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al.,
2001]. Astrocyte-secreted proteins that promote CNS synaptogenesis include
thrombospondins [Christopherson
et al.,
2005]. While thrombospondins induce the formation
of ultrastructurally normal synapses bearing pre- and postsynaptic specializations that are
presynaptically active but postsynaptically silect, an unidentified astrocyte signal induces
postsynaptic function by inserting functional AMPA receptors into postsynaptic sites
[Christopherson
et al.,
2005]. This is reminiscent of the two-step model for activation of
silent synapses in the developing brain thought to be important for synapse refinement and
and circuit modification wherein silent structural synapses are initially formed and some
become postsynaptically functional in a second step involving an activity-dependent
mechanism [Malenka and Nicoll, 1997]. The above findings implicate astrocytes as active
players in both of these steps. Although thrombospondin levels are normally low in the adult
brain, reemergence of thrombospondins in reactive astrocytes [Moller
et al.,
1996; Lin
et al.,
2003] could account for the formation of aberrant sysnapses that result in epilepsy at
astrocytic scars as well as the tendency of axotomized axons to synaptically differentiate and
fail to regenerate when they contact reactive astrocytes [Liuzzi and Lasek, 1987]. If so,
pharmacological manipulation of thrombospondins may help to promote synaptic plasticity
and repair in CNS diseases.
Intriguing new data also point to a role for the complement pathway components C1q and
C3 in synaptic elimination, being upregulated when neurons were exposed to astrocytes
[Stevens
et al.,
2007]. Activated microglia secrete most complement cascade components,
including particularly high amounts of C1q, and are localized in brain regions during a
narrow window of postnatal development that coincides with the peak of synapse formation
and elimination [Dalmau et al., 1998; Fiske and Brunjes, 2000]. Conceivably,
pharmacological inhibition of the classical complement cascade may inhibit synapse loss and
neurodegeneration in neurodegenerative diseases like AD, motor neuron disease and multiple
sclerosis.
Estradiol (E
2
) can promote dendritic outgrowth, spinogenesis, and synaptogenesis in
several discrete loci within the developing and adult brain [Woolley and McEwen,
1992,1993,1994; Calizo and Flanagan-Cato, 2000; Sakamoto
et al.,
2003]. Astrocytes are
important in E
2
-induced dendritic spine synapse formation and efficacy [Mong
et al.,
1999].
Evidence now points to PGE
2
as a mediator of mediator cell-to-cell communication involving
crosstalk between astrocytes and neurons [Rage
et al.,
1997; Bezzi
et al.,
1998]. Astrocytes
release glutamate in response to PGE
2
[Bezzi
et al.,
1998], which can activate glutamate
receptors on neighboring neurons and modulate their dendritic spine density [McKinney
et
al.,
1999; Luthi
et al.,
2001]. A novel mechanism of neuronal spine plasticity has recently
been reported, in which E
2
induces PGE
2
synthesis that in turn increases the density of spine-
like processes [Amateau and McCarthy, 2002]. This effect is region-specific in that it was
observed in the preoptic area but not the hippocampus, and was dependent on the activation
of AMPA-kainate receptors by glutamate that may originate from astrocytes.
Neuronal cell loss is a common feature of many neurological maladies that affect the
brain including traumatic brain injury, stroke, and AD [Morrison and Hof, 1997]. Stem cell-
based approaches have received considerable attention as a potential means of treatment
[Oliveira and Hodges, 2005; Lindvall and Kokaia, 2006; Vora et al., 2006]. Transplanted cells
may serve as a reservoir, providing trophic support to surviving cells and synapses, or they
may actually replace and partially repopulate damaged areas. However, it remains to be
determined whether stem cells can ameliorate memory dysfunction in these disorders. In this
