The consumption of caffeine (an adenosine receptor antagonist) correlates inversely with depression and memory deterioration, and adenosine A 2A receptor (A 2A R) antagonists emerge as candidate therapeutic targets because they control aberrant synaptic plasticity and afford neuroprotection. Therefore we tested the ability of A 2A R to control the behavioral, electrophysiological, and neurochemical modifications caused by chronic unpredictable stress (CUS), which alters hippocampal circuits, dampens mood and memory performance, and enhances susceptibility to depression. CUS for 3 wk in adult mice induced anxiogenic and helpless-like behavior and decreased memory performance. These behavioral changes were accompanied by synaptic alterations, typified by a decrease in synaptic plasticity and a reduced density of synaptic proteins (synaptosomal-associated protein 25, syntaxin, and vesicular glutamate transporter type 1), together with an increased density of A 2A R in glutamatergic terminals in the hippocampus. Except for anxiety, for which results were mixed, CUS-induced behavioral and synaptic alterations were prevented by (i) caffeine (1 g/L in the drinking water, starting 3 wk before and continued throughout CUS); (ii) the selective A 2A R antagonist KW6002 (3 mg/kg, p.o.); (iii) global A 2A R deletion; and (iv) selective A 2A R deletion in forebrain neurons. Notably, A 2A R blockade was not only prophylactic but also therapeutically efficacious, because a 3-wk treatment with the A 2A R antagonist SCH58261 (0.1 mg/kg, i.p.) reversed the mood and synaptic dysfunction caused by CUS. These results herald a key role for synaptic A 2A R in the control of chronic stress-induced modifications and suggest A 2A R as candidate targets to alleviate the consequences of chronic stress on brain function.R epeated stress elicits neurochemical and morphological changes that negatively affect brain functioning (1, 2). Thus, repeated stress is a trigger or a risk factor for neuropsychiatric disorders, namely depression, in both humans and animal models (2, 3). Given the absence of effective therapeutic tools, novel strategies to manage the impact of chronic stress are needed, and analyzing particular lifestyles can provide important leads. Notably, caffeine consumption increases in stressful conditions (4) and correlates inversely with the incidence of depression (5, 6) and the risk of suicide (7,8). However, the molecular targets operated by caffeine to afford these beneficial effects have not been defined.Caffeine is the most widely consumed psychoactive drug. The only molecular targets for caffeine at nontoxic doses are the main adenosine receptors in the brain, namely the inhibitory A 1 receptors (A 1 R) and the facilitatory A 2A receptors (A 2A R) (9). A 2A R blockade affords robust protection against noxious brain conditions (10), an effect that might result from the ability of neuronal A 2A R to control aberrant plasticity (11, 12) and synaptotoxicity (13-15) or from A 2A R's impact on astrocytes (16) or microglia (17). T...

No abstract

There is considerable evidence showing that the neurodegenerative processes that lead to sporadic Parkinson's disease (PD) begin many years before the appearance of the characteristic motor symptoms. Neuropsychiatric, sensorial and cognitive deficits are recognized as early non-motor manifestations of PD, and are not attenuated by the current anti-parkinsonian therapy. Although loss-of-function mutations in the parkin gene cause early-onset familial PD, Parkin-deficient mice do not display spontaneous degeneration of the nigrostriatal pathway or enhanced vulnerability to dopaminergic neurotoxins such as 6-OHDA and MPTP. Here, we employed adult homozygous C57BL/6 mice with parkin gene deletion on exon 3 (parkin −/−) to further investigate the relevance of Parkin in the regulation of non-motor features, namely olfactory, emotional, cognitive and hippocampal synaptic plasticity. Parkin −/− mice displayed normal performance on behavioral tests evaluating olfaction (olfactory discrimination), anxiety (elevated plus-maze), depressive-like behavior (forced swimming and tail suspension) and motor function (rotarod, grasping strength and pole). However, parkin −/− mice displayed a poor performance in the open field habituation, object location and modified Y-maze tasks suggestive of procedural and short-term spatial memory deficits. These behavioral impairments were accompanied by impaired hippocampal long-term potentiation (LTP). These findings indicate that the genetic deletion of parkin causes deficiencies in hippocampal synaptic plasticity, resulting in memory deficits with no major olfactory, emotional or motor impairments. Therefore, parkin −/− mice may represent a promising animal model to study the early stages of PD and for testing new therapeutic strategies to restore learning and memory and synaptic plasticity impairments in PD.

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.

No abstract