New Targets for Schizophrenia Treatment

Approximately 3.2 million Americans and 115 thousand Canadians have schizophrenia. With current medications, only 16 percent will experience alleviation of their cognitive symptoms or improve their social functioning appreciably. The drugs, called antipsychotics, also come with a grocery list of negative side effects, especially in the long term.

Antipsychotics target receptors for dopamine and serotonin, neurotransmitters that transfer information between junctions in the brain called synapses. Long term antipsychotic use can bring about involuntary movement disorders, gynecomastia, impotence, weight gain, and metabolic syndrome.

Recent studies suggest myelin and oligodendrocytes play a significant role in the biology that leads to schizophrenic symptoms. Targeting these brain structures may pave the way for a new era of schizophrenia treatment.

Myelin is compacted cell membrane that wraps itself around the nerve fibers (also called axons) of neurons like toilet paper rolled onto a cardboard tube. In the brain and spinal cord, myelin is created by cells called oligodendrocytes. Myelin speeds up action potentials (bursts of electricity that encode information), which allows neurons to communicate with each other faster and over greater distances. Myelin also keeps nerve fibers nourished so they have enough energy to function properly.

Schizophrenia is linked to white matter changes in regions all over the brain—white matter changes characteristic of aberrant myelination. Scientists studying the brains of schizophrenic individuals have also noticed fewer oligodendrocytes in the hippocampus (a brain region involved in learning and memory) and the dorsolateral prefrontal cortex (involved in many executive functions like working memory and abstract reasoning). Altered expression of oligodendrocyte-related genes and proteins is seen in several areas of the cortex, the hippocampus, and the basal ganglia. Basically, no matter what new neuroscientific tool is used, myelin and oligodendrocytes appear to be widely affected in the schizophrenic brain.

How does aberrant myelination and oligodendrocyte dysfunction contribute to the false beliefs, the unclear and confused thinking, and the reduced social engagement that plagues individuals with schizophrenia?

The answer, in part, may be due to a lack of synchronization.

Neurons have rhythmic patterns of activity. The brain waves that arise because of this rhythmic activity oscillate at many different frequencies. Oscillations at the same frequency couple different regions of the brain into functional assemblies. It syncs them.

In “Deeper Insights Emerge into How Memories Form,” written by R. Douglas Fields for Scientific American last month, Fields uses an orchestra to explain this concept of synchronicity. “Much like the synchronization of the string section and French horns in an orchestra, synchronous brain rhythms could potentially couple neurons in the prefrontal cortex and hippocampus together for the mouse to learn to fear a particular location.”

Fields were explaining synchronization in the context of new memories forming. I intend to commandeer his orchestra analogy to explain the lack of synchronization in the brains of schizophrenic individuals.

A specific type of neuron—parvalbuminergic interneurons—generate brain waves in the cortex and the hippocampus. These interneurons are the conductors of the orchestra, gently tapping their baton against the podium, coaxing the strings section and the French horns to play in unison.

In schizophrenia, these interneurons are dysfunctional. They’re all there, but they’re not working properly—the conductor is standing at the front, but he’s not doing his job. It’s the dysfunction of these interneurons and the dysfunction of the oscillations they’re supposed to produce that underlie deficits in attention and working memory in a schizophrenic brain.

“The dysfunction of parvalbuminergic interneurons may be the result of impaired myelin plasticity,” wrote a group of researchers in a recent review led by Florian J. Raabe of the Department of Psychiatry and Psychotherapy at University Hospital in Germany.

Myelin functions to fine-tune the speed of action potentials. The thicker the myelin, the faster the action potential is going to travel.

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Different degrees of myelination in different white matter tracts can make it so impulses traveling different distances and from different places will arrive in a common region at the same time.

Let’s say the strings section is twice as far away from the conductor as the French horns are, and they both start playing at the same time. If the sound between both sections are traveling at the same speed, the sound from the French horns is going to reach the conductor first, because it doesn’t have to go nearly as far.

The sound from the strings section could be sped up if its route to the conductor was myelinated. Speed up that sound enough and you can make sure the sound from both sections reaches the conductor at the same time.

The converse is also true. Different degrees of myelination can ensure impulses originating from the same place make it to different regions at the same time. The signals from the conductor to the string section can be sped up so it reaches them at the same time it reaches the French horns.

Impaired myelin plasticity could throw off the timing of impulses traveling to and from parvalbuminergic interneurons. The conductor isn’t getting the information he needs at the right time to sync the different sections of the orchestra. And he can’t get the information to them in a way that will make them play in unison. No synchronization means no neural oscillations. No oscillations means difficulty with attention, working memory, and other cognitive abilities.

Myelin also supports neurons by making sure they have enough energy to do their jobs. Parvalbuminergic interneurons are highly active cells, requiring a lot of energy and a lot of food. Without the right nutrition, they can’t generate the brain oscillations they need to. Without some stimulation, the conductor falls asleep at his podium and the orchestra falls into disarray. Myelin acts like the conductor’s assistant, feeding him coffee to keep him awake and alert.

Aberrant myelination contributes to the lack of synchronization in the brain of a schizophrenic individual because of a lack of timing control and because of a lack of support of the critical oscillation generators in the brain. New therapies that target myelin and oligodendrocytes and stimulate myelination may alleviate some of the symptoms of schizophrenia.

Screening antipsychotics for myelination-inducing properties or screening remyelination therapies for effectiveness in schizophrenia models would be effective ways to develop new treatment options efficiently.