Adenosine A2A receptors in bone marrow-derived cells but not in forebrain neurons are important contributors to 3-nitropropionic acid-induced striatal damage as revealed by cell-type-selective inactivation.

Endogenous adenosine acting at the adenosine A 2A receptor (A 2A R) can modify brain injury in a variety of neurological disorder models. However, both A 2A R activation and inactivation have been shown to be neuroprotective in different situations, raising the intriguing possibility that A 2A Rs in distinct cellular elements may have different and even opposing effects. In this study, we developed three novel transgenic models to dissect out cell-type-specific actions of A 2A Rs on striatal damage by the mitochondrial toxin 3-nitropropionic acid (3-NP). Whereas global inactivation of A 2A Rs exacerbated 3-NP-induced neurological deficit behaviors and striatal damage, selective inactivation of A 2A Rs in forebrain neurons (using the Cre/loxP strategy) did not affect neurological deficit or striatal damage after the acute systemic treatment of 3-NP and intrastriatal injection of malonate. However, selective inactivation of A 2A Rs in bone marrow-derived cells (BMDCs) by transplanting bone marrow cells from global A 2A R knock-out (KO) mice into wild-type C57BL/6 mice produced a similar phenotype of global A 2A R KO mice, i.e., exacerbation of 3-NP-induced striatal damage. Thus, cell-type-selective inactivation of A 2A Rs reveals that A 2A Rs in BMDCs but not in forebrain neurons are an important contributor to striatal damage induced by mitochondrial dysfunction.