The Glutamate Hypothesis of Schizophrenia

Schizophrenia is a complex disorder that affects approximately 1% of the world’s population. It’s one of the most important causes of chronic disability. Glutamate neurotransmission seems to be related to its manifestation. In this sense, the glutamate hypothesis of schizophrenia is a new approach that seeks to explain the cause and possible treatment of this disorder.

This hypothesis emphasizes the deficiency of the activity of a neurotransmitter called glutamate. A process called hypofunction of glutamate occurs in the brain. To better understand the mechanism of this neurotransmitter in schizophrenia, we must know how it works and what schizophrenia consists of.

What is glutamate?

Glutamate is one of the main neurotransmitters in the nervous system. It’s responsible for 80% of the energy consumed by our brain. In addition, it participates in some metabolism processes, in the production of antioxidants, in motor and sensory systems, and in emotions and behavior.

This neurotransmitter mediates excitatory responses and intervenes in neuroplasticity processes. This refers to the brain’s ability to adapt as a result of experience. Glutamate also intervenes in learning processes and relates to other neurotransmitters, such as GABA and dopamine.

When the synaptic vesicles release glutamate, it activates different pathways. In addition, this neurotransmitter is associated with its precursor GABA. GABA deactivates the pathways that glutamate has activated. Therefore, GABA acts as glutamate’s antagonist.

In addition, glutamate intervenes in cognitive, memory, motor, sensory, and emotional information. That’s the main reason why people have begun to study its relationship with schizophrenia given its function at the cognitive and behavioral levels.

What is schizophrenia?

Schizophrenia is a serious mental disorder. It greatly affects one’s quality of life. According to the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), it usually manifests with the following symptoms:

• Hallucinations: The person perceives visual or auditory manifestations that don’t exist.
• Delusions: The person feels convinced about something that isn’t true. In other words, they have a false belief that they maintain with great conviction.
• Disorganized language: Confusing use of language, such as frequently getting sidetracked or speaking with inconsistency.
• Negative symptoms: Apathy (a lack of energy to move) or decreased emotional expression.
• Disorganized or catatonic behavior.

To be able to be diagnosed with schizophrenia, two or more of the above symptoms must be present in a period of one month. In addition, continuous signs of change must show for at least 6 months. A person’s life must also be affected by these symptoms.

On the other hand, the disease isn’t diagnosed when the symptoms are caused by the effects of some substance. In addition, if the patient has a history of an autism spectrum disorder, schizophrenia is diagnosed only if the hallucinations and delusions are severe.

Origin of the glutamate hypothesis

The glutamate hypothesis originated as a way to try to respond to the growing need for a theory that explained schizophrenia. The existing theories didn’t allow people to fully understand the mechanisms of this disease.

In the beginning, it was believed that a dopamine problem caused schizophrenia. Subsequently, researchers realized that glutamate played a key role in addition to dopamine and that it could be related to this disease. This is how the glutamate hypothesis arose. It proposed that a hypofunction of glutamate in the cortical projections causes schizophrenia. In other words, a deficit of this neurotransmitter exists in the cortical region of the brain.

Now, the glutamate hypothesis of schizophrenia doesn’t exclude the dopamine hypothesis. It proposes that a hypofunction of glutamate generates an increase in dopamine. In other words, this hypothesis complements the dopamine theory.

The glutamate receptors generate activity in the GABAergic interneurons, which in turn inhibit the glutamate receptors. Then, they prevent hyperactivation. Therefore, no excess of glutamate exists. The process causes an increase in neuronal death. In schizophrenia, this system is affected.

Receptors involved according to the glutamate hypothesis

As mentioned above, the glutamate hypothesis refers to a dysfunction in glutamate receptors. In schizophrenia, they generate less cortical activity, which leads to the manifestation of certain symptoms. In other words, when the glutamate receptors don’t function correctly, this disorder manifests.

Scientists discovered the importance of these receptors when they administered intravenous substances that blocked them. In turn, cognitive and behavioral symptoms similar to those in schizophrenia manifested.

In addition, scientists have also studied the following glutamate receptors related to schizophrenia:

• Ionotropic receptors: These receptors interact with ions such as calcium and magnesium. They include the NMDA, AMPA, and kainate receptors. In addition, they transmit fast signals.
• Metabotropic receptors: These receptors bind to G proteins and have a characteristically slow transmission.

Although there are some accurate results, there are also other contradictory results. The ionotropic NMDA receptor has been studied a lot. The action of the AMPA and kainate receptors has also been studied, but the results aren’t conclusive.

In addition, when NMDA receptors work poorly, they cause neuronal death. This, in turn, cases behavioral dysfunctions typical of schizophrenia. As for the AMPA and kainate receptors, consistent data from different authors is needed for the data to be considered relevant.

In contrast, metabotropic receptors are associated with neuronal protection. When altered, glutamate diminishes in these receptors. Therefore, they cause behavioral problems typical of schizophrenia.

Therapeutic possibilities that stem from the glutamate hypothesis

Scientists have created pharmacological substances thanks to the glutamate hypothesis. They intend to imitate the role of glutamate receptors and have yielded fairly good results.

However, this doesn’t mean that the process is simple or that the treatment is effective. It’s not easy to control the activation of the receptors. Plus, hyperactivation could also be harmful.

In addition, because studies have emphasized global symptoms, most experiments have been carried out on animals. Therefore, we can’t know for certain the exact relationship between a symptom and brain localization in humans.

The glutamate hypothesis is a great advancement, but we shouldn’t forget that environmental factors also play a role in schizophrenia. Future research could combine various aspects to better understand this disorder. Perhaps an integrated approach may help understand all of the factors associated with it.