Dysregulation of brain adenosine is detrimental to the expression of conditioned freezing but not general Pavlovian learning

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Abstract

Glutamatergic and dopaminergic neurotransmission is modulated by adenosine, whose ambient level in the brain is in turn regulated by the metabolic enzyme, adenosine kinase (ADK). Brain adenosinergic tone can therefore be effectively reduced and increased by up- and down-regulation of ADK expression, respectively. Although changes in brain ADK levels can yield multiple behavioral effects, the precise functional significance of telencephalon (neocortical and limbic structures) adenosine remains ill-defined. Among the phenotypes identified in transgenic mice with brain-wide ADK overexpression (ADKTG mice) and reduced adenosinergic tone, working memory deficiency and potentiated response to systemic N-methyl-d-aspartate receptor blockade were exacerbated by the introduction of local ADK disruption (elevated adenosinergic tone) restricted to the telencephalon (ADKTG:ADKTel-def mice). These two phenotypes, which are central to schizophrenia cognitive/negative symptoms, appear to be regulated by adenosinergic activities within and outside the telencephalon in a complementary manner. Here, we extended this unique comparison between ADKTG mice ADKTG:ADKTel-def mice to another prominent phenotype previously documented in ADKTG mice — namely, impaired Pavlovian conditioned freezing. We found that ADKTG:ADKTel-def mice again were associated with a more severe phenotype while sharing a similar phenotype profile. Furthermore, we qualified that this Pavlovian phenotype did not translate into a general deficiency in associative learning, since no such deficit was evident in three other (aversive and appetitive) Pavlovian learning paradigms. The present study has thus identified a hitherto unknown function of brain adenosine: the execution of conditioned freezing behavior, which is dependent on the balance of adenosinergic changes between the telencephalon and the rest of the brain.

Highlights

▸ Brain adenosine modulation on Pavlovian learning is investigated in two mutant models. ▸ Up- and down-regulation of cortical adenosine severely impaired conditioned freezing. ▸ The conditioned freezing impairment does not generalize to other Pavlovian paradigms. ▸ Adenosine homeostasis is critically important for maintaining normal brain function. ▸ Regional specific effects are relevant for development of adenosine-based therapies.

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