Modulation of the GABAergic pathway for the treatment of fragile X syndrome

Figures & data

Figure 1 Neurobiology in FXS.

Notes: (A) In the normal neurobiology of the synapse, FMRP regulates the expression of GABA receptors and the metabolism and catabolism of GABA. (B) The affected neurobiology in FXS, with reduced GABA synthesis and transport, fewer GABA_A and GABA_B receptors, and therefore overall reduced GABAergic activity. (C) The neurobiology in FXS with GABAergic treatments. The sites of action for the medications are indicated by stars on the various receptors and enzymes. Arbaclofen focuses on the presynaptic GABA_B receptors to increase their activity with a secondary inhibitory effect on the presynaptic release of glutamate. Ganaxolone, acamprosate, and riluzole all work on the GABA_A receptors to increase the reduced activity. Ganaxolone, however, has higher affinity to the extrasynaptic δ subunit containing GABA_A receptors. Vigabatrin reduces the resynthesis of GABA to glutamate, which is already increased in FXS.
Abbreviations: FMRP, fragile X mental retardation protein; FXS, fragile X syndrome; GABA, gamma-aminobutyric acid; GABA-T, gamma-aminobutyric acid transaminase; GAD, glutamic acid decarboxylase.