We found that the impaired homeostatic synaptic downscaling in Fmr1 KO neurons is caused by loss-of-function dephosphorylation of an epilepsy-associated ubiquitin E3 ligase, neural precursor cell expressed developmentally down-regulated gene 4-2, Nedd4-2.
Examples include CAPRIN1 and AFF2 (both linked to FMR1, which is involved in fragile X syndrome), VIP (involved in social-cognitive deficits), and other genes such as SCN2A and KCNQ2 (linked to epilepsy), NRXN1, and CHD7, which causes ASD-associated CHARGE syndrome.
Our findings reveal that FMRP plays a critical role in suppressing limbic epileptogenesis and predict that the enhanced susceptibility of patients with FXS to epilepsy is a direct consequence of the loss of an important homeostatic factor that mitigates vulnerability to excessive neuronal excitation.
Both the abnormal activation of several signaling pathway and morphological abnormality that are caused by the loss of FMRP can lead to a high susceptibility to epilepsy.
The Fmr1 knockout (KO) mouse is characterized by an increased audiogenic seizure (AGS) susceptibility and is considered a good animal model for epilepsy and seizures in the human fragile-X (FRAX) syndrome.
Deficiency of FMRP (fragile X mental retardation protein) appears to lead to increased neuronal excitability and susceptibility to epilepsy, but particularly seems to facilitate mechanisms leading to the BFEC pattern.
All four patients have epilepsy and a more severe degree of mental retardation than is usual in fragile X syndrome resulting from FMR1 triplet repeat expansion.