Pharmacological rescue of Ras signaling, GluA1-dependent synaptic plasticity, and learning deficits in a fragile X model

Abstract

Fragile X syndrome, caused by the loss of Fmr1 gene function, is the most common form of inherited mental retardation, with no effective treatment. Using a tractable animal model, we investigated mechanisms of action of a few FDA-approved psychoactive drugs that modestly benefit the cognitive performance in fragile X patients. Here we report that compounds activating serotonin (5HT) subtype 2B receptors (5HT 2B -Rs) or dopamine (DA) subtype 1-like receptors (D 1 -Rs) and/or those inhibiting 5HT 2A -Rs or D 2 -Rs moderately enhance Ras-PI3K/PKB signaling input, GluA1-dependent synaptic plasticity, and learning in Fmr1 knockout mice. Unexpectedly, combinations of these 5HT and DA compounds at low doses synergistically stimulate Ras-PI3K/PKB signal transduction and GluA1-dependent synaptic plasticity and remarkably restore normal learning in Fmr1 knockout mice without causing anxiety-related side effects. These findings suggest that properly dosed and combined FDAapproved psychoactive drugs may effectively treat the cognitive impairment associated with fragile X syndrome.

Therapeutic Strategies in Fragile X Syndrome: From Bench to Bedside and Back

“…The following strategies were confirmed in studies using Drosophila models of fragile X syndrome (FXS): metabotropic glutamate receptor (mGluR) [167], gamma-aminobutyric acid (GABA) [168] (but see [169]), lithium [167], minocycline [170], phosphodiesterase-4 (PDE-4) [ A recent study suggested that simultaneous stimulation of D1R and serotonin (5HT) receptors rescued impaired synaptic AMPA receptor insertion and plasticity, and improved fear conditioning and Y maze learning deficits [115]. § Simultaneous inhibition of mGlu5 and CB1R was additive in this study.…”

“…In the case of FXS, increased density and immature appearance of dendritic spines were detected in patients and mouse models [171,193], and have been widely used to test therapeutic strategies. Pharmacologic and genetic modification of many molecular targets, including neurotransmitter receptors, [62] Lymphoblastoid cells [64], fibroblasts [66] AMPA receptor internalization Increased [43,62,114] N o Altered cellular signaling Increased [64,111,113] or decreased PI3K/mTOR phosphorylation [115]; increased ERK1/2 phosphorylation [112]; increased GSK3β phosphorylation [116] Lymphoblastoid cells [64], lymphocytes and brain tissue [65], fibroblasts [66] Cellular…”

CaV3.2 calcium channels control NMDA receptor-mediated transmission: a new mechanism for absence epilepsy

“…Organotypic hippocampal cultured slices were prepared from postnatal 6-to 7-d-old (P6-P7) male and female Sprague Dawley rats, wild-type mice, and Ca V 3.2 knockout (Orestes et al 2009) mice bred congenically on the C57BL/6 background, following our previous studies (Qin et al 2005;Lim et al 2014). All procedures for animal surgery and maintenance were performed following protocols approved by the animal care and use committee of the University of Virginia and in accordance with National Institutes of Health guidelines.…”

“…Pre-embedding immunogold labeling was carried out following the procedures of previous studies (Erisir and Harris 2003;Kielland et al 2009). In brief, 1 µg/mL rabbit anti-GluA2/3 (Millipore, AB1506) was used to detect AMPA-Rs because of the nonrectified AMPA responses seen in CA1 and L5 pyramidal neurons (Zhu 2009;Lim et al 2014) and TRN neurons (values for rectification: R VB stim = 1.51 ± 0.06 and R cortex stim = 1.54 ± 0.08; n = 19 from nine animals), an indicator of incorporation of GluA2 subunits in the majority of AMPA-Rs. A mouse monoclonal anti-GluN1 (Luo et al 1997) was used to detect the obligatory GluN1 subunits of NMDA-Rs.…”

Cdk5 is a New Rapid Synaptic Homeostasis Regulator Capable of Initiating the Early Alzheimer-Like Pathology

“…Cultured slices were prepared from postnatal 6-7-day-old male and female rats following previously reported procedure Myers et al 2012;Lim et al 2014). All procedures for animal surgery and maintenance were performed following protocols approved by the Animal Care & Use Committee of the University of Virginia (Protocol No.…”