The Glutamate Hypothesis For Schizophrenia

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

This hypothesis emphasizes the lack of activity in 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 need to know how it works and what schizophrenia consists of.

What is glutamate?

Glutamate is one of the most important neurotransmitters in the nervous system. It is responsible for 80% of the energy consumed by our brain. In addition, it participates in some metabolic processes, in the production of antioxidants, in motor and sensory systems, and in emotions and behaviors.

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

When synaptic vesicles release glutamate, different pathways are activated. In addition, this neurotransmitter is associated with its precursor GABA. GABA inactivates the pathways that glutamate has activated. Therefore, GABA acts as its glutamate antagonist.

In addition , glutamate interferes with cognitive, memory, motor, sensory and emotional information. This is the main reason why people have started studying its relationship to schizophrenia given its function at cognitive and behavioral levels.

What is schizophrenia?

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

• Hallucinations : The person perceives visual or audible manifestations that do not exist.
• Delusions : The person feels convinced of something that is not true. In other words, they have a false belief that they maintain with great conviction.
• Disorganized language : Confusing use of language, which is often derailed or spoken with inconsistency.
• Negative symptoms : Apathy (lack of energy to move) or reduced emotional expression.
• Disorganized or catatonic behavior.

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

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

The origin of the glutamate hypothesis

The glutamate hypothesis emerged as a way of trying to respond to the growing need for a theory that explained schizophrenia. The existing theories did not allow people to fully understand the mechanisms of this disease.

Initially, it was thought that a dopamine problem was causing schizophrenia. Researchers then 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 is suggested that a hypofunction of glutamate in the cortical protrusions causes schizophrenia. In other words, there is a deficiency of this neurotransmitter in the cortical region of the brain.

Now u do not close the glutamate hypothesis for the schizophrenia dopamine hypothesis. It is suggested 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 GABAergic interneurons, which in turn inhibit the glutamate receptors. Then they prevent hyperactivation. Therefore, there is no excess of glutamate. 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 of glutamate receptors. In schizophrenia, they generate less cortical activity, leading to the manifestation of certain symptoms. In other words, when the glutamate receptors do not work properly, this disorder manifests itself.

Researchers discovered the importance of these receptors when they gave intravenous drugs that blocked them. In turn, cognitive and behavioral symptoms similar to schizophrenia were manifested .

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

• Ionotropic receptors : These receptors work together with ions such as calcium and magnesium. They include NMDA, AMPA and kainate receptors. In addition, they transmit fast signals.
• Metabotropic receptors : These receptors bind to G-proteins and have a characteristic slow transfer.

Although there are some exact results, there are other conflicting results. The ionotropic NMDA receptor has been extensively studied. The effect of the AMPA and kainate receptors has also been studied, but the results are not conclusive.

In addition, when NMDA receptors work poorly, they cause neuronal death. This in turn causes behavioral dysfunctions that are typical of schizophrenia. Regarding the AMPA and kainate receptors, consistent data from different authors are required for the data to be considered relevant.

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

Therapeutic options derived from the glutamate hypothesis

Researchers have created pharmacological drugs thanks to the glutamate hypothesis. They are intended to mimic the role of glutamate receptors and have given relatively good results.

However, this does not mean that the process is simple or that the treatment is effective. It is not easy to control the activation of the receptors. In addition, hyperactivation can also be harmful.

In addition, because studies have focused on global symptoms, most experiments have been performed on animals. Therefore, we can not know for sure the exact relationship between a symptom and a brain localization in humans.

The glutamate hypothesis is a great improvement, but we should not forget that environmental factors also play a role in schizophrenia. Future research may combine different aspects to better understand this disorder. Perhaps an integrated approach can help us understand all the factors associated with it.