neurons in CNS – terminally differentiated; incapable of division glial cells – certain subtypes possess ability to divide of interest in terms of understanding this ability – applicable to neurons?

ability to divide Æmost CNS (brain) tumors linked to glial cells

astrocytes 1) clean up brain "debris" 2) transport nutrients (neurotrophins) to neurons 3) hold neurons in place 4) digest parts of dead neurons 5) regulate content of extracellular space 6) contribute to formation of blood brain barrier

astrocyte labeled with anti-GFAP antibody Neuron growing on an astrocytic neuroglia cell

GFAP: glial cell fibrillary acidic protein

fibrous astrocytes: prevalent in white matter; highly filamentous protoplasmic astrocytes: abundant in gray matter; less filamentous oligodendrocytes

form myelin sheath around axons in CNS

stained for galactocerebroside

microglia

1) involved in immune response in CNS 2) help clean up debris/dying cells 3) probably a distinct lineage of cells from other glia

may be linked to destruction of myelin-producing oligodendrocytes in certain forms of multiple sclerosis

Microglial cells (yellow) ingest branched oligodendrocyte cells (purple) ---the process thought to occur in multiple

sclerosis.

ependymal cells

1) line surfaces of brain 2) form barriers between compartments (BBB)

radial glia

DiI fill of an individual radial glia cell (red) in the mouse embryonic olfactory bulb counterstained for tissue architecture (green)

1) important during development of the CNS 2) provide pathways for neuronal growth and targeting 3) in adult: Müller cells (retina); Bergmann cells

(cerebellum) are derived from radial glia Schwann cells

1) form myelin sheath – analogous to oligodendrocytes 2) surround other axons w/o forming myelin

electron micrograph showing a Schwann cell (G) surrounding an axonal process (A)

satellite cells 1) important for structure of peripheral nervous system – support cell 2) common in ganglia 3) may contribute to insulation of neuron

Note: course text uses this term to generally describe all glial

This type I neuron is ensheathed by processes from a satellite glial cell (S), which forms a thin myelin sheath. On the right is the axon hillock.

neuronal & glial elements are in close apposition to one another

VM in most glia is very negative (-90 mV) compared to neurons spatial distribution of K conductance in glia

changing [K]out Æ changes VM behaves like a “K+ electrode”

most glia incapable of regenerative activity (very low or no gNa) other transport mechanisms in glia

subsets of glia have been shown to contain:

1. voltage-gated Na+ and Ca2+ channels

but no AP’s!

  1. Cl-channels

  2. Na+/K+ pumps; HCO3-/H+ exchanger

  3. neurotransmitter transporters (glu, GABA, gly, …)

  4. neurotransmitter receptors

™ intracellular gap junctions

gap junction

intercellular gap junctions gap junctional proteins = CONNEXINS (Cx)

*oligodendrocytes: express Cx32 astrocytes: express Cx30, Cx43

neurons: express Cx36

adult rat CNS

neuron-astrocytes in close apposition at nodes

  • neurons form gap junctions only with other neurons – no sharing of signals directly between neurons & glia

  • glial cells with glial cells (oligo’s form gap junctions only with astrocytes) may couple indirectly with other oligo’s via astrocytes (oligoÅÆastroÅÆoligo) glial junctions may be used to reduce concentration gradients

*Rash et al. J. Neurosci 21:1983-2000 (2001).

formation of myelin… role of PMP22 Schwann cell – neuron interaction directed by Schwann cell expression of PMP22 (Peripheral Myelin Protein-22)

… formation of myelin long standing questions: -control of node spacing -sequestering of ion channels (neuronal vs. glial roles) -role of astrocytes at node (astro’s c/ high concentration of NaV channels at point of contact) -nature of communication between glia and neurons in myelin formation

™ neurotrophic functions of glia

glial cells secrete:

nerve growth factor(s)

neurite growth-promoting factors

laminin glial derived nexin

neurite growth-inhibiting factors

NI-35/250 other GIP’s (growth inhibiting proteins)

stop inappropriate targeting of axons

glial cells provide physical “highway” for axonal growth/pathfinding

radial glial guide neuronal migration

™ recovery from injury – role of microglia

MICROGLIA are the major central nervous system cell (~20% of all glia) involved in the central neuroimmune response to injury. Microglia secrete cytokines (growth factors used for intercellular signaling) and other molecules that interact with neurons and glia in the brain

illustrates recruitment of microglia (intense labeling) to the lesion site (center)

glia regulate the extracellular [K] by acting to spatially buffer neurons from changes in [K]out

glial cell take up extra [K] Ædistribute to other glial cells via gap junctions

™ neurotransmitters & glial cells: reuptake/responses/release

glia have been shown to express a number of neurotransmitter transporters -glutamate; glycine; GABA… -role in termination of chemical synaptic transmission

» The loss of glial glutamate transporters GLAST or GLT-1 produces elevated extracellular glutamate levels, neurodegeneration characteristic of excitotoxicity, and a progressive paralysis. » The loss of the neuronal glutamate transporter EAAC1 does not elevate extracellular glutamate but does produce mild neurotoxicity and resulted in epilepsy.

evidence for functional neurotransmitter receptors exist in variety of glia -physiological function of these receptors remains unclear

response of Müller cell (retinal glial cell) to the inhibitory transmitter, GABA

release of neurotransmitters by glia

Above,Astrocytes communicate via intracellular Ca2+ waves

a) Binding of glutamate causes a rise in intracellular Ca2+ via activation of IP3, which propagates through gap junctions (GJ) with adjacent cells.

b) ATP release from astrocytes may occur through unpaired gap junctions (Hemi), the cystic fibrosis transmembrane conductance regulator (CFTR), ATP-binding cassette transporters (Trans), and other stretch-activated Clchannels (SaCl).

c) ATP binding to membrane receptors causes a rise in intracellular Ca2+ by activating metabotropic (P2Y) or ionotropic (P2X) receptors. This is associated with the vesicular release of glutamate, and the release of ATP via an unknown mechanism. The K+ released into the extracellular space by neuronal firing is taken up by membrane transporters in astrocytes and distributed by gap junctions through the astrocytic syncytium.

from Fields & Stevens-Graham (2002) Science 556-562.