Adenosine kinase (ADK) deficiency in human patients (OMIM:614300) disrupts the methionine cycle and triggers hypermethioninemia, hepatic encephalopathy, cognitive impairment, and seizures. To identify whether this neurological phenotype is intrinsically based on ADK deficiency in the brain or if it is secondary to liver dysfunction, we generated a mouse model with a brain-wide deletion of ADK by introducing aNestin-Cretransgene into a line of conditional ADK deficient Adk^fl/flmice. These Adk^Δbrainmice developed a progressive stress-induced seizure phenotype associated with spontaneous convulsive seizures and profound deficits in hippocampus-dependent learning and memory. Pharmacological, biochemical, and electrophysiological studies suggest enhanced adenosine levels around synapses resulting in an enhanced adenosine A₁receptor (A₁R)-dependent protective tone despite lower expression levels of the receptor. Theta-burst-induced LTP was enhanced in the mutants and this was dependent on adenosine A_2Areceptor (A_2AR) and tropomyosin-related kinase B signaling, suggesting increased activation of these receptors in synaptic plasticity phenomena. Accordingly, reducing adenosine A_2Areceptor activity in Adk^Δbrainmice restored normal associative learning and contextual memory and attenuated seizure risk. We conclude that ADK deficiency in the brain triggers neuronal adaptation processes that lead to dysregulated synaptic plasticity, cognitive deficits, and increased seizure risk. Therefore, ADK mutations have an intrinsic effect on brain physiology and may present a genetic risk factor for the development of seizures and learning impairments. Furthermore, our data show that blocking A_2AR activity therapeutically can attenuate neurological symptoms in ADK deficiency.SIGNIFICANCE STATEMENTA novel human genetic condition (OMIM #614300) that is based on mutations in the adenosine kinase (Adk) gene has been discovered recently. Affected patients develop hepatic encephalopathy, seizures, and severe cognitive impairment. To model and understand the neurological phenotype of the human mutation, we generated a new conditional knock-out mouse with a brain-specific deletion ofAdk(Adk^Δbrain). Similar to ADK-deficient patients, Adk^Δbrainmice develop seizures and cognitive deficits. We identified increased basal synaptic transmission and enhanced adenosine A_2Areceptor (A_2AR)-dependent synaptic plasticity as the underlying mechanisms that govern these phenotypes. Our data show that neurological phenotypes in ADK-deficient patients are intrinsic to ADK deficiency in the brain and that blocking A_2AR activity therapeutically can attenuate neurological symptoms in ADK deficiency.

Rett syndrome (RTT; OMIM#312750) is mainly caused by mutations in the X-linked MECP2 gene (methyl-CpG-binding protein 2 gene; OMIM*300005), which leads to impairments in the brain-derived neurotrophic factor (BDNF) signalling. The boost of BDNF mediated effects would be a significant breakthrough but it has been hampered by the difficulty to administer BDNF to the central nervous system. Adenosine, an endogenous neuromodulator, may accomplish that role since through A_2AR it potentiates BDNF synaptic actions in healthy animals. We thus characterized several hallmarks of the adenosinergic and BDNF signalling in RTT and explored whether A_2AR activation could boost BDNF actions. For this study, the RTT animal model, the Mecp2 knockout (Mecp2^-/y) (B6.129P2 (C)-Mecp2tm1.1Bird/J) mouse was used. Whenever possible, parallel data was also obtained from post-mortem brain samples from one RTT patient. Ex vivo extracellular recordings of field excitatory post-synaptic potentials in CA1 hippocampal area were performed to evaluate synaptic transmission and long-term potentiation (LTP). RT-PCR was used to assess mRNA levels and Western Blot or radioligand binding assays were performed to evaluate protein levels. Changes in cortical and hippocampal adenosine content were assessed by liquid chromatography with diode array detection (LC/DAD). Hippocampal ex vivo experiments revealed that the facilitatory actions of BDNF upon LTP is absent in Mecp2^-/y mice and that TrkB full-length (TrkB-FL) receptor levels are significantly decreased. Extracts of the hippocampus and cortex of Mecp2^-/y mice revealed less adenosine amount as well as less A_2AR protein levels when compared to WT littermates, which may partially explain the deficits in adenosinergic tonus in these animals. Remarkably, the lack of BDNF effect on hippocampal LTP in Mecp2^-/y mice was overcome by selective activation of A_2AR with CGS21680. Overall, in Mecp2^-/y mice there is an impairment on adenosinergic system and BDNF signalling. These findings set the stage for adenosine-based pharmacological therapeutic strategies for RTT, highlighting A_2AR as a therapeutic target in this devastating pathology.

Rett syndrome (RTT) is an X-linked neurodevelopmental disorder caused mainly by mutations in the MECP2 gene, being one of the leading causes of mental disability in females. Mutations in the MECP2 gene are responsible for 95% of the diagnosed RTT cases and the mechanisms through which these mutations relate with symptomatology are still elusive. Children with RTT present a period of apparent normal development followed by a rapid regression in speech and behavior and a progressive deterioration of motor abilities. Epilepsy is one of the most common symptoms in RTT, occurring in 60 to 80% of RTT cases, being associated with worsening of other symptoms. At this point, no cure for RTT is available and there is a pressing need for the discovery of new drug candidates to treat its severe symptoms. However, despite being a rare disease, in the last decade research in RTT has grown exponentially. New and exciting evidence has been gathered and the etiopathogenesis of this complex, severe and untreatable disease is slowly being unfolded. Advances in gene editing techniques have prompted cure-oriented research in RTT. Nonetheless, at this point, finding a cure is a distant reality, highlighting the importance of further investigating the basic pathological mechanisms of this disease. In this review, we focus our attention in some of the newest evidence on RTT clinical and preclinical research, evaluating their impact in RTT symptomatology control, and pinpointing possible directions for future research.

The increasing consumption of sugar and fat seen over the last decades and the consequent overweight and obesity, were recently linked with a deleterious effect on cognition and synaptic function. A major question, which remains to be clarified, is whether obesity in the elderly is an additional risk factor for cognitive impairment. We aimed at unravelling the impact of a chronic high caloric diet (HCD) on memory performance and synaptic plasticity in aged rats. Male rats were kept on an HCD or a standard diet (control) from 1 to 24 months of age. The results showed that under an HCD, aged rats were obese and displayed significant long-term recognition memory impairment when compared to age-matched controls. Ex vivo synaptic plasticity recorded from hippocampal slices from HCD-fed aged rats revealed a reduction in the magnitude of long-term potentiation, accompanied by a decrease in the levels of the brain-derived neurotrophic factor receptors TrkB full-length (TrkB-FL). No alterations in neurogenesis were observed, as quantified by the density of immature doublecortin-positive neurons in the hippocampal dentate gyrus. This study highlights that obesity induced by a chronic HCD exacerbates age-associated cognitive decline, likely due to impaired synaptic plasticity, which might be associated with deficits in TrkB-FL signaling.