Summary: A rare genetic mutation that causes blindness also appears to be associated with above-average intelligence, a new study reports.
Source: Leipzig University
Synapses are the contact points in the brain through which nerve cells “talk” to each other. Disturbances in this communication lead to diseases of the nervous system, because altered synaptic proteins, for example, can alter this complex molecular mechanism. This can lead to mild symptoms, but also very severe disabilities in those affected.
The interest of the two neurobiologists, Professor Tobias Langenhan and Professor Manfred Heckmann, respectively from Leipzig and Würzburg, was aroused when they read in a scientific publication a mutation that damages a synaptic protein.
At first, affected patients caught the attention of scientists because the mutation left them blind. However, the doctors then noticed that the patients were also of above-average intelligence.
“It’s very rare that a mutation results in an improvement rather than a loss of function,” says Langenhan, professor and holder of a chair at the Rudolf Schönheimer Institute of Biochemistry at the Faculty of Medicine.
The two neurobiologists from Leipzig and Würzburg have been using fruit flies for many years to analyze synaptic functions.
“Our research project was designed to insert the patients’ mutation into the corresponding gene in the fly and use techniques such as electrophysiology to test what happens to the synapses next. We thought the mutation makes patients so smart because it improves communication between neurons that involve the damaged protein,” says Langenhan.
“Of course, you can’t make these measurements on human patient brain synapses. You need to use animal models for this.
“75% of the genes that cause disease in humans also exist in fruit flies”
First, the scientists, in collaboration with Oxford researchers, showed that the fly protein called RIM appears molecularly identical to that of humans. This was essential to be able to study changes in the human brain in the fly. In the next step, the neurobiologists inserted mutations into the fly’s genome that looked exactly like those in sick people. They then carried out electrophysiological measurements of synaptic activity.
“We actually observed that the animals carrying the mutation showed a much greater transmission of information at the level of the synapses. This amazing effect on the synapses of the fly is probably found in the same or similar way in human patients, and could explain their increased cognitive performance, but also their blindness,” concludes Professor Langenhan.
Scientists have also discovered how increased transmission occurs at synapses: the molecular components of the sending nerve cell that trigger synaptic impulses come together due to the mutation effect and result in an increased release of neurotransmitters. A new method, super-resolution microscopy, was one of the techniques used in the study.
“It gives us a tool to look at and even count individual molecules and confirms that the molecules in the firing cell are closer together than they normally are,” says Professor Langenhan, who was also assisted in the study by the research group of Professor Hartmut Schmidt of the Carl Ludwig Institute in Leipzig.
“The project beautifully demonstrates how an extraordinary model animal like the fruit fly can be used to gain a very deep understanding of human brain disease. Animals are genetically very similar to humans. It is estimated that 75% of the genes implicated in the disease in humans are also found in the fruit fly,” says Professor Langenhan, pointing to other research on the subject at the Faculty of Medicine:
“We have started several joint projects with human geneticists, pathologists and the team of the Integrated Center for Research and Treatment (IFB) AdiposityDiseases; based at the University Hospital of Leipzig, they study disorders of brain development, the development of malignant tumors and obesity. Here too, we will insert pathogenic mutations into the fruit fly to replicate and better understand human disease.
About this genetics and intelligence research news
Author: Susan Huster
Source: Leipzig University
Contact: Susann Huster – University of Leipzig
Picture: Image is in public domain
Original research: Access closed.
“Human cognition-enhancing CORD7 mutation increases number of active zones and synaptic release” by Tobias Langenhan et al. Brain
Human cognition-enhancing CORD7 mutation increases number of active zones and synaptic release
Humans with the CORD7 (cone-rod dystrophy 7) mutation have increased verbal IQ and working memory. This autosomal dominant syndrome is caused by the exchange of a single amino acid R844H (human numbering) located in the 3ten C helix2A domain of RIMS1/RIM1 (molecule 1 interacting with Rab3).
RIM is an evolutionarily conserved multi-domain protein and an essential component of presynaptic active areas, which is centrally involved in fast Ca2+– triggered release of neurotransmitters. How the CORD7 mutation affects synaptic function is unclear so far.
Here we have established Drosophila melanogaster as a disease model to clarify the effects of the CORD7 mutation on RIM function and synaptic vesicle release.
To this end, using protein expression and X-ray crystallography, we solved the molecular structure of the Drosophila VS2A domain at 1.92 Å resolution and by comparison with its mammalian counterpart established that the location of the CORD7 mutation is structurally conserved in the RIM fly.
Additionally, CRISPR/Cas9-assisted genome engineering was used for the generation of rim alleles encoding R915H CORD7 swap or R915E, R916E (fly numbering) substitutions to effect local charge reversal at 3ten helix.
Through electrophysiological characterization by two-electrode voltage clamp and focal recordings, we determined that the CORD7 mutation exerts a semi-dominant rather than a dominant effect on synaptic transmission, resulting in faster and more efficient synaptic release and increased readily releasable pool size but reduced sensitivity for the rapid calcium chelator BAPTA.
Moreover, the rim The CORD7 allele increased the number of presynaptic active zones but left their nanoscopic organization unchanged, as revealed by super-resolution microscopy of the presynaptic scaffold protein Bruchpilot/ELKS/CAST.
We conclude that the CORD7 mutation leads to tighter release coupling, an increase in the size of the readily releasable pool, and more release sites, thereby promoting more efficient synaptic transmitter release.
These results strongly suggest that similar mechanisms may underlie the CORD7 disease phenotype in patients and that enhanced synaptic transmission may contribute to their increased cognitive abilities.