From “The Cornell Chronicle”: “Autism-linked gene shapes nerve connections” 

From “The Cornell Chronicle”

11.30.22
Alan Dove Weill | Weill Cornell Medicine

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Brain connectivity is changed upon removal of an autism-associated gene. Neuron is on one side of the brain (labeled in red) and nerve endings are coming from the other side of the brain (labeled in green). Image courtesy of Camilo Ferrer.

A gene linked to autism spectrum disorders plays a critical role in early brain development and may shape the formation of both normal and atypical nerve connections in the brain, according to a new study by Weill Cornell Medicine investigators.

Graphical abstract
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The study, published Nov. 28 in Neuron [below], employed a combination of sophisticated genetic experiments in mice and analysis of human brain imaging data to better understand why mutations in a gene called Gabrb3 are linked to a high risk of developing autism spectrum disorder (ASD) and a related condition called Angelman Syndrome. Both conditions involve abnormal behaviors and unusual responses to sensory stimuli, which appear to stem, at least in part, from the formation of atypical connections between neurons in the brain.

“Neuronal connections in the brain, and developmental synchronization of neuronal networks, are perturbed in individuals with autism spectrum disorders, and there are specific genes that are implicated in the pathogenesis of ASD,” said co-first author Dr. Rachel Babij, a former student in the Weill Cornell/Rockefeller/Sloan Kettering Tri-Institutional MD-PhD program in the laboratory of Natalia De Marco García, an associate professor in the Feil Family Brain and Mind Research Institute at Weill Cornell Medicine. 

The gene Gabrb3 encodes part of a critical receptor protein found in inhibitory connections in the brain, which tamp down neuronal activity to maintain order in the nervous system, like police officers directing traffic. During development, Gabrb3 also appears to help determine how brain connections form.

To figure out how Gabrb3 works, Babij and her colleagues tracked cellular signaling inside the brains of both normal animals and those lacking the gene in the early stages of their development. The preclinical experiments, which Babij performed alongside co-first author Camilo Ferrer, a postdoctoral associate in the De Marco García lab, and others, revealed that mice lacking Gabrb3 fail to form the normal network of connections between neurons in a specific brain region involved in sensory processing.

“It’s not a pervasive problem in which every single neuron will fail to contact, or inappropriately contact, their targets; but it’s actually a subset of cells that are more susceptible to this,” said De Marco García, who is the senior author on the paper.

In collaboration with Dr. Theodore Schwartz’s lab at Weill Cornell, the authors showed that the net result of Gabrb3 deletion is an increase in functional connections between the two hemispheres of the brain in the genetically modified mice, compared to those with a functional Gabrb3 gene. The genetically modified mice are also hypersensitive to touch. “Basically, what we see is that these neurons are more responsive to sensory stimuli after deletion of this gene,” De Marco García said.

The team then collaborated with the laboratory of Dr. Conor Liston at Weill Cornell to examine the role of the gene using neuroimaging data from human subjects. The investigators found a correlation between the spatial distribution of the human GABRB3 gene and atypical nerve connectivity in those with ASD. “The lower the expression of GABRB3 in specific brain regions, the more atypical nerve connections these regions were likely to contain,” said De Marco García said.

While cautioning that it is impossible to draw direct parallels between the preclinical and human data, De Marco García suggests that both analyses point to a model of neurologic disorders in which alterations in genes such as GABRB3 could drive specific changes in neuronal connection patterns, which in turn lead to abnormal behaviors. Interactions between different genes, each with slightly different effects, could yield substantially different outcomes.

Babij concurs. “What makes one person develop schizophrenia while another person develops ASD, when both have some element of inhibitory neuron dysfunction? I think something about the specific subtypes of neurons affected and the mutations impacting them could play into how people develop these different diseases,” she said.

Many Weill Cornell Medicine physicians and scientists maintain relationships and collaborate with external organizations to foster scientific innovation and provide expert guidance. The institution makes these disclosures public to ensure transparency. For this information, see profiles for Dr. Liston and Dr. Schwartz.

Science paper:
Neuron

See the full article here .

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Once called “the first American university” by educational historian Frederick Rudolph, Cornell University represents a distinctive mix of eminent scholarship and democratic ideals. Adding practical subjects to the classics and admitting qualified students regardless of nationality, race, social circumstance, gender, or religion was quite a departure when Cornell was founded in 1865.

Today’s Cornell reflects this heritage of egalitarian excellence. It is home to the nation’s first colleges devoted to hotel administration, industrial and labor relations, and veterinary medicine. Both a private university and the land-grant institution of New York State, Cornell University is the most educationally diverse member of the Ivy League.

On the Ithaca campus alone nearly 20,000 students representing every state and 120 countries choose from among 4,000 courses in 11 undergraduate, graduate, and professional schools. Many undergraduates participate in a wide range of interdisciplinary programs, play meaningful roles in original research, and study in Cornell programs in Washington, New York City, and the world over.

Cornell University is a private, statutory, Ivy League and land-grant research university in Ithaca, New York. Founded in 1865 by Ezra Cornell and Andrew Dickson White, the university was intended to teach and make contributions in all fields of knowledge—from the classics to the sciences, and from the theoretical to the applied. These ideals, unconventional for the time, are captured in Cornell’s founding principle, a popular 1868 quotation from founder Ezra Cornell: “I would found an institution where any person can find instruction in any study.”

