From metabolic intermediary to neurotransmitter: purinergic signaling in neurophysiology and vulnerability of brain circuits.

Purinergic signaling represents an ancient intercellular communication system. Operating at the interface between bioenergetic metabolism and damage detection, extracellular purines such as adenosine 5'-triphosphate (ATP) and adenosine (ADO) are recruited into the nervous system for neurotransmission and homeostatic control. Here, we discuss how purine-dependent mechanisms modulate excitation-inhibition balance, neuroplasticity, and neurodevelopment. In the hippocampus, ADO exerts inhibitory tonic functions, while ATP is released during high neuronal activity, being considered a destabilizing factor during pathological conditions. In the striatum, purinergic signaling intersects with dopaminergic and glutamatergic pathways in the fine-tuning of motor control, with ADO receptors modulating corticostriatal transmission and influencing vulnerability to excitotoxicity and neurodegeneration. Focusing on the cerebellum, we illustrate how purinergic signaling contributes to neurodevelopment and neuroplasticity, and how dysfunctions of the purinergic signaling system give rise to associated neuropathologies. In the brainstem, we demonstrate how purinergic signaling modulates autonomic and respiratory circuits to maintain cardiorespiratory homeostasis through astrocyte-neuron communication. Despite its adaptive value, purinergic signaling is optimized for transient, activity-, or damage-dependent activation. Thus, we argue that, under contemporary conditions characterized by chronic stress and extended lifespan, the purinergic signaling system may undergo a shift from predominantly acute to chronic engagement. This evolutionary mismatch may promote maladaptive purinergic activity, contributing to its involvement in synaptic dysfunction, neuroinflammation, and selective vulnerability of brain circuits. Moreover, we integrate evolutionary, neurophysiological, and neuropathological perspectives to propose purinergic signaling as a key mechanistic bridge linking neural function, bioenergetic metabolism, molecular pathways, and neurodegenerative diseases.