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Brain region-specific control of microglia by adenosine A2A-adenosine receptors: uncoupling anxiety and cognition in female rodents

2018; Elsevier BV; Volume: 28; Linguagem: Inglês

10.1016/j.euroneuro.2017.12.058

1873-7862

Júlia Borges Duarte, Rita Gaspar, L. Caetano, Patrícia Patrício, Cristina Cunha, António Mateus‐Pinheiro, Nuno Dinis Alves, Adilza Raquel Cavalcanti Dos Santos, Samira G. Ferreira, Vanessa Morais Sardinha, J. Oliveira, Nuno Sousa, Robson de Macêdo Cunha, F. Ambrósio, Ana João Rodrigues, Luísa Pinto, Catarina A. Gomes,

Adenosine and Purinergic Signaling

Microglia morphology is critical for brain functioning and undergoes profound remodeling in neuropsychiatric diseases. Rats prenatally exposed to glucocorticoids (iuDEX), which become anxious and have cognitive deficits at adulthood, exhibit gender-specific changes in microglia morphology in the medial pre-frontal cortex (mPFC), involved in anxiety pathophysiology [1]. Gender differences in microglia morphology, the higher prevalence of anxiety in women and the negative impact of anxiety in cognition, led us to specifically evaluate cognitive behaviour and associated circuits (mPFC-dorsal hippocampus, dHIP), as well as microglia morphology in female rats prenatally exposed to dexamethasone (1 mg/kg, subcutaneous injection to pregnant rats). Statistical analysis was performed in GraphPad Prism: Student’s t test was used to compare two independent means; differences were considered significant at p<0.05. We report that iuDEX, besides anxious-like behavior, present deficits in recognition memory (SAL: 0.47±0.06, n=9; iuDEX: 0.21±0.03, n=10; p<0.001), assessed by novel object recognition test and lack of neuronal synchronization in different frequency bands between mPFC and dHIP, evaluated by in vivo electrophysiology: delta (1-4 Hz; SAL: 0.71±0.05, n=9; iuDEX: 0.47±0.08, n=7; p=0.0254; theta (4-12 Hz; SAL: 0.79±0.04, n=9; iuDEX: 0.44±0.07, n=5; p=0.0003), beta (12-20 Hz; SAL: 0.80±0.03, n=8; iuDEX: 0.58±0.04, n=5; p=0.0018) and low gamma (20-40 Hz; SAL: 0.76±0.03, n=9; iuDEX: 0.60±0.06, n=6; p=0.0179). These functional deficits are parallel with alterations in microglial cells morphology, assessed by immunohistochemistry with a microglia marker (Iba-1) followed by manual reconstruction of confocal images, using the Neurolucida software. Prenatal exposure to DEX triggered a hyper-ramification of microglia in the dHIP and a de-ramification in the mPFC, showing a heterogenous remodeling of microglia morphology both postnatally and at adulthood in different brain regions, that differently affect mood and cognition. The chronic blockade of adenosine A2A receptors (A2AR), using a selective A2AR antagonist, SCH 58261 (0.1 mg/kg for 21 days before post-natal 90), which are core regulators of microglia morphology and physiology [1], ameliorated cognitive deficits (iuDEX + SCH: 0.35±0.02, n=7; iuDEX: 0.21±0.03, n=10; p=0.0304), but not anxiety-like behavior (iuDEX+SCH: 0.19±0.04, n=10; iuDEX: 0.20±0.04, n=7; p=0.9997), assessed by elevated plus maze test. Moreover, this treatment restored microglia morphology in the dHIP and reverted mPFC-dHIP desynchronization: delta (1-4 Hz; DEX+SCH: 0.59±0.08, n=10; p=0.3464 as compared with iuDEX), theta (4-12 Hz; DEX+SCH: 0.67±0.06, n=8; p=0.0366 as compared with iuDEX), beta (12-20 Hz; SAL: DEX+SCH: 0.61±0.05, n=10; p=0.7365, as compared with iuDEX) and low gamma (20-40 Hz; DEX+SCH: 0.52±0.06, n=10; p=0.4171 as compared with iuDEX). These results contrast with observations in the mPFC, where prenatal DEX induced microglia de-ramification, not reverted by blocking A2AR, which did not ameliorate anxiety [1]. Considering the role of microglia in shaping neuronal circuits, alterations in these cells during development may lead to an impairment in brain wiring, with implication in behaviour. Our results demonstrate microglia and adenosinergic system involvement in different components of mood disorders, namely anxiety and cognition.