Frankfurt University. Germany: German-American team of researchers finds neurophysiological correlates for cognitive and emotional symptoms in a Schizophrenia mouse model.
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.
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.
Publication:
Krabbe et al.: Increased dopamine
D2 receptor activity in the striatum alters the firing pattern of
dopamine neurons in the ventral tegmental area, in PNAS 9.2.2015,
www.pnas.org/cgi/doi/10.1073/pnas.1500450112