Glutamatergic Theory Of Schizophrenia

The glutamatergic theory of schizophrenia offers us a new possible cause and treatment of this mental disorder whose protagonist is glutamate
Glutamatergic theory of schizophrenia

Schizophrenia is a complex disorder that affects about 1% of the world population, constituting one of the most important causes of chronic disability. In recent years it has been correlated with alterations in glutamate neurotransmission, although the degree of this link has not yet been well defined. The glutamatergic theory of schizophrenia therefore offers us a new possible cause and treatment of this mental disorder, where the protagonist becomes the glutamate mechanism.

This hypothesis revolves around a hypofunction of the neurotransmitter called glutamate. To better understand the functioning of this neurotransmitter and its link with schizophrenia, however, it is necessary to know how it works and what this disorder consists of. Let’s see in this article what exactly the glutamatergic theory of schizophrenia is .

What is glutamate?

Glutamate is one of the main neurotransmitters in the nervous system.  It is responsible for 80% of the energy consumed by our brain. Furthermore, it participates in some metabolic processes, in the production of antioxidants, in the motor and sensory, emotional and behavioral systems.

Crying girl sitting on the ground

This neurotransmitter acts by mediating the exciting responses and intervening in the processes of neuroplasticity, that is the ability of our brain to adapt as a result of lived experiences. It also intervenes in learning processes and works together with other neurotransmitters such as GABA (of which it is a precursor) and dopamine.

When glutamate is secreted by synaptic vesicles, it activates impulses which are then inhibited by GABA, which then acts as a glutamate antagonist.

It also intervenes in the field of cognitive information, memory, motor, sensory and emotional information. Given its importance on a cognitive and behavioral level, scholars have focused on its possible relationship with schizophrenia.

What is schizophrenia?

Schizophrenia refers to a severe mental disorder that greatly affects a person’s quality of life. According to the current Diagnostic and Statistical Manual of Mental Disorders , it causes the following symptoms:

  • Hallucinations. Visual or auditory perceptions that don’t really occur.
  • Delusions. They are about the subject’s certainty about something unfounded, such as a judgment or a false belief.
  • Disconnected language. Confusing use of language, for example cheating frequently or saying incoherent sentences.
  • Negative symptoms. They refer to apathy (lack of energy to move) or reduced emotional expression.
  • Disorganized or catatonic behavior.

In order to be able to diagnose schizophrenia, at least two of the symptoms listed must occur, for the duration of a month or less if adequate treatment has been received. Continuous signs of alteration must also persist for at least six months, in addition to the degradation of one or more fundamental areas for the individual (work, relationships or personal care).

The disorder is excluded if the symptoms listed are given by the consumption of a substance. In the event that the individual already has a history of autism spectrum disorders, schizophrenia is diagnosed only if the hallucinations and delusions are severe.

Origin of the glutamatergic theory

The glutamatergic theory was born in an attempt to find an exact cause for schizophrenia;  it had already been supported by other approaches, however, which proved insufficient to explain the mechanism.

Schizophrenia was initially believed to be due to a dopamine-related problem. Later the researchers realized the important role of glutamate, in addition to that of dopamine. The glutamatergic theory was therefore proposed, which hypothesizes that schizophrenia depends on a hypofunction of glutamate in cortical interactions. In other words, a reduction in the normal function of this neurotransmitter in the cortical region of the brain.

Well, the glutamatergic theory of schizophrenia does not exclude the dopaminergic hypothesis, on the contrary, it completes it. In fact, he claims that in the case of glutamate hypofunction, an increase in dopamine occurs.

Glutamate neurons generate impulses which are then inhibited by y-aminobutyric acid (GABA), which thus prevents overactivation and excess glutamate. This process prevents neuronal death and is impaired in cases of schizophrenia.

Receptors that intervene according to the glutamatergic theory

As already mentioned, the glutamate theory is associated with a dysfunction of the glutamate receptors, which in the case of schizophrenia generate less cortical activity causing certain symptoms. In other words, when the glutamate receptors fail to perform their function, schizophrenia occurs.

The importance of these receptors was discovered following the intravenous administration of substances aimed at blocking them, causing cognitive and behavioral symptoms similar to those of schizophrenia.

The glutamate receptors studied in relation to schizophrenia are the following:

  • Ionotropic : interact with ions such as calcium or magnesium. For example, NMDA, AMPA and kainate receptors. They are characterized by fast transmission.
  • Metabotropic : receptors that bind to G proteins and are slow in transmission.

It should be emphasized that although there are data that validate the theory, there are others that are contradictory. The ionotropic receptors most studied and which show the best results are the NMDAs. AMPA and kainate receptors have also been studied, but with unsubstantiated results.

When NMDA receptors malfunction, they cause neuronal death and consequently the 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.

Schizophrenic woman with hallucinations

Metabotropic receptors, on the other hand, are associated with neuronal protection. Their alteration compromises the activity of glutamate, thus causing the behavioral problems typical of schizophrenia.

Therapeutic possibilities starting from the glutamatergic theory

Starting from the glutamatergic theory, pharmacological substances have been created that try to mimic the function of glutamate receptors. Apparently, the results obtained on an experimental level have been good.

This does not mean that the treatment is effective or that the process is simple. It is not easy to control the activation of the receptors, and the overactivation of the same could be harmful. Furthermore, since studies have focused on general and non-specific symptoms, most of them on guinea pigs, it is not possible to establish the exact relationship between a symptom and brain location in humans.

The glutamatergic theory represents a great scientific advance, but it is good to remember that schizophrenia is due not only to biological but also environmental factors. The goal is that in the future research continues to combine different aspects to better understand the origin of this disorder.

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