Stimulation of 5-HT2C Receptors Improves Cognitive Deficits Induced by Human Tryptophan Hydroxylase 2 Loss of Function Mutation.

Del'Guidice Thomas, et al.
Neuropsychopharmacology, 2014

Abstract

Polymorphisms in the gene encoding the serotonin synthesis enzyme Tph2 have been identified in mental illnesses, including bipolar disorder, major depression, autism, schizophrenia, and ADHD. Deficits in cognitive flexibility and perseverative behaviors are shared common symptoms in these disorders. However, little is known about the impact of Tph2 gene variants on cognition. Mice expressing a human TPH2 variant (Tph2-KI) were used to investigate cognitive consequences of TPH2 loss of function and pharmacological treatments. We applied a recently developed behavioral assay, the automated H-maze, to study cognitive functions in Tph2-KI mice. This assay involves the consecutive discovery of three different rules: a delayed alternation task, a non-alternation task, and a delayed reversal task. Possible contribution of locomotion, reward, and sensory perception were also investigated. The expression of loss-of-function mutant Tph2 in mice was associated with impairments in reversal learning and cognitive flexibility, accompanied by perseverative behaviors similar to those observed in human clinical studies. Pharmacological restoration of 5-HT synthesis with 5-hydroxytryptophan or treatment with the 5-HT(2C) receptor agonist CP809.101 reduced cognitive deficits in Tph2-KI mice and abolished perseveration. In contrast, treatment with the psychostimulant methylphenidate exacerbated cognitive deficits in mutant mice. Results from this study suggest a contribution of TPH2 in the regulation of cognition. Furthermore, identification of a role for a 5-HT(2) receptor agonist as a cognition-enhancing agent in mutant mice suggests a potential avenue to explore for the personalized treatment of cognitive symptoms in humans with reduced 5-HT synthesis and TPH2 polymorphisms.

Articles similar to "Stimulation of 5-HT2C Receptors Improves Cognitive Deficits Induced by Human Tryptophan Hydroxylase 2 Loss of Function Mutation."

• The properties of 5-Hydroxytryptophan: Concentrations of Indoleamine Metabolic Intermediates in the Ventricular Cerebrospinal Fluid of Advanced Parkinson's Patients With Severe Postural Instability and Gait Disorders. (Postural instability and gait disorders (PIGD) are the primary causes of disability in many but not all advanced Parkinson's disease (PD) patients...)
• The properties of 5-Hydroxytryptophan: Aromatic L-amino Acid Decarboxylase Enzyme Activity in Deficient Patients and Heterozygotes. ( Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare autosomal recessive disorder characterised by developmental delay, motor retardation and autonomic dysfunction... The presently described assays for AADC activity measurement allow an efficient, reproducible and non-invasive way to confirm the diagnosis of AADC deficiency. Since AADC enzyme activity is much higher with L-dopa as a substrate, this method is to be preferred over activity measurement with 5-HTP as a substrate for diagnostic purposes.)
• The properties of 5-Hydroxytryptophan: Serotonin a La Carte: Supplementation With the Serotonin Precursor 5-hydroxytryptophan. (This paper reviews the preclinical and clinical evidence regarding the use of the dietary supplement 5-hydroxytryptophan (5-HTP) for the treatment of depression... The presently described assays for AADC activity measurement allow an efficient, reproducible and non-invasive way to confirm the diagnosis of AADC deficiency. Since AADC enzyme activity is much higher with L-dopa as a substrate, this method is to be preferred over activity measurement with 5-HTP as a substrate for diagnostic purposes.)

Previous article

Chemical Characterization and DNA Fingerprinting of Griffonia simplicifolia Baill.

Next article

Formulations of Dietary Supplements and Herbal Extracts for Relaxation and Anxiolytic Action: Relarian.