Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Engineered mouse mimics cognitive aspects of schizophrenia

16.02.2006


Researchers have developed a mouse strain in which the abnormal activity of the dopamine machinery in a specific part of the brain causes cognitive and behavioral impairments mimicking those in human schizophrenics.



The achievement is important, because creating an animal model of any schizophrenic characteristics has not been done before. And schizophrenia’s genetic and physiological complexities have seriously hindered efforts to understand the disorder.

Dr.s Christoph Kellendonk, Eleanor H. Simpson, Eric R. Kandel and colleagues reported their development of the mouse model in an article in the February 16, 2006, issue of Neuron.


In a preview of the study in the same issue of Neuron, neuroscientist Solomon Snyder wrote that the researchers’ findings--along with studies implicating specific genes in schizophrenia--"afford a basis for optimism" that the engineered mice could provide an animal model for schizophrenia. "In this case, the transgenic mice developed by Kellendonk and colleagues may provide a valuable tool for understanding this most malignant of mental disorders," wrote Snyder.

Kellendonk and his colleagues based their experiments on a widely accepted theory that hyperactivity in the brain’s dopamine machinery plays a central role in schizophrenia. Dopamine is a major neurotransmitter in the brain--a chemical messenger that one neuron launches at its neighbor to trigger a nerve impulse in the receiving neuron.

The major antipsychotic drugs are believed to "dial down" the dopamine machinery by blocking receptors for dopamine on the surface of neurons. Also, amphetamines, which release dopamine, are known to aggravate schizophrenic symptoms.

The researchers also based their experiments on evidence that abnormalities in the brain region known as the striatum can affect cognitive function in schizophrenics--by indirectly influencing the prefrontal cortex, a major center for cognitive function.

To mimic the hyperactive dopamine machinery, the researchers created a genetically altered mouse strain in which dopamine receptors were overexpressed only in the striatum. What’s more, they engineered the mouse strain so that they could shut down this overexpression by giving the mice the antibiotic doxycycline.

The researchers found that the engineered animals showed no difference from normal mice in their general cognitive functioning, activity level, sensorimotor functioning, or anxiety.

However, the mice did show the same kinds of specific cognitive deficits seen in human schizophrenics. In tests using mazes, the animals showed deficits in "working memory"--the temporary storage of information required for a task. The animals also showed poorer behavioral flexibility; they were less able than normal mice to reverse their association of a particular odor with a reward.

Biochemical analyses of the animals’ brains revealed that the excess dopamine receptor activity in the striatum contributed to abnormal prefrontal cortical function.

Importantly, found the researchers, they could not reverse these cognitive deficits by using the antibiotic to damp down the dopamine machinery. This finding suggests that the effect of the abnormal dopamine machinery was developmental, they said.

"If increased activation of [dopamine] receptors indeed contributes to the cognitive deficits of patients with schizophrenia, our data could explain why antipsychotics do not greatly ameliorate cognitive deficits," wrote the researchers. "The physiological alterations that are responsible for cognitive deficits may be present long before the first psychotic episode, when treatment usually commences. Thus, treatment with typical antipsychotics may be too late to reverse the physiological alterations that are responsible for the cognitive deficits."

The researchers cautioned that "Rodent models of schizophrenia have significant limitations. The neuronal circuits affected in people are more complex than the analogous circuits in rodents. In particular, the relative size of the prefrontal cortex that is involved in the cognitive deficits is much smaller in rodents than in primates. Some of the cognitive symptoms such as hallucinations or delusions are impossible to address.

"However, rodent models have the advantage of allowing direct tests of cause-effect relationships for specific aspects of the disease, such as some of the cognitive deficits," they concluded. "We here have been able to introduce genetically a single molecular alteration in a restricted and regulated fashion and to study its behavioral and physiological consequences."

The researchers said that their findings suggest that cognitive symptoms of schizophrenia may arise from subtle genetic differences in the dopamine receptor gene in schizophrenics that increase receptor activity.

Heidi Hardman | EurekAlert!
Further information:
http://www.neuron.org
http://www.cell.com

More articles from Life Sciences:

nachricht Multi-institutional collaboration uncovers how molecular machines assemble
02.12.2016 | Salk Institute

nachricht Fertilized egg cells trigger and monitor loss of sperm’s epigenetic memory
02.12.2016 | IMBA - Institut für Molekulare Biotechnologie der Österreichischen Akademie der Wissenschaften GmbH

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Novel silicon etching technique crafts 3-D gradient refractive index micro-optics

A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.

Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...

Im Focus: Quantum Particles Form Droplets

In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.

“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...

Im Focus: MADMAX: Max Planck Institute for Physics takes up axion research

The Max Planck Institute for Physics (MPP) is opening up a new research field. A workshop from November 21 - 22, 2016 will mark the start of activities for an innovative axion experiment. Axions are still only purely hypothetical particles. Their detection could solve two fundamental problems in particle physics: What dark matter consists of and why it has not yet been possible to directly observe a CP violation for the strong interaction.

The “MADMAX” project is the MPP’s commitment to axion research. Axions are so far only a theoretical prediction and are difficult to detect: on the one hand,...

Im Focus: Molecules change shape when wet

Broadband rotational spectroscopy unravels structural reshaping of isolated molecules in the gas phase to accommodate water

In two recent publications in the Journal of Chemical Physics and in the Journal of Physical Chemistry Letters, researchers around Melanie Schnell from the Max...

Im Focus: Fraunhofer ISE Develops Highly Compact, High Frequency DC/DC Converter for Aviation

The efficiency of power electronic systems is not solely dependent on electrical efficiency but also on weight, for example, in mobile systems. When the weight of relevant components and devices in airplanes, for instance, is reduced, fuel savings can be achieved and correspondingly greenhouse gas emissions decreased. New materials and components based on gallium nitride (GaN) can help to reduce weight and increase the efficiency. With these new materials, power electronic switches can be operated at higher switching frequency, resulting in higher power density and lower material costs.

Researchers at the Fraunhofer Institute for Solar Energy Systems ISE together with partners have investigated how these materials can be used to make power...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

ICTM Conference 2017: Production technology for turbomachine manufacturing of the future

16.11.2016 | Event News

Innovation Day Laser Technology – Laser Additive Manufacturing

01.11.2016 | Event News

#IC2S2: When Social Science meets Computer Science - GESIS will host the IC2S2 conference 2017

14.10.2016 | Event News

 
Latest News

UTSA study describes new minimally invasive device to treat cancer and other illnesses

02.12.2016 | Medical Engineering

Plasma-zapping process could yield trans fat-free soybean oil product

02.12.2016 | Agricultural and Forestry Science

What do Netflix, Google and planetary systems have in common?

02.12.2016 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>