Modulation of dendritic spines and synaptic function by Rac1: a possible link to Fragile X syndrome pathology.

Rac1, a protein of the Rho GTPase subfamily, has been implicated in neuronal and spine development as well as the formation of synapses with appropriate partners. Dendrite and spine abnormalities have been implicated in several psychiatric disorders such as Fragile X syndrome, where neurons show a high density of long, thin, and immature dendritic spines. Although abnormalities in dendrites and spines have been correlated with impaired cognitive abilities in mental retardation, the causes of these malformations are not yet well understood. Fragile X syndrome is the most common type of inherited mental retardation caused by the absence of FMRP protein, a RNA-binding protein implicated in the regulation of mRNA translation and transport, leading to protein synthesis. We suggest that FMRP might act as a negative regulator on the synthesis of Rac1. Maintaining an optimal level of Rac1 and facilitating the reorganization of the cytoskeleton likely leads to normal neuronal morphology during activity-dependent plasticity. In our study, we first demonstrated that Rac1 is not only associated but necessary for normal spine development and long-term synaptic plasticity. We further showed that, in Fmr1 knockout mice, lack of FMRP induces an overactivation of Rac1 in the mouse brain and other organs that have been shown to be altered in Fragile X syndrome. In those animals, pharmacological manipulation of Rac1 partially reverses their altered long-term plasticity. Thus, regulation of Rac1 may provide a functional link among deficient neuronal morphology, aberrant synaptic plasticity and cognition impairment in Fragile X syndrome.

Neurochemical, behavioral and architectural changes after chronic inactivation of NMDA receptors in mice.

Schizophrenia is a psychotic illness characterized by problems in perception, learning, and memory. Post-mortem clinical data revealed abnormalities in neuronal organization, reduced soma and dendritic tree size. In rodents, reduction of glutamatergic neurotransmission by NMDA receptor antagonists mimics symptoms of schizophrenia. However, the dosage, treatment and species used in previous studies have not been consistent, leading to a lack of correlation between the findings reported in low-dose, long-term treatment models and the results in acute or chronic high dose administration. Thus, the present study investigates whether long-term, low-dose blockade of NMDA receptors with MK-801 in the early postnatal period results in molecular, cellular, morphological and behavioral changes in the mouse, alterations that have been singly described by using different drugs and dosages in either mice or rats. We found that early postnatal administration of 0.1mg/kg MK-801 for 15 days altered protein translation, synapse formation, hippocampus-dependent learning and neuronal development, resembling findings reported in schizophrenia. These results suggest that there are strong parallels between this animal model and schizophrenia, which validates it as an animal model for this condition and lends further strength of the NMDA receptor hypofunction as a useful model for the study of psychosis.