Baclofen-associated neurophysiologic target engagement across species in fragile X syndrome

Abstract

Background Fragile X syndrome (FXS) is the most common inherited form of neurodevelopmental disability. It is often characterized, especially in males, by intellectual disability, anxiety, repetitive behavior, social communication deficits, delayed language development, and abnormal sensory processing. Recently, we identified electroencephalographic (EEG) biomarkers that are conserved between the mouse model of FXS (Fmr1 KO mice) and humans with FXS. Methods In this report, we evaluate small molecule target engagement utilizing multielectrode array electrophysiology in the Fmr1 KO mouse and in humans with FXS. Neurophysiologic target engagement was evaluated using single doses of the GABAB selective agonist racemic baclofen (RBAC). Results In Fmr1 KO mice and in humans with FXS, baclofen use was associated with suppression of elevated gamma power and increase in low-frequency power at rest. In the Fmr1 KO mice, a baclofen-associated improvement in auditory chirp synchronization was also noted. Conclusions Overall, we noted synchronized target engagement of RBAC on resting state electrophysiology, in particular the reduction of aberrant high frequency gamma activity, across species in FXS. This finding holds promise for translational medicine approaches to drug development for FXS, synchronizing treatment study across species using well-established EEG biological markers in this field. Trial registration The human experiments are registered under NCT02998151.

FPT, a 2-Aminotetralin, Is a Potent Serotonin 5-HT1A, 5-HT1B, and 5-HT1D Receptor Agonist That Modulates Cortical Electroencephalogram Activity in Adult Fmr1 Knockout Mice

“…49,50 Like FPT, baclofen, which has shown some efficacy in treating FXS and ASD, 51,52 increases delta power in both WT and Fmr1 KO mice. 53 Decreases in slow wave delta power have been reported in Fmr1 KO rats. 18 Therefore, FPT's effect of increasing delta power might benefit patients with FXS.…”

“…We have not yet tested if FPT’s powerful anticonvulsant effects in juvenile Fmr1 KO mice persist in adult animals, but FPT did not reduce excessive relative gamma power recorded above the left somatosensory cortex in adult Fmr1 KO mice; this result is reminiscent of other medication candidates for FXS. The GABA B agonist, baclofen, and the GABA A positive allosteric modulator, BAER-10140, although effective at preventing AGS in Fmr1 KO mice, do not, in most studies, correct the elevations in cortical gamma power in Fmr1 KO mice. ,,, Thus, with the major caveat of age as a confounding variableAGS were tested in juvenile mice, and EEG was recorded in adult micethe elevated cortical gamma power phenotype in adult Fmr1 KO mice does not appear, at present, to reflect susceptibility to AGS. As AGS emanate predominantly from the inferior colliculus, the excessive cortical gamma power in Fmr1 KO mice may be a neurophysiological alteration independent of AGS …”

“…FPT robustly increased relative delta (0.5−4 Hz) and decreased relative alpha power across all channels, with more pronounced effects in Fmr1 KO mice. Notably, delta oscillations are associated with attention and decision-making processes. , Like FPT, baclofen, which has shown some efficacy in treating FXS and ASD, , increases delta power in both WT and Fmr1 KO mice . Decreases in slow wave delta power have been reported in Fmr1 KO rats .…”

“…The GABA B agonist, baclofen, and the GABA A positive allosteric modulator, BAER-10140, although effective at preventing AGS in Fmr1 KO mice, do not, in most studies, correct the elevations in cortical gamma power in Fmr1 KO mice. 42,47,48,53 present, to reflect susceptibility to AGS. As AGS emanate predominantly from the inferior colliculus, the excessive cortical gamma power in Fmr1 KO mice may be a neurophysiological alteration independent of AGS.…”

Fragile X Syndrome as an interneuronopathy: a lesson for future studies and treatments

“…The use of compounds directly linked to the GABAergic system (e.g., Baclofen, R-Baclofen and Ganaxolone that are GABA B agonist) has been shown to rescue some of the molecular and behavioral phenotypes which characterize FXS in patients and in murine models (Heulens et al, 2012;Schaefer et al, 2015;Veenstra-VanderWeele et al, 2017;Jonak et al, 2022), suggesting that the rectification of the E/I imbalance through an enhancement of the GABAergic system could be a potential treatment for FXS. Although positive results were obtained in preclinical studies and in a Phase II clinical trial, these therapeutic approaches did not result into a broad treatment for FXS patients (Castagnola et al, 2017).…”