CNC.IBILI

Neuro5 | Main Goals

The main objective of the group is to publish scientific papers with increasingly higher impact and to succeed in securing competitive grants to pursue this main objective.
The main scientific strategy to achieve these goals is to focus on purinergic neuromodulation (NM) systems to attempt developing novel therapeutic strategies to manage brain diseases. Since this requires an understanding of the mechanisms of action of these NM systems in physiological and pathological conditions, this particular focus on purinergic NM systems also allows a unique angle to approach basic neurophysiological features of brain functioning as well as mechanisms of brain disease. This also provides an opportunity for a pleiotropic interaction with the different Research Lines at CNC-IBILI, as described below:

i. our previous efforts showing a particular ability of caffeine and A2AR antagonists to control aberrant synaptic plasticity in physio-pathological conditions places synaptic mechanisms (Flagship 1 of Research Line 1) at the central stage. By understanding how purines affect synaptic plasticity we aim to better understand basic processes of synaptic plasticity. Also, by understanding how purines control aberrant synaptic plasticity and synaptotoxicity in animal models of brain disease, we aim to unravel key dysfunctional pathways (main candidates are metabolic and mitochondrial impairments in nerve terminals);

i. our ability to identify a key role of A2AR to control astrocytic Na+/K+-ATPase makes A2AR potential key player in the control of neuron-astrocyte communication to control metabolic support of brain activity (Flagship 2 of Research Line 1). This is in line with the recognition of caffeine (an adenosine receptor antagonist) as an ergogenic substance, albeit its impact and that of purinergic NM on brain metabolism is unknown;

ii. the understanding of the particular brain regions and specific neuronal pathways where A2AR signal to control behavior responses (learning & memory, locomotion, motor coordination, decision-making, impulsivity, mood, anxiety) will allow a unique window of opportunity to map in detail the pathways involved in such responses; this is best illustrated by the development of a novel optoA2AR (merging the extracellular and transmembrane domains of rhodopsin, conferring light sensitivity, with the intracellular domains of A2AR, recruiting A2AR signaling pathways), which allowed mapping through p-CREB immunoreactivity the specific neurons forming a memory engram in a spatial memory task;

v. the recognized safety profile of A2AR antagonists (tested in over 30,000 Parkinsonian patients) together with the availability of validated PET ligands to monitor A2AR, paves the way to join efforts with the imaging groups focusing on cognition at IBILI to test the impact of manipulating A2AR in defined patients and to test if changes of A2AR (which is up-regulated in animal models of brain disease) in different brain regions can be foreseen as a biomarker of different brain diseases (Flagship 3 of Research line 1). This is a major benefit resulting from CNC-IBILI merging;

v. we will continue (should funding permits) our efforts to understand the role of A2AR in aging under the working hypothesis that an over-functioning of A2AR is a hallmark of brain aging; we hope that this rationale can be extended to other age-related processes (Research line 2);

vi. our continuous efforts in the study of the purinergic system (receptors, heteromers and their interactome with brain-specific localizations, metabolic pathways for the genesis and removal of extracellular adenosine, purinergic formatting of the interaction within synapses and with astrocytes, microglia and blood vessels), have as a final goal to provide the rationale for the design of tools with increasing selectivity to target the manifold potential sites of action and roles of purines to control brain dysfunction in neuropsychiatric diseases (Research line 3).