Approaching Synapses with Nanoscale Aptamer-Based Biosensors

“Given the complex, and multifactorial nature of neurodegenerative pathophysiology, strategies aimed at the synapse could provide a useful addition to the therapeutic toolbox” – this quote by B. Dejanovic et al. published in Nature Reviews Drug Discovery this year, highlights the critical need for innovative tools to probe synaptic function. Synapses, where neurons communicate, are tightly regulated by astrocytes, which manage their energy needs (neuroenergetics). Astrocytes shuttle neuroenergetic molecules (e.g., glutamine, lactate, and adenosine) to meet energy demands. Disruptions in these astrocyte-mediated pathways are now recognized as common features in neurodegenerative disorders, suggesting that impaired neuroenergetics may be at the origin of such diseases. Understanding neuroenergetics is crucial for developing therapies that target the root cause of neurodegeneration, not just its symptoms.SYNAPTA aims to fill this gap by developing nanoscale biosensors that detect multiple neuroenergetic molecules at synaptic dimensions. To achieve this ambitious vision, we will: 1) isolate receptors (DNA aptamers) that reversibly capture neuroenergetic molecules, 2) create a library of DNA aptamer-based biosensors with ~10 nm spatial resolution, 3) design multiplexed sensors, 4) integrate these biosensors into scanning ion conductance microscopy (SICM) and electrophysiology platforms to enable 5) high-resolution, real-time chemical and electrical mapping of synaptic activity. This system will enable millisecond recordings of neuroenergetic molecules at <10 nm resolution, surpassing current technologies. Led by my multidisciplinary expertise in aptamer discovery, chemical biosensing, and neural interfaces, SYNAPTA will consolidate these fields to uncover how astrocyte-neuron interactions affect synaptic function and disease progression. SYNAPTA will advance our understanding of neurodegenerative mechanisms and open new possibilities for therapeutic interventions.