Phenotypic Alteration of Astrocytes Induced by Ciliary Neurotrophic Factor in the Intact Adult Brain, As Revealed by Adenovirus-Mediated Gene Transfer

Abstract

Synthesis of the ciliary neurotrophic factor (CNTF) and its specific receptor (CNTFR␣) is widespread in the intact CNS, but potential biological roles for this system remain elusive. Contradictory results have been obtained concerning a possible effect on the morphological and biochemical phenotype of astrocytes. To reassess this question, we have taken advantage of adenovirus-mediated gene transfer into the rat brain to obtain the local release of CNTF. Stereotaxic administration of CNTF recombinant adenovirus vectors into the striatum led to phenotypic changes in astrocytes located in regions that were related axonally to striatal neurons at the injection site. Astrocytes appeared hypertrophied and displayed an increase in both GFAP and CNTF immunoreactivity. This response was observed up to 5 weeks after injection, the longest time studied. It was not observed after the administration of a control vector. The methodology used in the present study, allowing us to analyze the effect of the factor in areas remote from the injection site, has provided conclusive evidence that CNTF affects the astroglial phenotype in the intact CNS. The characteristics of these effects may explain why contradictory results have been obtained previously, because this signaling system seems to have a low efficiency and therefore requires a high local concentration of the factor close to the target cells. One might speculate as to the involvement of a CNTF astroglioastroglial signaling system in the organized response of a population of astrocytes to changes in CNS homeostasis detected locally, even by a single cell.

Ciliary Neurotrophic Factor Activates Astrocytes, Redistributes Their Glutamate Transporters GLAST and GLT-1 to Raft Microdomains, and Improves Glutamate HandlingIn Vivo

“…Part of these phenotypic changes has been reported previously at shorter time periods using injections of recombinant CNTF (see Introduction) and adenovirusmediated gene transfer of CNTF in the rat striatum (Lisovoski et al, 1997) and retina (van Adel et al, 2005). In addition, the changes in the phenotype of astrocytes were reproduced in our in vitro model of primary striatal neuron/astrocyte cultures, demonstrating that whatever the delivery system used, extracellular Figure 6.…”

“…An increase in CNTF concentra-tion leads to astrocyte hypertrophy and GFAP overexpression in vitro (Levison et al, 1998) and in vivo (Kahn et al, 1995;Winter et al, 1995;Lisovoski et al, 1997). In addition, the levels of endogenous CNTF are increased in conditions associated with astrocytic activation such as mechanical injury (Ip et al, 1993) or excitotoxic lesion (Haas et al, 2004).…”

Inflammatory responses and their impact on β-galactosidase transgene expression following adenovirus vector delivery to the primate caudate nucleus

“…Instead, this vector has been used for the delivery of antitumor genes in the clinical setting. [35][36][37][38] Consideration of the prior immune Table 1). These results suggest that apoptosis may be a factor in the lack of ␤-galactosidase expression in U030.…”

Non‐viral gene therapy for diabetic retinopathy

“…Many viral gene delivery systems have been reported for the retina such as adenoviral vectors [Mori et al, 2002], adeno-associated viral vectors [Weber et al, 2003], lentiviral vectors [Cheng et al, 2002], and herpes simplex viral vectors [Spencer et al, 2000]. Although they are promising, these viral gene delivery systems have potential side effects including eliciting immune responses, toxicity, and induction of mutations [Lisovoski et al, 1997;Easton et al, 1998;Lehrman, 1999;Thomas et al, 2001;Li et al, 2002;Baum et al, 2003]. These side effects may not be limited to the eye but may also occur in other tissues such as the brain [Dudus et al, 1999;Hennig et al, 2003].…”