Rescue of fragile X syndrome phenotypes in Fmr1 KO mice by the small-molecule PAK inhibitor FRAX486

Abstract

Fragile X syndrome (FXS) is the most common inherited form of autism and intellectual disability and is caused by the silencing of a single gene, fragile X mental retardation 1 (Fmr1). The Fmr1 KO mouse displays phenotypes similar to symptoms in the human condition-including hyperactivity, repetitive behaviors, and seizures-as well as analogous abnormalities in the density of dendritic spines. Here we take a hypothesis-driven, mechanism-based approach to the search for an effective therapy for FXS. We hypothesize that a treatment that rescues the dendritic spine defect in Fmr1 KO mice may also ameliorate autism-like behavioral symptoms. Thus, we targeted a protein that regulates spines through modulation of actin cytoskeleton dynamics: p21-activated kinase (PAK). Our results demonstrate that a potent small molecule inhibitor of group I PAKs reverses dendritic spine phenotypes in Fmr1 KO mice. Moreover, this PAK inhibitor-which we call FRAX486-also rescues seizures and behavioral abnormalities such as hyperactivity and repetitive movements, thereby supporting the hypothesis that a drug treatment that reverses the spine abnormalities can also treat neurological and behavioral symptoms. Finally, a single administration of FRAX486 is sufficient to rescue all of these phenotypes in adult Fmr1 KO mice, demonstrating the potential for rapid, postdiagnostic therapy in adults with FXS.

Activity-dependent FMRP requirements in development of the neural circuitry of learning and memory

“…PSD-95) and other key synaptic regulators (e.g. CaMKII), which are all well positioned to control the choice between activitydependent synapse pruning versus stabilization (Zhang et al, 2001;Zalfa et al, 2007;Chen et al, 2010;Bongmba et al, 2011;Dolan et al, 2013). FMRP expression is itself positively regulated by activity (Antar et al, 2004;Gabel et al, 2004;Wang et al, 2008), with peak brain expression coincident with critical period synaptic refinement (Lu et al, 2004;Singh et al, 2007;Tessier and Broadie, 2008).…”

PAKs inhibitors ameliorate schizophrenia-associated dendritic spine deterioration in vitro and in vivo during late adolescence

“…There are many other neuropsychiatric disorders with synaptic changes that might benefit from these compounds. The Tonegawa laboratory previously published that PAK inhibition and knockout are protective against synaptic deterioration in an animal model for Fragile X syndrome (38,39). In addition, several lines of evidence have suggested the involvement of PAKs in Alzheimer's disease and mental retardation (40)(41)(42)(43).…”

Modeling fragile X syndrome in the <i>Fmr1</i> knockout mouse

“…Seizures associated with FXS are infrequent, are often partial, and are typically controlled with medications (82,83). Fmr1 KO mice have not been reported to display spontaneous seizures, but are more susceptible to audiogenic seizures, induced by exposure to a 125 decibel, high-intensity siren (48,81,(84)(85)(86)(87)(88)(89)(90)(91)(92)(93). Audiogenic seizure vulnerability in Fmr1 KO mice may reflect seizure susceptibly in FXS, although audiogenic seizure severity in Fmr1 KO mice varied in degree depending on age and background strain (86,91,94,95).…”