi”
“One-way valves”
Hydrocephalus
Hydrocephalus – excessive CSF in
cranial cavity
1) Communicating Hydrocephalus –
impairment of reabsorption in arachnoid
villi or of flow in subarachnoid space
2) Noncommunicating (obstructive)
hydrocephalus – obstructions of flow
within ventricular system
“Normal-Pressure”
Hydrocephalus
• Spinal tap reveals normal pressure readings, but MRI of the head will
show enlargement of all four ventricles
– An infection or inflammation of the meninges damages arachnoid villi,
and causes impaired CSF absorption
• Patients typically have progressive dementia, urinary incontinence, and
gait disturbance
• CSF shunt to venous blood or to the peritoneal cavity helps reducing
CSF pressure
Lumbar Puncture
• Procedure to collect CSF from subarachnoid space is called
lumbar puncture
• The spinal cord ends as a gradual taper, known as the conus
medullaris, typically coming to an end at the lower border of
L1 or at the upper border of L2.
– The nerve roots of the cauda equina “sprout” from the
conus medullaris and extend caudally within the vertebral
canal as far as the caudal end of the sacrum.
• Spinal nerves exit the vertebral canal inferior to their named
vertebrae, except for cervical spinal nerves, which exit through
the intervertebral foramina superior to their named vertebrae
Lumbar Puncture
Blumenfeld, Neuroanatomy
The Extracellular Space
 The average width of the space
between brain cells is 20 nm
 Glial cells express
neurotransmitter receptors, and
neurons have extrajunctional
receptors >>> capable of
receiving messages sent via BECF
– Numerous trophic molecules
secreted by brain cells diffuse in the
BECF to their target cells
Leaky regions of the BBB
Blood-Brain Barrier
 CNS blood vessels exclude
certain substances from
brain tissue : “blood-brain
barrier”
 Brain needs to be
protected from the
constituent variations of
blood
 Neurons within the circumventricular organs are
directly exposed to blood solutes and
macromolecules
 Part of neuroendocrine control system for maintaining
osmolality, appropriate hormone levels etc.
 Humoral signals are integrated by connections of
circumventricular organ neurons to endocrine,
autonomic, and behavioral centers within the CNS
The BBB function of brain
capillaries
 Brain capillary endothelial
cells are fused to each other
by tight junctions
– The tight junctions prevent
water-soluble ions and molecules
from passing from the blood into
the brain via paracellular route
– Electrical resistance of the
cerebral capillaries is 100 to 200
times higher than other systemic
capillaries
Glial Cells
 The three major types of
glial cells in the CNS are
astrocytes, oligodendrocytes,
and microglial cells
 Glial cells are about 10-fold
more numerous than
neurons, and they can
proliferate throughout life
Glial Types
GLIAL CELL TYPE
SYSTEM
LOCATION
GFAP
Fibrous
CNS
White matter
Positive
Protoplasmic
CNS
Gray matter
Weakly
positive
Radial glial cells
CNS
Throughout brain during
development
Positive
Müller cells
CNS
Retina
Positive
Bergmann glia
CNS
Cerebellum
Positive
Ependymal cells
CNS
Ventricular lining
Positive
Oligodendrocytes
CNS
Mainly white matter
Negative
Microglial cells
CNS
Throughout the brain
Negative
Satellite cells
PNS
Sensory and autonomic ganglia
Weakly
positive
Schwann cells
PNS
Peripheral axons
Negative
Enteric glial cells
ENS
Gut wall
Positive
Astrocytes
Astrocytes
• Astrocytes modifies and controls the immediate environment of neurons
– Fibrous astrocytes have long, thin and well defined processes
– Protoplasmic astrocytes have shorter, frilly processes
• The cytoskeleton of all the astrocytes composed of a unique protein “glial
fibrillar acidic protein”
• During development, radial glial cells are present:
– create an organized scaffolding by spanning the developing forebrain from the
ventricle to the pial surface
• Müller cells are retinal astrocytes
• Bergmann glial cells are located in the cerebellum
Astrocytes
• Astrocytes contain all the glycogen present in the brain
– also contain all the enzymes needed for metabolizing glycogen
• The brain’s glucose needs is supplied by blood, in the absence of
glucose from blood, astrocytic glycogen could sustain the brain for
about 5 minutes
 Astrocytes break glycogen down to glucose and even
further to lactate, which is aerobically metabolized by nearby
neurons >>> substrate buffering
Role of Müller Cells in Spatial
Buffering
Astrocytes Synthesize
Neurotransmitters
 Astrocytes synthesize at least 20 neuroactive compounds,
including glutamate and GABA
 Glutamate precursor glutamine is manufactured only in
astrocytes, by astrocyte-specific enzyme glutamine
synthetase
 Glutamine is released by astrocytes to the BECF to be taken
up by neurons
Role of Astrocytes in the glutamateglutamine cycle
 Glutamine is also important for the GABA synthesis
 Neuronal glutamic acid decarboxylase converts glutamine to
GABA
 After its use as neurotransmitter by neurons, some of glutamate is
taken up into astrocytes via high-affinity uptake systems
 This system maintain extracellular glutamate concentration
around 1uM
 If transmembrane ion gradients break down under pathologic
conditions, high-affinity uptake systems may work in reverse
• Excessive accumulation of glutamate in the BECF –induced by
ischemia, anoxia, hypogylcemia, or trauma- can lead to neural injury
• In anoxia and ischemia, the sharp drop in cellular ATP levels inhibits
the Na-K pump and leads to large increases in [K+]o and [Na+]i
– These changes result in membrane depolarization along with a burst of
glutamate release from vesicles
• The inability of astrocytes to remove glutamate from the BECF under
these pathologic conditions makes extracellular glutamate levels too
high to become toxic for neurons
Oligodendrocytes
• The primary function of oligodendrocytes in the CNS is to
provide and maintain myelin sheaths on axons
– Myelin is the insulating electrical tape of the nervous system
• Oligodendrocytes in white matter
has 15 to 30 processes, each
connecting a myelin sheath to
the oligodendrocyte’s cell body
– Each myelin sheath wraps many
times around the long axis of one axon
Myelin
 The constituent proteins in
PNS and CNS myelins are
somewhat different
 In the Peripheral nervous
system, a single Schwann
cell provides a single myelin
segment to a single axon of
a myelinated nerve
Ensheathed versus
myelinated axons
Oligodendrocytes
• Oligodendrocytes and myelin contain most of the enzyme
carbonic anhydrase in the brain
– Carbonic anhydrase is important in CO2/HCO3- buffer system
• pH imbalance in the brain reduces seizure threshold
• Oligodendrocytes are also involved with iron metabolism
Microglial Cells
• Microglial cells derive from cells related to the
monocyte/macrophage lineage
– Microglia represent 20% of the total glial cells within CNS
• These cells are rapidly activated by injury to the brain,
proliferate and become phagocytic
• Microglia are also the most effective antigen-presenting cells
within the brain