Brief Definit ive Report

Microglia are the resident myeloid phagocytes of the central nervous system (CNS), where they fulfill important functions in normal phys-iology and in the response to injury or disease (Saijo and Glass, 2011). Activated microglia, which are a hallmark of neuroinflammation, may contribute to CNS damage and chronic neurodegeneration through the release of harm-ful cytokines, reactive oxygen species, or un-controlled phagocytosis (Lucin and Wyss-Coray, 2009). For example, microglia contribute to neu-rodegeneration in superoxide dismutase 1 trans-genic mouse models for amyotrophic lateral sclerosis (Boillée et al., 2006), and microglia lacking fractalkine receptor, CX3CR1, promote protein aggregation and disease in tau trans-genic models of Alzheimer’s disease and related tauopathies (Bhaskar et al., 2010). Interestingly, microglial activation appears indicative of disease activity in multiple sclerosis (MS) patients based on positron emission tomography (PET) imag-ing with a ligand that binds to peripheral ben-zodiazepine receptors on activated microglia (Banati et al., 2000). These observations raise the possibility that selective inhibition of microglia may be beneficial in certain CNS disorders with a neuroinflammatory component, but today no treatments targeting aberrantly activated mi-croglia are available to test this hypothesis. Ganciclovir (GCV) is a prodrug nucleoside analogue, which in its canonical function re-quires bioactivation by viral thymidine kinase (tk) from viruses of the Herpesviridae family, in-cluding cytomegalovirus, Epstein-Barr virus, or HSV (Matthews and Boehme, 1988; Faulds and Heel, 1990). GCV was developed in the 1970s as an antiviral treatment and is currently used clinically to control cytomegalovirus and other viral infections. More recently, it has been used in research studies for the targeted deletion of cells genetically engineered to express HSV tk (HSVtk; Culver et al., 1992; Fillat et al., 2003) or for imaging tk expressing transgenic cells using modified, radiolabeled GCV analogues (Min et al., 2003). Besides its potent effects o