Modulation of NMDAR-dependent synaptic pruning by TRPV1 and D2R

• Applicant: Daniele Stajano, Ph.D.
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells ; Developmental Neurobiology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 560932718

The brain, fundamental to cognitive and social capabilities, depends on a well-organized neural network shaped by experience-driven activity. This development involves synaptic pruning, an activity-dependent process that fine-tunes neuronal connections by selectively eliminating redundant synapses. NMDA receptor (NMDAR)-mediated Long-Term Depression (LTD) initiates pruning by decreasing synaptic transmission. The host research group has shown that GSK3β dephosphorylation is required for LTD maintenance, enabling synaptic pruning via autophagy. Furthermore, recent findings indicate that pruning can integrate external environmental stimuli into neural activity, facilitating selective retention or elimination of dendritic spines. Preliminary data and current literature suggest that TRPV1—a neuronal calcium channel responsive to inflammatory signals—can preserve spines from pruning under physiological conditions by enhancing GSK3β phosphorylation. In contrast, Dopamine 2 Receptors (D2R) appear to modulate NMDA signaling and GSK3β, potentially promoting pruning. This pruning outcome hinges on the nanoscale organization and density of neurotransmitter and neuromodulator receptors, which serve as sensors of local neuronal activity and inter-regional connectivity. Understanding the relationship between the nanoscale architecture of synaptic receptors, their activation, and their modulation of synaptic pruning under physiological conditions is critical for advancing our knowledge of neurodevelopment. Our molecular hypothesis posits that D2R and TRPV1 play pivotal roles in modulating NMDAR-induced synaptic pruning during neurodevelopment by their spatial co-organization and influence on GSK3β signaling. Thus, we aim to: (i) determine how TRPV1 and D2R influence the outcome of synaptic pruning induced by NMDA-LTD, (ii) explore the regulatory effects of these receptors on GSK3β during NMDAR-mediated pruning, and (iii) map the nanoscale distribution of TRPV1 and D2R at the surface of individual NMDAR-positive spines, examining how this distribution shifts following NMDA activation. In summary, our study seeks to elucidate the complex interactions among dopamine signaling, NMDARs, and TRPV1 channels in controlling synaptic pruning, enhancing our understanding of brain development and potentially guiding future therapeutic strategies for conditions involving disrupted pruning processes.

• DFG Programme: WBP Fellowship
• International Connection: France
• Participating Institution: Bordeaux Neurocampus
• Host: Eric Hosy, Ph.D.