Vitamin B6 Deficiency Enhances the Noradrenergic System, Leading to Behavioral Deficits

Summary: Study reveals vitamin B6 deficiency may contribute to the development of schizophrenia symptoms.

Source: TMIMS

Schizophrenia is a heterogeneous psychiatric disorder characterized by positive symptoms such as hallucinations and delusions, negative symptoms such as apathy and lack of emotion, and cognitive impairment.

Researchers reported that VB6 (pyridoxal) levels in peripheral blood of a subpopulation of patients with schizophrenia is significantly lower than that of healthy controls.

More than 35% of patients with schizophrenia have low levels of VB6 (clinically defined as male: < 6 ng/ml, female: < 4 ng/ml). VB6 level is inversely proportional to severity score on the positive and negative symptom scale (PANSS), suggesting that VB6 deficiency might contribute to the development of schizophrenia symptoms.

In fact, a recent review has shown the decreased VB6 in patients with schizophrenia as the most convincing evidence in peripheral biomarkers for major mental disorders.

Additionally, the researchers recently reported that high-dose VB6 (pyridoxamine) was effective in alleviating psychotic symptoms, particularly the PANSS negative and general subscales, in a subset of patients with schizophrenia.

Although a link between lower VB6 level and schizophrenia is widely hypothesized, the mechanism behind this remains poorly understood.

VB6 is not synthesized de novo in humans, but is primarily obtained from foods. In the present study, to clarify the relationship between VB6 deficiency and schizophrenia, we generated VB6-deficient (VB6(-)) mice through feeding with a VB6-lacking diet as a mouse model for the subpopulation of schizophrenia patients with VB6 deficiency.

After feeding for 4 weeks, plasma VB6 level in VB6(-) mice decreased to 3% of that in control mice. The VB6(-) mice showed social deficits and cognitive impairment.

This is a diagram from the study
(A) VB6(-) mice showed hyperactivate noradrenergic (NAergic) signaling, resulting in behavioral deficits comparable to schizophrenia. (B) These are ameliorated by VB6 supplementation into the brain or treatment with the 2A adrenoreceptor agonist guanfacine (GFC), which suppresses NA release. Credit: TMIMS

Furthermore, the VB6(-) mice showed a marked increase in 3-methoxy-4-hydroxyphenylglycol (MHPG) in the brain, suggesting enhanced NA metabolism in VB6(-) mice. We confirmed the increased NA release in the prefrontal cortex and the striatum of VB6(-) mice through in vivo microdialysis.

These findings suggest that the activities of NAergic neuronal systems are enhanced in VB6(-) mice.

Furthermore, VB6 supplementation directly into the brain using an osmotic pump ameliorated the hyperactivation of the NAergic system and behavioral abnormalities. indicating that the enhanced NA turnover and the behavioral deficits shown in the VB6(-) mice are attributed to VB6 deficiency in the central nervous system.

In addition, the 2A adrenergic receptor agonist guanfacine also improved the hyperactivated NAergic system in the frontal cortex and behavioral disorders.

These results show that the behavioral deficits in VB6(-) mice may be caused by an enhancement of NAergic signaling.

Schizophrenic patients with VB6 deficiency, who account for more than 35% of all patients, present with relatively severe clinical symptoms and treatment resistance.

The findings suggest that a new therapeutic strategy targeting the NAergic system might be effective for these patients.

They will also provide evidence based on pathophysiology for a new therapeutic strategy called “VB6 treatment for schizophrenia,” which the researchers are currently conducting clinical research on.

About this neuroscience research news

Source: TMIMS
Contact: Kazuya Toriumi – TMIMS
Image: The image is credited to TMIMS

Original Research: Open access.
Vitamin B6 deficiency hyperactivates the noradrenergic system, leading to social deficits and cognitive impairment” by Kazuya Toriumi, Mitsuhiro Miyashita, Kazuhiro Suzuki, Nao Yamasaki, Misako Yasumura, Yasue Horiuchi, Akane Yoshikawa, Mai Asakura, Noriyoshi Usui, Masanari Itokawa & Makoto Arai. Translational Psychiatry


Abstract

Vitamin B6 deficiency hyperactivates the noradrenergic system, leading to social deficits and cognitive impairment

We have reported that a subpopulation of patients with schizophrenia have lower levels of vitamin B6 (VB6) in peripheral blood than do healthy controls.

In a previous study, we found that VB6 level was inversely proportional to the patient’s positive and negative symptom scale (PANSS) score for measuring symptom severity, suggesting that the loss of VB6 might contribute to the development of schizophrenia symptoms.

In the present study, to clarify the relationship between VB6 deficiency and schizophrenia, we generated VB6-deficient (VB6(−)) mice through feeding with a VB6-lacking diet as a mouse model for the subpopulation of schizophrenia patients with VB6 deficiency. After feeding for 4 weeks, plasma VB6 level in VB6(−) mice decreased to 3% of that in control mice.

The VB6(−) mice showed social deficits and cognitive impairment. Furthermore, the VB6(−) mice showed a marked increase in 3-methoxy-4-hydroxyphenylglycol (MHPG) in the brain, suggesting enhanced noradrenaline (NA) metabolism in VB6(−) mice. We confirmed the increased NA release in the prefrontal cortex (PFC) and the striatum (STR) of VB6(−) mice through in vivo microdialysis.

Moreover, inhibiting the excessive NA release by treatment with VB6 supplementation into the brain and α2A adrenoreceptor agonist guanfacine (GFC) suppressed the increased NA metabolism and ameliorated the behavioral deficits.

These findings suggest that the behavioral deficits shown in VB6(−) mice are caused by enhancement of the noradrenergic (NAergic) system.

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