The aim of this paper is to present an overview of three peptides that, by improving synaptic function, enhance learning and memory in laboratory rodents. We summarize their structure, their mechanisms of action, and their effects on synaptic and cognitive function. First we describe FGL, a peptide derived from the neural cell adhesion molecule which improves cognition by the activation of the PKC pathway that triggers an activity-dependent delivery of AMPA receptors to the synapses. Then we describe PTD4-PI3KAc peptide that by activating PI3K signaling pathway it promotes synapse and spine formation and enhances hippocampal dependent memory. Lastly, we describe a new peptide derived from the well-known tumor suppressor PTEN that prevents pathological interactions between PTEN and PDZ proteins at synapses during exposure to Amyloid beta. This action prevents memory deterioration in mouse model of Alzheimer’s disease. Together, this review indicates how learning and memory can be improved by manipulating synaptic function and number through pharmacological treatment with peptides, and it establishes synaptic function as a valid target for cognitive enhancement.
Fig. 1. A possible model for the signalling involved in FGL-mediated hippocampal LTP enhancement. Left: Normal LTP event. Right: FGL binding to FGFR promotes its autophosphorylation. Phosphorylation of the receptor’s C-terminal tail at Tyr766 permits the docking of phospholipase C gamma (PLC-γ), which catalyses the dissociation of phosphatidylinositol 4,5-bisphosphate (PIP2) into inositol trisphosphate (IP3) and diacylglycerol (DAG). IP3 receptors are found in the smooth endoplasmic reticulum (SER) and their activation provokes an efflux of Ca2+ from this intracellular compartment into the cytosol. Subsequently, classic PKC isoforms attach to the synaptic plasma membrane through their interaction with DAG, and their activation is completed by IP3-mediated Ca2+ release. If a depolarization event occurs at the same time, NMDAR channels will open and produce an influx of extracellular calcium into the synapse. Calcium calmodulin Kinase II (CaMKII), which interacts with the cytoplasmic tail of NMDARs, fixes the calcium that enters via its calmodulin modules, promoting CaMKII autophosphorylation and activation. Finally, both PKC and CaMKII phosphorylate the GluA1 subunit of AMPAR at Ser831, which improves the delivery of new AMPAR molecules to the synaptic plasma membrane, with a consequent enhancement of LTP.