Schizophrenia: Impaired activity of the selective dopamine neurons

Schizophrenia is not only associated with positive symptoms such as hallucinations and delusions, but also with negative symptoms e.g. cognitive deficits and impairments of the emotional drive. Until now, the underlying mechanisms for these negative symptoms have not been well characterized. In the current edition of the Proceedings of the National Academy of Sciences (PNAS) a German-American team of researchers, with the cooperation of the Goethe University, reports that a selective dopamine midbrain population that is crucial for emotional and cognitive processing shows reduced electrical in vivo activity in a disease mouse model.

Schizophrenia is a severe and incurable psychiatric illness, which affects approximately one percent of the world population. While acute psychotic states of the disease have been successfully treated with psychopharmaceutical drugs (antipsychotic agents) for many decades, cognitive deficits and impairments of motivation do not respond well to standard drug therapy. This is a crucial problem, as the long-term prognosis of a patient is determined above all by the severity of these negative symptoms. Therefore, the shortened average life-span of about 25 years for schizophrenia patients remained largely unaltered in recent decades.

“In order to develop new therapy strategies we need an improved neurobiological understanding of the negative symptoms of schizophrenia” explains Prof. Roeper of the Institute for Neurophysiology of the Goethe University. His American colleagues, Prof. Eleanor Simpson and Prof. Eric Kandel at Columbia University in New York recently made an important initial step in this direction. They created a new transgenic mouse model based on striatal overexpression of dopamine typ 2 receptors, which displayed typical signs of cognitive and emotional negative symptoms similar to those occurring in patients with schizophrenia. The researchers detected typical impairment in working memory with corresponding neurochemical changes in dopamine in the prefrontal cortex. However, the underlying neurophysiological impairments of dopamine neurons remained unresolved.

Now, Prof. Eleanor Simpson and Prof. Jochen Roeper, in cooperation with the mathematician Prof. Gaby Schneider of the Goethe University and the physiologist Prof. Birgit Liss of the University of Ulm have succeeded in defining the neurophysiological impairments with the dopamine system. They were able to show, with single cell recordings in the intact brain of mice, that those dopamine midbrain neurons responsible for emotional and cognitive processing displayed altered patterns and frequencies of electrical activity. In contrast, adjacent dopamine neurons, which are involved in motor control, were not affected.

What is schizophrenia?

Individuals with schizophrenia may hear voices that are not there. Some may be convinced that others are reading their minds, controlling how they think, or plotting against them. This can distress patients severely and persistently, making them withdrawn and frantic.

Others may find it hard to make sense of what a person with schizophrenia is talking about. In some cases, the individual may spend hours completely still, without talking. On other occasions he or she may seem fine, until they start explaining what they are truly thinking.

The effects of schizophrenia reach far beyond the patient - schizophrenia does not only affect the person with the disorder. Families, friends and society are affected too. A sizable proportion of people with schizophrenia have to rely on others, because they are unable to hold a job or care for themselves.

With proper treatment, patients can lead productive lives - according to the National Institute of Mental Health1 (NIMN), treatment can help relieve many of the symptoms of schizophrenia. However, the majority of patients with the disorder have to cope with the symptoms for life. This does not mean that a person with schizophrenia who receives treatment cannot lead a rewarding, productive and meaningful life in his or her community.

Schizophrenia most commonly strikes between the ages of 15 to 25 among men, and about 25 to 35 in women. In many cases the disorder develops so slowly that the sufferer does not know he/she has it for a long time. While, with other people it can strike suddenly and develop fast.

Schizophrenia, possibly many illnesses combined - it is a complex, chronic, severe, and disabling brain disorder and affects approximately 1% of all adults globally. Experts say schizophrenia is probably many illnesses masquerading as one. Research indicates that schizophrenia is likely to be the result of faulty neuronal development in the brain of the fetus, which later in life emerges as a full-blown illness.

Schizophrenia: Impaired activity of the selective dopamine neurons The researchers were also able to show that - in line with the persistence of cognitive deficits in mice and patients- the pathological discharge patterns of dopamine neurons persisted even after the causal transgene had been switched off in adult mice. “This result emphasizes the presence of a critical early phase for the development of cognitive deficits in schizophrenia” according to Roeper. He and his colleagues are currently examining how the neuronal activity of dopamine neurons changes during the working memory tasks. “Our results show that altered neuronal activity of selective dopamine neurons is crucial for schizophrenia”, Jochen Roeper summarises the importance of the research work.

Cannabis And Schizophrenia
Cannabis (pot) has been proven to nearly quadruple the risk of developing Schizophrenia. In 1969-70, Swedish military conscripts (>97% of the country’s male population aged 18-20) were followed for 35 years. At the start of this study, none of the conscripts had Schizophrenia. Over 35 years, those who had used cannabis more than 50 times at the beginning of the study had 3.7 times the normal rate of developing Schizophrenia. This association was not explained by use of other psychoactive drugs or personality traits. Schizophrenia normally occurs in 1% of the population. 86% of individuals with Schizophrenia are disabled and unemployed. Thus, if cannabis was legalized, the prevalence of Schizophrenia could more than triple. This would cause a massive increase in the national unemployment rate.


Jochen Roeper
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Goethe University Frankfurt

  Proceedings of the National Academy of Sciences

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