Synaptogenic Activity of the PI3K Signaling Pathway
Driven by a common interest in understanding the role of synapses in behavior, I joined Dr. Ferrús laboratory to investigate the molecular mechanisms of synaptic modifications. Our primary goal was to identify new molecular pathways that modify the number of synapses to then assess the role of 'the synapse' in behavior. We demonstrated that activation of the PI3K signaling pathway promoted the formation of new functional synapses in a variety of neuronal populations in Drosophila and in human neurons (Martin-Peña et al 2006).
The newly formed synapses were functional because they elicited (1) a significant enhancement in electrophysiological activity and (2) a proportional switch in behavior:
Electrophysiological studies were carried out in the larval neuromuscular junction (NMJ), in collaboration with Dr. Gonzalo G. de Polavieja and Dr. Amanda Sorribes. The results showed that motoneurons with a higher number of synapses in the NMJ displayed an increased probability of neurotransmitter release, most likely due to the higher number of release points, and an increased amplitude in their spontaneous and evoked post-synaptic potentials, indicative of an elevated quantum content (Martin-Peña et al 2006).
In addition, calcium imaging was performed in local interneurons and projection neurons of the olfactory lobe, in collaboration with Dr. Ronald Davis. Odor responses in living animals showed that the calcium influx into neurons of the olfactory lobe were proportional to their number of synapses (Acebes et al 2011). The behavioral response to odors was also proportional to the number of synapses and to the magnitude of the calcium influx. Together, these results supported the fact that the number of synapses in a given neuron dictates the magnitude of an animal's behavior in a proportional manner to the cellular response.
Activation of several components of the PI3K pathway, including PI3K and Akt, also induced the formation of additional synapses in projection neurons of the ellipsoid body in the adult fly brain (Martin-Peña et al 2006). The locomotor activity of these flies was proportional to the number of synapses that were created in the ellipsoid body. These data indicated that the cell type did not condition the synaptogenic activity of this pathway; all neuronal types tested were equally sensitive to PI3K activity and formed new, functionally active synapses.
In the ellipsoid body, we observed that PI3K-induced synaptogenesis was effective even in aged individuals, suggesting that PI3K activating compounds could potentially display a therapeutic usage to ameliorate cognitive impairments associated with aging or neurodegenerative diseases.
