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 a Nestin-Cre transgene into a line of conditional ADK deficient Adk fl/fl mice. These Adk ⌬brain mice 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 A 1 receptor (A 1 R)-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 2A receptor (A 2A R) and tropomyosinrelated kinase B signaling, suggesting increased activation of these receptors in synaptic plasticity phenomena. Accordingly, reducing adenosine A 2A receptor activity in Adk ⌬brain mice 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 2A R activity therapeutically can attenuate neurological symptoms in ADK deficiency.

Deficits in social memory, cognition, and aberrant responses to stimulants are common among persons affected by schizophrenia and other conditions with a presumed developmental etiology. We previously found that expression changes in the adenosine metabolizing enzyme adenosine kinase (ADK) in the adult brain are associated with deficits in various cognitive domains. To distinguish between developmental and adult functions of ADK, we used two transgenic mouse lines with widespread disruption of ADK expression in the adult brain, but differences in the onset of ADK deletion. Specifically, we compared Nestin-Cre:ADK-flox (ADK) mice with global loss of ADK in the whole brain, beginning in mid-gestation and persisting for life, with Gfa2-Cre:ADK-flox (ADK) mice that have normal ADK expression throughout development, but lose astrocyte-specific ADK-expression in young adulthood. Because ADK-expression in adulthood is generally confined to astrocytes, adult ADK mice show a similar expression profile of ADK in key areas of the brain related to neuropsychiatric behavior, compared to adult ADK mice. We sought to determine a neurodevelopmental role of ADK on the expression of psychiatric behaviors in adult male and female mice. Adult ADK mice showed significant deficits in social memory in males, significant contextual learning impairments in both sexes, and a hyper-responsiveness to amphetamine in males. In contrast, ADK mice showed normal social memory and contextual learning but hypo-responsiveness to amphetamine in males. Our results demonstrate a key developmental role of ADK in mediating behaviors in adulthood related to neuropsychiatric disease and support the greater prevalence of these disorders among males.