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showed good tolerability and resulted in a dose-dependent increase in dopamine transporter expression
[10]
measure via positron emission tomography (PET) scan, but little to no symptomatic improvement .
[71]
Analogous to our own findings demonstrating amyloid-b could impair PDGF receptor signaling , one
of the pathogenic processes in PD, a-synuclein, impairs some PDGF-induced processes (chemotaxis)
[80]
but not others (intracellular signaling to ERK) . In addition to PDGF-BB, PDGF-CC has demonstrated
neuroprotective effects in several neuronal toxicity studies, including 6-OH-dopamine-induced neuronal
[81]
cell death, in signaling pathways associated with GSK3b .
NEUROPROTECTIVE EFFECTS OF PDGF RECEPTOR TRANSACTIVATION
Growth factor receptors such as the PDGFb receptor can be activated directly by their endogenous ligand
or be transactivated by signals initiated through other receptors in the absence of PDGF ligand [82,83] . Classic
transactivation of growth factor receptors occurs within minutes after activation of GPCRs. For example,
the activation of D2-family dopamine receptors initiates an intracellular signaling cascade that increases
[84]
PDGFb receptor phosphorylation and activity, including an increase in ERK1/2 phosphorylation . The
transactivation of RTK receptors by GPCR initiation may regulate a signaling cascade that differs from
[85]
those activated by direct ligand binding .

5-HT7 receptors are Gαs-coupled receptors; their activation leads to an increase both in adenylyl cyclase
activity and in the intracellular level of cyclic AMP . 5-HT7 receptors are expressed in the prefrontal
[86]
[87]
cortex, hippocampus, thalamus, hypothalamus, and the amygdala in both neurons and support cells .
[88]
5-HT7 receptors increase the number of dendrites and promote synapse formation in neurons . 5-HT
receptors including the 5-HT7 receptor are also able to transactivate PDGFb receptors (and TrkB receptors) [89,90] .
PDGFb receptors can inhibit NR2B-containing NMDA receptors and this can result in neuroprotective
effects. Similarly, transactivating PDGFb receptors, downstream of dopamine receptors, also results in
[91]
neuroprotection against NMDA-induced toxicity . 5-HT7 receptor agonists also lead to an increase in the
expression of PDGFb receptors and its phosphorylation at tyrosine 1021, the PLCγ binding site associated
[89]
with PDGF-induced inhibition of NMDA-evoked currents . After the application of 5-HT7 receptor
agonists to cultured cells or primary hippocampal or cortical cultures, the cells are resistant to NMDA-
[72]
induced toxicity due to the upregulation and activation of PDGFb receptors . In addition, activation of
the 5-HT7 receptor also selectively changes the expression and phosphorylation state of the NR2B subunit
of the NMDA receptor, similar to what was observed with dopamine and PDGF-BB-induced changes in
[72]
NMDA receptor expression . Interestingly, although long-term agonist treatment with 5-HT7 ligands
inhibits NMDA receptor activity via PDGFb receptors, acute, direct activation of 5-HT7 receptors increases
NMDA-evoked currents .
[92]

PDGFb receptor transactivation may also play a role in BBB function. PDGFb receptor signaling protects
endothelial cell function and BBB integrity after b-arrestin activation subsequent to protease-activated
receptor 1 . Thus, in addition to GPCR-PDGFb receptor transactivating and directly impacting neuronal
[93]
health, transactivation or indirect activation of PDGF signaling may also impact BBB integrity in the
context of stroke or other neurological diseases.

PDGF AS A BIOMARKER
As noted above, the impact of the PDGF system on the vasculature may be more important clinically than
the direct effects of this signaling pathway on neurons. Similarly, although there are intriguing possibilities
for the development of novel treatments targeting the PDGF system in neuronal health, using PDGF
ligands as biomarkers for disease may be more impactful, at least in the short term. For example, the
presence of PDGF-AA in cerebrospinal fluid (CSF) of HIV-infected individuals was negatively associated