Role of Scn1b in Colonic Myenteric Neuron Function in a Model of Developmental and Epileptic Encephalopathy

Abstract

Many neurological diseases present with comorbid gastrointestinal (GI) abnormalities, suggesting parallel altered functionality of the central nervous system (CNS) and enteric nervous system (ENS). A potential mechanistic link between CNS and GI disorders is aberrant function of voltage-gated sodium channel (VGSC) alpha and β subunits, which are expressed in both CNS and ENS. VGSCs control the generation and propagation of action potentials in neurons and therefore play a critical role in neuronal excitability and signaling. VGSC β1/β1B subunits, encoded by SCN1B, modulate ion channel expression, trafficking, gating, and voltage-dependence. VGSC gene variants are linked to developmental and epileptic encephalopathies (DEEs) and GI motility disorders. Additionally, DEE patients with VGSC – and other voltage-gated ion channel (VGIC) gene variants – often exhibit chronic constipation. The overall goal of my PhD thesis research was to test the hypothesis that aberrant activity or expression of VGICs contributes to the mechanism of GI dysfunction in the Scn1b-null mouse model of DEE. The first research project contained in this thesis investigated GI symptoms among patients with DEEs linked to variants in VGIC genes in an effort to identify commonalities between patients exhibiting GI symptoms. We found that GI symptoms are prevalent and often severe in DEE patients and are not fully explained by factors often implicated in GI dysfunction, e.g. functional mobility, diet, or medications. By focusing on DEE patients with variants in genes encoding VGICs, these results highlight the need to better understand the role of aberrant function of voltage-gated ion channels that may directly contribute to the observed GI pathology.

The second portion of my thesis research investigated a functional role of VGSC β1/β1B subunits in GI motility. A subset of DEE patients has biallelic loss-of-function variants in SCN1B. In addition to aberrations in neuronal firing within the CNS, multiple physicians report SCN1B-linked DEE patients presenting with GI symptomology, including constipation. The objective of this project was to understand how β1/β1B subunits contribute to GI function using a Scn1b-null mouse model. Our results indicate that β1/β1B are involved in maintaining proper frequency and regularity of colonic contractions, likely via transcriptional regulation of voltage-gated ion channel expression.

Taken together, the results of my thesis work shed light on the prevalence and potential causes of GI symptoms in VGIC-linked diseases, including DEE, and provide a mechanistic role for SCN1B in colonic motility.