Studying Fragile X knockout (KO) mice, which lack FMRP, Dr. Banerjee’s team observed that PKCe expression is significantly suppressed in a hormone-secreting center of the brain, the hypothalamus, and the cognitive hub, hippocampus, which regulates hypothalamic activity. They also observed suppression of the sociability hormone oxytocin in the hypothalamus. Simultaneously, increased cell-surface localization of an excitation-causing protein, AMPAR, in the hippocampal nerve cells presumably increased anxiety in the KO mice.

The scientists attempted to compensate for suppressed PKCe signaling by treating the KO mice at an early age with the selective PKCe stimulator DCPLA. Quite strikingly, this resulted in a therapeutic correction of oxytocin expression in the hypothalamus, normalization of cell-surface AMPAR localization in the hippocampus, and correction of later-life hyper-anxiety and autistic-like social behavior deficits in adulthood!

Therapeutic Strategy for Permanent Correction of FXS-associated Defects

Thus, this project brings the promise of elucidating a pathway that is compromised in KO mice and uses a therapeutic strategy to correct the signaling pathway shortly after birth. This strategy is likely to correct early neurodevelopment in the brain and thereby afford a global, permanent correction of neuroconnectivity and behavior in the FXS mice.

The impression that Fragile X mouse studies do not translate to human therapy is often based on treatments that are offered beyond the point of critical development when the brain can best be nudged to form the right connections. Therefore, it is highly important to conduct preclinical studies such as this during early brain development. Such studies will have a greater likelihood of eventually translating into successful human clinical trials.