Supplement betaine reduces behavioral symptoms in mice

A dietary supplement, betaine, reduced behavioral symptoms in mice with a genetic mutation that causes schizophrenia, according to a new study published in the journal Cell Reports.

Genetic studies of people diagnosed with schizophrenia have found possible links between the disease and variations in the kinesin family 3b (kif3b) gene as well as another gene involved in the body's internal synthesis of betaine. Researchers have categorized all 45 members of the kinesin superfamily of genes in mammals, most of which encode motor proteins that move materials throughout the cell. Normally, the KIF3B protein links together with another kinesin superfamily protein and transports cargo throughout a neuron by traveling up and down the cell's skeleton.

Mice used in the recent research had only one functional copy of the kif3b gene and are often used as an animal model of schizophrenia. These mice avoid social interactions and show the same weak response as human patients with schizophrenia in a test called prepulse inhibition, which measures how startled they are by a sudden, loud sound preceded by a quieter sound.

Kif3b mutant mice raised on a diet supplemented with three times the normal amount of betaine had normal behavior, indicating that betaine supplements could treat schizophrenia symptoms. To figure out why betaine had this effect on mice, researchers grew nerve cells with the kif3b mutation in the laboratory and added fluorescent labels so they could watch the cellular skeleton take shape.

The shape of a healthy neuron is reminiscent of a tree: a cell body surrounded by branches, the dendrites, attached to a long trunk, the axon. Kif3b mutant neurons grown in the lab have an unusual, hyperbranched structure with too many dendrites. Similar hyperbranched neurons are also seen in brain samples donated by people with schizophrenia, regardless of what treatments or medications they took while they were alive.

During healthy neuron development, the main body of the cell fills with a skeleton component called tubulin. Meanwhile, the front growth cone of the cell builds outwards in a spiky, erratic dance due to the movements of another skeleton component called filamentous actin. In kif3b mutants, this dancing movement, which experts refer to as lamellipodial dynamics, is noticeably reduced and the division between tubulin and actin is blurred.

The actin in a neuron's cellular skeleton is assembled in part by another protein called CRMP2. Chemical analyses of the brains of kif3b mutant mice and human schizophrenia patients reveal significant chemical damage to CRMP2, which causes the proteins to clump together.

The supplement betaine was first isolated from sugar beets and is often associated with sweetness or umami flavor. Healthy levels of betaine come from both external food sources and internal synthesis in the body. Betaine supplements are already used clinically to treat the metabolic disease homocystinuria. Betaine is known to prevent the type of chemical damage, carbonyl stress, that causes this CRMP2 dysfunction.

By protecting CRMP2 from damage, betaine treatment allows kif3b mutant neurons to build proper structures. With a structurally sound skeleton to navigate, the remaining functional KIF3B protein can shuttle cargo around the cell. Other test tube experiments revealed that KIF3B and CRMP2 can bind together, but their exact relationship remains unclear.

Schizophrenia is estimated to affect about 1 in 100 people globally and is one of the leading causes of disability worldwide.

"There are treatments for schizophrenia, but they have side effects and unfortunately there is still no effective drug for patients to take that we can explain biochemically why it works," said Nobutaka Hirokawa, MD, PhD, lead author of the study from the University of Tokyo Graduate School of Medicine. “We know that the amount of betaine decreases in schizophrenia patients' brains, so this study strongly suggests betaine could be therapeutic for at least some kinds of schizophrenia.”