Receptors in brain linked to schizophrenia, autism

August 11, 2015
When mice are engineered to lack the mGluR5 receptor in parvalbumin cells (right), they have fewer inhibitory (red) connections controlling the activity of excitatory neurons. Credit: Salk Institute

The loss of a critical receptor in a special class of inhibitory neurons in the brain may be responsible for neurodevelopmental disorders including autism and schizophrenia, according to new research by Salk scientists.

The importance of the receptor, called mGluR5, in other areas of the had been previously established. Until now, however, no one had studied their specific role in a cell type known as parvalbumin-positive interneurons, thought to be important in general cognition and generating certain types of oscillatory wave patterns in the brain.

"We found that without this receptor in the parvalbumin , mice have many serious behavioral deficits," says Terrence Sejnowski, head of Salk's Computational Neurobiology Laboratory, which led the research published in Molecular Psychiatry on August 11, 2015. "And a lot of them really mimic closely what we see in ."

Scientists had previously discovered that when molecular signaling was disrupted in these cells during development, the brain's networks didn't form correctly. Separate studies have revealed that mGluR5 receptors, which transmit glutamate signaling in the brain, are linked to addiction disorders, anxiety and Fragile X Syndrome. But, in these cases, mGluR5 is affected in excitatory cells, not like the parvalbumin-positive interneurons.

The Salk team wondered what the role of mGluR5 was in the parvalbumin cells since the cells were deemed so important in . They partnered with Athina Markou's team from the Department of Psychiatry at the University of California, San Diego, to examine what happened when the receptor was selectively deleted from these cells after the brain's initial formation. Without the receptor in these cells, they found, mice had a host of developmental problems, including obsessive, repetitive grooming behavior and anti-social tendencies. Moreover, the patterns of activity in the animals' brains resembled those seen in humans suffering from schizophrenia.

"This discovery implies that changes after birth, not just before birth, are affecting the way the network is set up," says Margarita Behrens, corresponding author and Salk staff scientist.

The results suggest that an alteration in mGluR5 receptors in these may be a critical step in the formation of some , adds Sejnowski. It's good news, he says, because the molecular change is potentially reversible.

"The cells are still alive, and if we can figure out how to go in and change some of these molecular switches, we might actually be able to put the cells back into healthy, functioning states," he says.

Behrens says the study also should be a signal of caution to the pharmaceutical industry to be wary of drugs that affect mGluR5 throughout the whole brain. "There are a lot of clinical trials ongoing looking at modulating mGluR5 for anxiety and Fragile X Syndrome," she says. "But our results suggest that if you affect parvalbumin neurons, you might get behavioral changes you weren't expecting."

More research is needed to show whether the parvalbumin cells' mGluR5 receptors are linked to disease in humans and, if so, what causes the loss or disruption to the .

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5 comments

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JVK
1 / 5 (1) Aug 11, 2015
...what causes the loss or disruption to the receptors.


Thanks for asking.

The accumulation of viral microRNAs leads to receptor loss via mutations, which perturb protein folding in the absence of RNA-mediated repair via nutrient-dependent microRNAs, DNA repair occurs in the context of RNA-mediated gene duplication and RNA-mediated amino acid substitutions that stabilize the organized genomes of all living genera via the conserved molecular mechanisms of biophysically constrained protein folding chemistry.

See for examples: Nutrient-dependent/pheromone-controlled adaptive evolution: a model. http://www.ncbi.n...24693353

If you don't like the examples, you are probably a neo-Darwinian theorist -- not that there's anything wrong with that. Someone must be wrong about biologically-based cause and effect. How could it not be a theorist? Serious scientists support their claims with experimental evidence of biologically-based cause and effect.
JVK
1 / 5 (1) Aug 11, 2015
See also: Glutamate-Dependent Neuroglial Calcium Signaling Differs Between Young and Adult Brain
http://www.scienc...abstract

reported here in January 2013 as: http://medicalxpr...wed.html

"....by analyzing the gene and protein expression in the brain the researchers discovered that the mGluR5 largely disappear in the glial cells of adult mice meaning that these cells do not directly respond to synaptic neuronal signalling, thus calling into question the concepts that drive most of ongoing research in the field."

Most of the concepts that have driven the ongoing research in the field must be replaced since they were not based on anything known to serious scientists about the role that viruses play in perturbed cell type differentiation. Viruses link entropic elasticity to genomic entropy when nutrient-dependent microRNAs and RNA-mediated DNA repair fail to compensate for the accumulation of viral microRNAs.
Vietvet
1 / 5 (1) Aug 11, 2015
"This review describes how heavy metals impede protein folding and promote protein aggregation, how cells regulate quality control systems to protect themselves from metal toxicity and how metals might contribute to protein misfolding disorders."
http://www.mdpi.c.../4/1/252
JVK
1 / 5 (1) Aug 11, 2015
Protein folding is RNA-mediated and it is biophysically constrained by nutrients in the context of ecological variation, which is linked to ecological adaptations via metabolic networks and genetic networks.

Conserved molecular mechanisms link the epigenetic landscape to the physical landscape of DNA in all living genera via microRNAs.

Simply put, it is very simple-minded to put the mGluR5 gene and protein expression in the brain into the context of heavy metal damage, which must typically be repaired in the context of RNA-mediated events. If you like simple-minded simplicity, you can ask an evolutionary theorist about mutations and natural selection and accept whatever the theorist tells you.
loneislander
1 / 5 (1) Aug 12, 2015
This is pure folly. If there is something which causes autism it cannot be related to schizophrenia, and if something causes schizophrenia it cannot cause autism. This is like a broken arm causing blindness or something. This is a idle pursuit of pure folly. When people understand that autism is not a disorder, not a disease, but was essential for the development of our species and its culture - and that schizophrenia is indeed a disorder and is a consequence of the natural problems that arise from complexity then they will be on the right track.

Autism is not a disease. It is not a disorder.

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