Adenosine A_2A receptor in the monkey basal ganglia: Ultrastructural localization and colocalization with the metabotropic glutamate receptor 5 in the striatum

Abstract

The adenosine A2A receptor (A2AR) is a potential drug target for the treatment of Parkinson’s disease and other neurological disorders. In rodents, the therapeutic efficacy of A2AR modulation is improved by concomitant modulation of the metabotropic glutamate receptor 5 (mGluR5). To elucidate the anatomical substrate(s) through which these therapeutic benefits could be mediated, pre-embedding electron microscopy immunohistochemistry was used to conduct a detailed, quantitative ultrastructural analysis of A2AR localization in the primate basal ganglia and to assess the degree of A2AR/mGluR5 colocalization in the striatum. A2AR immunoreactivity was found at the highest levels in the striatum and external globus pallidus (GPe). However, the monkey, but not the rat, substantia nigra pars reticulata (SNr) also harbored a significant level of neuropil A2AR immunoreactivity. At the electron microscopic level, striatal A2AR labeling was most commonly localized in postsynaptic elements (58% ± 3% of labeled elements), whereas, in the GPe and SNr, the labeling was mainly presynaptic (71% ± 5%) or glial (27% ± 6%). In both striatal and pallidal structures, putative inhibitory and excitatory terminals displayed A2AR immunoreactivity. Striatal A2AR/mGluR5 colocalization was commonly found; 60–70% of A2AR-immunoreactive dendrites or spines in the monkey striatum coexpress mGluR5. These findings provide the first detailed account of the ultrastructural localization of A2AR in the primate basal ganglia and demonstrate that A2AR and mGluR5 are located to interact functionally in dendrites and spines of striatal neurons. Together, these data foster a deeper understanding of the substrates through which A2AR could regulate primate basal ganglia function and potentially mediate its therapeutic effects in parkinsonism.

Adenosine A2A receptor antagonism reverses inflammation-induced impairment of microglial process extension in a model of Parkinson's disease

“…While it is likely that the ability of A 2A receptors to affect motor symptoms of PD occurs through actions on neuronal receptors, it remains an open question as to whether block of glial A 2A receptors might mediate some of the neuroprotective effects [e.g., neuronal health; Yu et al (2008)]. A 2A receptors are highly expressed on glial cells in the substantia nigra of healthy monkeys, and to a lower extent in the SN of healthy rats (Bogenpohl et al, 2012). Moreover, A 2A receptors were upregulated in the substantia nigra following treatment with 20 mg/kg/day MPTP for 5 days in CX 3 CR1 GFP/+ mice (Figure 7).…”

Structural plasticity of GABAergic and glutamatergic networks in the motor thalamus of parkinsonian monkeys

“…These animals received weekly MPTP injections (0.2-0.8 mg/kg i. m.; cumulative doses: 2.8-26.79 mg/kg; Natland International, Morrisville, NC or Sigma, St. Louis, MO), until they reached comparable states of stable, moderate parkinsonism. As described in previous studies (Bogenpohl et al, 2012;Devergnas, Pittard, Bliwise, & Wichmann, 2014;Galvan, Hu, Smith, & Wichmann, 2010;Kliem, Pare, Khan, Wichmann, & Smith, 2009;Masilamoni et al, 2010;Masilamoni et al, 2011;Wichmann et al, 2001;Wichmann & Soares, 2006), we assessed the severity of parkinsonism weekly for 15-min periods in an observation cage that was equipped with infrared beams, allowing us to measure their body movements as infrared beam break events. In addition, we used a parkinsonism rating scale to quantify impairments in 10 aspects of motor function (speed of movement, incidence and severity of "freezing" episodes, extremity posture, trunk posture, presence and severity of tremor, amount of arm movements, amount of leg movements, finger dexterity, home cage activity, and balance).…”

Functional Neuroanatomy of the Basal Ganglia

“…The GPe receives a GABAergic projection from D 2 R-containing striatal MSNs, an inhibitory projection that represents the first synaptic relay station of the indirect pathway as is discussed below. Moreover, striatal projections innervating GPe neurons also show an enriched expression of adenosine type 2A receptors (A 2A -Rs), and thus antibodies against A 2A -Rs have been used to define the boundaries of the GPe nucleus accurately (Rosin et al 1988;Bogenpohl et al 2012). GPe neurons are also reciprocally connected with STN neurons from which they receive strong glutamatergic excitatory projections (vGlut2-positive).…”