Absence of Claudin 11 in CNS Myelin Perturbs Behavior and Neurotransmitter Levels in Mice

Abstract

Neuronal origins of behavioral disorders have been examined for decades to construct frameworks for understanding psychiatric diseases and developing useful therapeutic strategies with clinical application. Despite abundant anecdotal evidence for white matter etiologies, including altered tractography in neuroimaging and diminished oligodendrocyte-specific gene expression in autopsy studies, mechanistic data demonstrating that dysfunctional myelin sheaths can cause behavioral deficits and perturb neurotransmitter biochemistry have not been forthcoming. At least in part, this impasse stems from difficulties in identifying model systems free of degenerative pathology to enable unambiguous assessment of neuron biology and behavior in a background of myelin dysfunction. Herein we examine myelin mutant mice lacking expression of the Claudin11 gene in oligodendrocytes and characterize two behavioral endophenotypes: perturbed auditory processing and reduced anxiety/avoidance. Importantly, these behaviors are associated with increased transmission time along myelinated fibers as well as glutamate and GABA neurotransmitter imbalances in auditory brainstem and amygdala, in the absence of neurodegeneration. Thus, our findings broaden the etiology of neuropsychiatric disease to include dysfunctional myelin, and identify a preclinical model for the development of novel disease-modifying therapies.

Oligodendrocytes Support Neuronal Glutamatergic Transmission via Expression of Glutamine Synthetase

“…Indeed, there is evidence that impaired oligodendrocyte function and/or myelination is accompanied by changes in brain glutamate levels (Gao et al, 2018; Maheras et al, 2018; Nantes et al, 2017; Takanashi et al, 2014; Werner et al, 2001). Moving forward, studies on the role of glutamate in various pathological states should consider the possibility of dual roles for oligodendrocytes as victim and perpetrator of glutamate-related CNS dysfunction.…”

Claudin-12 deficiency causes nerve barrier breakdown, mechanical hypersensitivity and painfulness in polyneuropathy

“…We have previously shown that tight junction protein expression in the SN is dependent on LRP1 (11). Knockdown of Cldn11 and Cldn19, also expressed in Schwann cells, resulted in delayed nerve conduction velocity, abnormal behavioral responses and motor function deficiencies but nociception was not examined (17,58,59). Here, we now provide genetic evidence via full KO or siRNA that Cldn12 as well as Cldn19 are critical for the myelin barrier and normal mechanonociception.…”

“…and Cldn19 results in delayed nerve conduction velocity, abnormal behavioral responses and motor function deficiencies but nociception was not examined (Gow et al, 1999;Miyamoto et al, 2005;Maheras et al, 2018). Here, we now provide genetic evidence via full KO or siRNA that Cldn12 similar to Cldn19 are critical for the myelin barrier and normal mechanonociception.…”

Claudins in the brain: Unconventional functions in neurons

“…Activation of matrix metalloproteinases (MMPs) opens the BBB by degrading tight junction proteins, including Claudins‐5 and occludin . Meanwhile, Claudin‐11 regulates magnesium ion permeability across the myelin sheath membrane and is crucial for mice behavior and neurotransmitter release …”

“…44 Meanwhile, Claudin-11 regulates magnesium ion permeability across the myelin sheath membrane and is crucial for mice behavior and neurotransmitter release. 45 More recently, studies on the functional roles of the claudin superfamily proteins in neurons are gaining traction through work in model organisms. Out of six claudin-like molecules found in Drosophila melanogaster, two have been reported to be essential to make septate junctions to allow for maintaining the blood-brain barrier integrity in the fly brain.…”