Evaluation of Nav1.8 as a therapeutic target for Pitt Hopkins Syndrome

Abstract

Pitt Hopkins Syndrome (PTHS) is a rare syndromic form of autism spectrum disorder (ASD) caused by autosomal dominant mutations in the Transcription Factor 4 (TCF4) gene. TCF4 is a basic helix-loop-helix transcription factor that is critical for neurodevelopment and brain function through its binding to cis-regulatory elements of target genes. One potential therapeutic strategy for PTHS is to identify dysregulated target genes and normalize their dysfunction. Here, we propose that SCN10A is an important target gene of TCF4 that is an applicable therapeutic approach for PTHS. Scn10a encodes the voltage-gated sodium channel Na_v1.8 and is consistently shown to be upregulated in PTHS mouse models. In this perspective, we review prior literature and present novel data that suggests inhibiting Na_v1.8 in PTHS mouse models is effective at normalizing neuron function, brain circuit activity and behavioral abnormalities and posit this therapeutic approach as a treatment for PTHS.

Fig. 1. Disease-causing mutations in Tcf4 dysregulates Scn10a/Na_v1.8 expression in the CNS and results in abnormal physiology and behavior.

TCF4 is imported into the nucleus and forms homo- or heterodimers with itself or other bHLH-domain containing transcription factors. Dimers containing wild-type TCF4 directly bind the genomic locus of Scn10a and repress Scn10a expression. Dimers containing mutant TCF4 are incapable of binding DNA and result in de-repression of Scn10a expression. Resulting ectopic Scn10a/Na_v1.8 expression leads to hyperlocomotion, breathing abnormalities and intrinsic excitability deficits which are all rescued by inhibition of Na_v1.8.

Fig. 2. Sensory information processing deficits in the PTHS mouse model.

A Example event-related potential (ERP) grand averages from individual temporal components (P20, N40, P80 and P120) where time 0 = auditory stimulus onset. B Grand average ERPs in Tcf4^+/tr (n = 10) compared to Tcf4^+/+ (n = 12) animals at baseline and (C) following PF-04531083 administration. D Summary component analysis showing significantly reduced amplitudes in N40 peaks in Tcf4^+/tr mice compared to Tcf4^+/+ animals, which are not altered by PF-04531083 administration (2-way RM ANOVA, *p = 0.0163, main effect of genotype; ns p = 0.1317, main effect of treatment). All descriptive statistics and p values for the data presented in this figure are provided in Supplementary Table 1.

Fig. 3. Sensory information processing deficits are normalized by Na_v1.8 inhibition.

A Heat maps of event-related spectral perturbation (ERSP) in Tcf4^+/+ (left, n = 12) and Tcf4^+/tr (right, n = 10) animals depicting ERP-related changes due to genotype (vehicle) and rescue with PF-04531083 (SCN10a). B Heat maps of intertrial coherence (ITC) in Tcf4^+/+ (left, n = 12) and Tcf4^+/tr (right, n = 10) animals depicting ERP-related changes due to genotype (vehicle) and rescue with PF-04531083 (SCN10a). C Reduction of gamma ERSP following SCN10a antagonism in Tcf4^+/tr, but not in Tcf4^+/+ animals (2-way RM ANOVA, p = 0.0453 interaction of genotype X treatment; Bonferroni post hoc, *p = 0.0269 vehicle-treated Tcf4^+/tr versus PF-04531083-treated Tcf4^+/tr; ns p > 0.05 vehicle-treated Tcf4^+/+ versus PF-04531083-treated Tcf4^+/+). D High frequency disturbances in Tcf4^+/tr mice are corrected by SCN10a antagonist. There is significantly higher gamma ITC in vehicle-treated Tcf4^+/tr compared to Tcf4^+/+ vehicle-treated mice in the first 75 ms post-tone. Following SCN10a treatment, there is no effect of genotype (2-way RM ANOVA, p = 0.0027 interaction of genotype X treatment; Bonferroni post hoc, *p = 0.0446 vehicle-treated Tcf4^+/+ versus Tcf4^+/tr; ns p > 0.05 PF-04531083-treated Tcf4^+/+ versus Tcf4^+/tr). E Low frequency disturbances in Tcf4^+/tr mice are corrected by PF-04531083. Latency to peak theta (3–8 Hz) ITC is significantly increased in vehicle-treated Tcf4^+/tr compared to vehicle-treated Tcf4^+/+ mice. No significant effect of genotype is detected following treatment with the SCN10a antagonist (2-way RM ANOVA, p = 0.0123 interaction of genotype X treatment; Bonferroni post hoc, *p = 0.0303 vehicle-treated Tcf4^+/+ versus Tcf4^+/tr; ns p > 0.05 PF-04531083-treated Tcf4^+/+ versus Tcf4^+/tr).