Summary: A rare genetic mutation that causes blindness also appears linked to above-average cognitive performance, according to a new study.
Source: University of Leipzig
Synapses are the connection points where neurons communicate. Disruptions to this communication, for example through altered synaptic proteins, can impair neural signaling and lead to neurological disorders. Depending on the severity, such disruptions may cause mild symptoms or profound disabilities.
Neurobiologists Tobias Langenhan (Leipzig) and Manfred Heckmann (Würzburg) became interested in a particular synaptic mutation after reading a clinical report describing patients who carried a damaging change in a synaptic protein.
Initially, clinicians focused on the mutation because it produced progressive vision loss. However, investigators later observed that affected individuals also tended to show above-average intelligence.
“It is unusual for a mutation to produce an apparent gain of function rather than a loss,” says Langenhan, professor and chair at the Rudolf Schönheimer Institute of Biochemistry at the Faculty of Medicine.
To investigate how this single mutation influences synaptic function, the researchers used Drosophila melanogaster (fruit flies), a well-established model for studying neuronal mechanisms.
“Our approach was to reproduce the patients’ mutation in the equivalent fly gene and then measure synaptic activity using methods such as electrophysiology,” explains Langenhan. “We hypothesized that the mutation might enhance communication between neurons that depend on the affected protein, which could help explain the improved cognitive performance observed in humans.”
Direct synaptic measurements in human patients are not feasible, so animal models are essential for linking genetic changes to synaptic physiology.
First, the team—working with collaborators from Oxford—demonstrated that the fly version of the protein RIM is structurally and functionally comparable to the human protein. Establishing this molecular conservation was a necessary step before modeling the human mutation in flies.
Using precise genome editing, the scientists introduced mutations into the fly rim gene that matched those found in affected patients. Electrophysiological recordings at the neuromuscular junction then allowed the researchers to quantify how the mutations altered synaptic transmission.
The experiments revealed that flies carrying the mutation exhibited markedly increased synaptic information transfer. “This pronounced enhancement of synaptic transmission in flies likely reflects similar changes in human patients, potentially explaining both their elevated cognitive abilities and concurrent vision loss,” says Professor Langenhan.
The team also investigated the molecular mechanism behind the stronger synaptic release. Their data indicate that the mutation causes key presynaptic components to cluster more tightly within the transmitting nerve terminal. This closer arrangement promotes a greater and faster release of neurotransmitters during synaptic activity. The study employed super-resolution microscopy to visualize and quantify these nanoscale changes.
“Super-resolution imaging allowed us to observe and even count single molecules, confirming that these presynaptic proteins are more tightly packed in mutant animals than in controls,” adds Langenhan, who collaborated with Professor Hartmut Schmidt’s group at the Carl Ludwig Institute in Leipzig.
The project highlights how a genetically tractable model organism such as the fruit fly can provide deep mechanistic insight into human brain conditions. Flies share a large proportion of disease-related genes with humans—approximately three quarters of genes implicated in human disease have identifiable counterparts in Drosophila—making them valuable for genetic and physiological studies.
Building on these results, the researchers have launched collaborative projects with clinical geneticists, pathologists and teams at the Integrated Research and Treatment Center for AdiposityDiseases at Leipzig University Hospital. In those projects, disease-associated mutations are introduced into flies to model developmental brain disorders, tumor development, and metabolic conditions like obesity, with the aim of improving understanding of disease mechanisms.
About this genetics and intelligence research news
Author: Susann Huster
Source: University of Leipzig
Contact: Susann Huster – University of Leipzig
Image: The image is in the public domain
Original Research: Closed access. “The human cognition-enhancing CORD7 mutation increases active zone number and synaptic release” by Tobias Langenhan et al. Brain
Abstract
The human cognition-enhancing CORD7 mutation increases active zone number and synaptic release
Individuals carrying the CORD7 (cone-rod dystrophy 7) mutation exhibit enhanced verbal IQ and working memory. This autosomal dominant syndrome is caused by a single amino-acid substitution (R844H in human numbering) located in the 310 helix of the C2A domain of RIMS1/RIM1, a presynaptic scaffold protein that is essential for fast, calcium-triggered neurotransmitter release.
To clarify how the CORD7 mutation alters synaptic function, the researchers established Drosophila melanogaster as a disease model. They solved the crystal structure of the fly C2A domain at 1.92 Å resolution and showed that the CORD7 mutation maps to a structurally conserved position in the fly protein.
CRISPR/Cas9 genome engineering produced rim alleles encoding the equivalent R915H exchange or charge-reversing substitutions (R915E,R916E). Electrophysiological assays, including two-electrode voltage clamp and focal recordings, demonstrated that the CORD7 mutation produces a semi-dominant effect: synaptic release became faster and more efficient, the readily releasable pool of vesicles expanded, and sensitivity to the fast calcium chelator BAPTA decreased.
Super-resolution microscopy of the presynaptic scaffold protein Bruchpilot/ELKS/CAST revealed that the CORD7 allele increased the number of active zones without disrupting their nanoscale organization.
The findings indicate that the CORD7 mutation tightens coupling between calcium entry and vesicle release, enlarges the readily releasable pool, and increases the number of release sites, collectively enhancing synaptic transmitter release. These mechanisms likely contribute to the clinical phenotype in patients and suggest that elevated synaptic transmission may underlie their improved cognitive performance.