Inactivation of adenosine A2A receptors reverses working memory deficits at early stages of Huntington's disease models

Abstract

Cognitive impairments in Huntington's disease (HD) are attributed to a dysfunction of the cortico-striatal pathway and significantly affect the quality of life of the patients, but this has not been a therapeutic focus in HD to date. We postulated that adenosine A(2A) receptors (A(2A)R), located at pre- and post-synaptic elements of the cortico-striatal pathways, modulate striatal neurotransmission and synaptic plasticity and cognitive behaviors. To critically evaluate the ability of A(2A)R inactivation to prevent cognitive deficits in early HD, we cross-bred A(2A)R knockout (KO) mice with two R6/2 transgenic lines of HD (CAG120 and CAG240) to generate two double transgenic R6/2-CAG120-A(2A)R KO and R6/2-CAG240-A(2A)R KO mice and their corresponding wild-type (WT) littermates. Genetic inactivation of A(2A)R prevented working memory deficits induced by R6/2-CAG120 at post-natal week 6 and by R6/2-CAG240 at post-natal month 2 and post-natal month 3, without modifying motor deficits. Similarly the A2(A)R antagonist KW6002 selectively reverted working memory deficits in R6/2-CAG240 mice at post-natal month 3. The search for possible mechanisms indicated that the genetic inactivation of A(2A)R did not affect ubiquitin-positive neuronal inclusions, astrogliosis or Thr-75 phosphorylation of DARPP-32 in the striatum. Importantly, A(2A)R blockade preferentially controlled long-term depression at cortico-striatal synapses in R6/2-CAG240 at post-natal week 6. The reported reversal of working memory deficits in R6/2 mice by the genetic and pharmacological inactivation of A(2A)R provides a proof-of-principle for A(2A)R as novel targets to reverse cognitive deficits in HD, likely by controlling LTD deregulation.

Adenosine A2A Receptors in the Amygdala Control Synaptic Plasticity and Contextual Fear Memory

“…A 2A R upregulation was also detected in other brain regions involved in the processing of emotional information, such as the hippocampus and ventral striatum, and is in agreement with the previous observation that stressful events upregulate A 2A Rs (Fredholm et al, 2005;Cunha and Agostinho, 2010). Furthermore, A 2A Rs displayed a gain of function in the control of amygdala LTP after fear stress and the blockade of A 2A Rs decreased excessive plasticity in the amygdala, as it was previously found to occur in the hippocampus (Costenla et al, 2011) and in the striatum (Li et al, 2015b). This makes A 2A Rs attractive targets to manage conditions associated with abnormal fear expression, namely upon post-traumatic stress disorders.…”

Aberrant adenosine A2A receptor signaling contributes to neurodegeneration and cognitive impairments in a mouse model of synucleinopathy

“…This working hypothesis is based on two lines of experimental evidence: first, recent studies suggest a requisite facilitative role of the A 2A R in α-Syn pathology since A 2A R blockade decreases the number of α-Syn aggregates in cultured cells and reverses synaptic dysfunction in brain slices (Ferreira et al, 2015); also genetic inactivation of the A 2A R reduces dopaminergic neurodegeneration induced by over-expressing WT α-Syn in tyrosinehydroxylase-positive neurons (Kachroo and Schwarzschild, 2012). Second, many studies including ours have shown that A 2A R inactivation not only enhances working memory (Wei et al, 2011;Zhou et al, 2009), reversal learning (Wei et al, 2011), goal-directed behavior (Yu et al, 2009) and Pavlovian fear conditioning (Wei et al, 2014) in normal animals, but also reverses working memory impairments in animal models of PD (Kadowaki Horita et al, 2013), Alzheimer's disease (AD) (Canas et al, 2009b;Dall'Igna et al, 2007) and Huntington's disease (HD) (Li et al 2015b). In particular, we recently demonstrated that an abnormal activation of the A 2A R signalling in the hippocampus by an "optoA 2A R" approach is sufficient to elicit cognitive impairments (Li et al, 2015a).…”

“…It is known that A 2A R expression is sensitive to hypoxia (Kobayashi and Millhorn, 1999), inflammation and other brain insults that can trigger up-regulation of the A 2A R in different brain regions (Chen et al, 2013;Chen et al, 2014). Indeed, the A 2A R up-regulation has been documented in human brains of early PD (Villar-Menendez et al, 2014) and AD (Albasanz et al, 2008;Orr et al, 2015), and animal models of PD (Yu et al, 2008), AD (Orr et al, 2015), HD (Li et al, 2015b), amyotrophic lateral sclerosis (Ng et al, 2015), attention deficit hyperactivity disorder (Pandolfo et al, 2013), chronic unpredictable stress (Kaster et al, 2015). Notably, the upregulation of the A 2A R in disease models were demonstrated in neuronal (particularly the nerve terminals) (Kaster et al, 2015;Li et al, 2015b) and some glial elements (Orr et al, 2015;Yu et al, 2008).…”

The Role of Adenosine Tone and Adenosine Receptors in Huntington's Disease

“…Studies showed that the administration of the A 2A R antagonist SCH58261 in R6/2 mice reduced glutamate and adenosine outflow, normalized the alteration in emotional response, and reduced NMDAinduced toxicity, 226,227 but had no effect on locomotor capability. 226,228 Genetic and pharmacological inactivation of A 2A R reduced working memory deficits in R6/2 mice, 229 and the combined blockade of D 1 R and A 2A R improved cognitive dysfunction in a different transgenic HD mouse model (R6/1). 230 Taken together, these results suggest that A 2A R blockade may be able to reverse the cognitive impairment that develops in these HD mice.…”