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 A2AR 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.