Acute administration of NLX-101, a Serotonin 1A receptor agonist, improves auditory temporal processing during development in a mouse model of Fragile X Syndrome.

Background: Fragile X syndrome (FXS) is a leading known genetic cause of intellectual disability and autism spectrum disorders (ASD)-associated behaviors. A consistent and debilitating phenotype of FXS is auditory hypersensitivity that may lead to delayed language and high anxiety. Consistent with findings in FXS human studies, the mouse model of FXS, the Fmr1 knock out (KO) mouse, shows auditory hypersensitivity and temporal processing deficits. In electroencephalograph (EEG) recordings from humans and mice, these deficits manifest as increased N1 amplitudes in event-related potentials (ERP), increased gamma band single trial power (STP) and reduced phase locking to rapid temporal modulations of sound. In our previous study, we found that administration of the selective serotonin-1 A (5-HT_1A)receptor biased agonist, NLX-101, protected Fmr1 KO mice from auditory hypersensitivity-associated seizures. Here we tested the hypothesis that NLX-101 will normalize EEG phenotypes in developing Fmr1 KO mice.

Methods: To test this hypothesis, we examined the effect of NLX-101 on EEG phenotypes in male and female wildtype (WT) and Fmr1 KO mice. Using epidural electrodes, we recorded auditory event related potentials (ERP) and auditory temporal processing with a gap-in-noise auditory steady state response (ASSR) paradigm at two ages, postnatal (P) 21 and 30 days, from both auditory and frontal cortices of awake, freely moving mice, following NLX-101 (at 1.8 mg/kg i.p.) or saline administration.

Results: Saline-injected Fmr1 KO mice showed increased N1 amplitudes, increased STP and reduced phase locking to auditory gap-in-noise stimuli versus wild-type mice, reproducing previously published EEG phenotypes. An acute injection of NLX-101 did not alter ERP amplitudes at either P21 or P30, but significantly reduces STP at P30. Inter-trial phase clustering was significantly increased in both age groups with NLX-101, indicating improved temporal processing. The differential effects of serotonin modulation on ERP, background power and temporal processing suggest different developmental mechanisms leading to these phenotypes.

Conclusions: These results suggest that NLX-101 could constitute a promising treatment option for targeting post-synaptic 5-HT_1A receptors to improve auditory temporal processing, which in turn may improve speech and language function in FXS.