Acute and Repeated Administration of NLX-101, a Selective Serotonin-1A Receptor Biased Agonist, Reduces Audiogenic Seizures in Developing Fmr1 Knockout Mice

X Tao; A Newman-Tancredi; M A Varney; K A Razak

doi:10.1016/j.neuroscience.2022.11.014

Acute and Repeated Administration of NLX-101, a Selective Serotonin-1A Receptor Biased Agonist, Reduces Audiogenic Seizures in Developing Fmr1 Knockout Mice

Neuroscience. 2023 Jan 15:509:113-124. doi: 10.1016/j.neuroscience.2022.11.014. Epub 2022 Nov 21.

Authors

X Tao¹, A Newman-Tancredi², M A Varney², K A Razak³

Affiliations

¹ Graduate Neuroscience Program, University of California Riverside, Riverside, United States.
² Neurolixis SAS, Castres, France.
³ Graduate Neuroscience Program, University of California Riverside, Riverside, United States; Department of Psychology, University of California Riverside, Riverside, United States. Electronic address: khaleel@ucr.edu.

PMID: 36410632
DOI: 10.1016/j.neuroscience.2022.11.014

Abstract

Fragile XSyndrome (FXS) is a leading known genetic cause of Autism Spectrum Disorders (ASD) and intellectual disability. A consistent and debilitating phenotype of FXS is sensory hypersensitivity that manifests strongly in the auditory domain and may lead to delayed language and high anxiety. The mouse model of FXS, the Fmr1 KO mouse, also shows auditory hypersensitivity, an extreme form of which is seen as audiogenic seizures (AGS). The midbrain inferior colliculus (IC) is critically involved in generating audiogenic seizures and IC neurons are hyper-responsive to sounds in developing Fmr1 KO mice. Serotonin-1A receptor (5-HT_1A) activation reduces IC activity. Therefore, we tested whether 5-HT_1A activation is sufficient to reduce audiogenic seizures in Fmr1 KO mice. A selective and post-synaptic 5-HT_1A receptor biased agonist, 3-Chloro-4-fluorophenyl-[4-fluoro-4-[[(5-methylpyrimidin-2-ylmethyl)amino]methyl]piperidin-1-yl] methanone (NLX-101, 0.6, 1.2, 1.8 or 2.4 mg/kg, i.p.) was administered to Fmr1 KO mice 15 min before seizure induction. Whereas the 0.6 mg/kg dose was ineffective in reducing seizures, the 1.2, 1.8 and 2.4 mg/kg doses of NLX-101 dramatically reduced seizures and increased mouse survival. Treatment with a combination of NLX-101 and 5-HT_1A receptor antagonists prevented the protective effects of NLX-101, indicating that NLX-101 acts selectively through 5-HT_1A receptors to reduce audiogenic seizures. NLX-101 (1.8 mg/kg) was still strongly effective in reducing seizures even after repeated administration over 5 days, suggesting an absence of tachyphylaxis to the effects of the compound. Together, these studies point to a promising treatment option targeting post-synaptic 5-HT_1A receptors to reduce auditory hypersensitivity in FXS, and potentially across autism spectrum disorders.

Keywords: Autism; Biased agonists; Drug tolerance; Fragile X Syndrome; Sensory hypersensitivity; Serotonin receptors.

MeSH terms

Animals
Disease Models, Animal
Fragile X Mental Retardation Protein / genetics
Fragile X Syndrome* / drug therapy
Fragile X Syndrome* / genetics
Mice
Mice, Knockout
Receptor, Serotonin, 5-HT1A
Seizures / drug therapy
Serotonin*

Substances

Serotonin
3-chloro-4-fluorophenyl-(4-fluoro-4-(((5-methylpyrimidin-2-ylmethyl)amino)methyl)piperidin-1-yl)methanone
Receptor, Serotonin, 5-HT1A
Fragile X Mental Retardation Protein
Fmr1 protein, mouse