| Abstract | Fragile X syndrome (FXS), the most common cause of inherited human mental retardation, results from the loss of function of fragile X mental retardation protein (FMRP). To date, most researchers have thought that FXS neural pathologies are primarily caused by extreme dendritic branching and spine formation. With this rationale, several researchers attempted to PRUNE dendritic branches and reduce the number of spines in FXS animal models. We propose that increased dendritic arborization and spinogenesis in FXS are developed rather as secondary compensatory responses to counteract the compromised postsynaptic activity during uncontrollable metabotropic glutamate receptor (mGluR)-dependent long-term depression (LTD). When postsynaptic and electrical activities become dampened in FXS, dendritic trees can increase their sensitivity to brain-derived neurotrophic factor (BDNF) by using the molecular sensor called eukaryotic elongation factor 2 (eEF2) and taking advantage of the tight coupling of mGluR and BDNF-TrkB signaling pathways. Then, this activity-dependent elevation of the BDNF signaling can strategically alter dendritic morphologies to foster branching and develop spine structures in order to improve the postsynaptic response in FXS. Our model suggests a new therapeutic rationale for FXS: correcting the postsynaptic and electrical activity first, and then repairing structural abnormalities of dendrites. Then, it may be possible to successfully fix the dendritic morphologies without affecting the survival of neurons. Our theory may also be generalized to explain aberrant dendritic structures observed in other neurobehavioral diseases, such as tuberous sclerosis, Rett syndrome, schizophrenia, and channelopathies, which accompany high postsynaptic and electrical activity. |