The university is broadly organized into seven undergraduate colleges and seven graduate divisions at its main Ithaca campus, with each college and division defining its specific admission standards and academic programs in near autonomy. The university also administers two satellite medical campuses, one in New York City and one in Education City, Qatar, and Jacobs Technion-Cornell Institute in New York City, a graduate program that incorporates technology, business, and creative thinking. The program moved from Google’s Chelsea Building in New York City to its permanent campus on Roosevelt Island in September 2017.

Cornell is one of the few private land grant universities in the United States. Of its seven undergraduate colleges, three are state-supported statutory or contract colleges through the SUNY – The State University of New York system, including its Agricultural and Human Ecology colleges as well as its Industrial Labor Relations school. Of Cornell’s graduate schools, only the veterinary college is state-supported. As a land grant college, Cornell operates a cooperative extension outreach program in every county of New York and receives annual funding from the State of New York for certain educational missions. The Cornell University Ithaca Campus comprises 745 acres, but is much larger when the Cornell Botanic Gardens (more than 4,300 acres) and the numerous university-owned lands in New York City are considered.

Alumni and affiliates of Cornell have reached many notable and influential positions in politics, media, and science. As of January 2021, 61 Nobel laureates, four Turing Award winners and one Fields Medalist have been affiliated with Cornell. Cornell counts more than 250,000 living alumni, and its former and present faculty and alumni include 34 Marshall Scholars, 33 Rhodes Scholars, 29 Truman Scholars, 7 Gates Scholars, 55 Olympic Medalists, 10 current Fortune 500 CEOs, and 35 billionaire alumni. Since its founding, Cornell has been a co-educational, non-sectarian institution where admission has not been restricted by religion or race. The student body consists of more than 15,000 undergraduate and 9,000 graduate students from all 50 American states and 119 countries.

History

Cornell University was founded on April 27, 1865; the New York State (NYS) Senate authorized the university as the state’s land grant institution. Senator Ezra Cornell offered his farm in Ithaca, New York, as a site and $500,000 of his personal fortune as an initial endowment. Fellow senator and educator Andrew Dickson White agreed to be the first president. During the next three years, White oversaw the construction of the first two buildings and traveled to attract students and faculty. The university was inaugurated on October 7, 1868, and 412 men were enrolled the next day.

Cornell developed as a technologically innovative institution, applying its research to its own campus and to outreach efforts. For example, in 1883 it was one of the first university campuses to use electricity from a water-powered dynamo to light the grounds. Since 1894, Cornell has included colleges that are state funded and fulfill statutory requirements; it has also administered research and extension activities that have been jointly funded by state and federal matching programs.

Cornell has had active alumni since its earliest classes. It was one of the first universities to include alumni-elected representatives on its Board of Trustees. Cornell was also among the Ivies that had heightened student activism during the 1960s related to cultural issues; civil rights; and opposition to the Vietnam War, with protests and occupations resulting in the resignation of Cornell’s president and the restructuring of university governance. Today the university has more than 4,000 courses. Cornell is also known for the Residential Club Fire of 1967, a fire in the Residential Club building that killed eight students and one professor.

Since 2000, Cornell has been expanding its international programs. In 2004, the university opened the Weill Cornell Medical College in Qatar. It has partnerships with institutions in India, Singapore, and the People’s Republic of China. Former president Jeffrey S. Lehman described the university, with its high international profile, a “transnational university”. On March 9, 2004, Cornell and Stanford University laid the cornerstone for a new ‘Bridging the Rift Center’ to be built and jointly operated for education on the Israel–Jordan border.

Research

Cornell, a research university, is ranked fourth in the world in producing the largest number of graduates who go on to pursue PhDs in engineering or the natural sciences at American institutions, and fifth in the world in producing graduates who pursue PhDs at American institutions in any field. Research is a central element of the university’s mission; in 2009 Cornell spent $671 million on science and engineering research and development, the 16th highest in the United States. Cornell is classified among “R1: Doctoral Universities – Very high research activity”.

For the 2016–17 fiscal year, the university spent $984.5 million on research. Federal sources constitute the largest source of research funding, with total federal investment of $438.2 million. The agencies contributing the largest share of that investment are The Department of Health and Human Services and the National Science Foundation, accounting for 49.6% and 24.4% of all federal investment, respectively. Cornell was on the top-ten list of U.S. universities receiving the most patents in 2003, and was one of the nation’s top five institutions in forming start-up companies. In 2004–05, Cornell received 200 invention disclosures; filed 203 U.S. patent applications; completed 77 commercial license agreements; and distributed royalties of more than $4.1 million to Cornell units and inventors.

Since 1962, Cornell has been involved in unmanned missions to Mars. In the 21st century, Cornell had a hand in the Mars Exploration Rover Mission. Cornell’s Steve Squyres, Principal Investigator for the Athena Science Payload, led the selection of the landing zones and requested data collection features for the Spirit and Opportunity rovers. NASA-JPL/Caltech engineers took those requests and designed the rovers to meet them. The rovers, both of which have operated long past their original life expectancies, are responsible for the discoveries that were awarded 2004 Breakthrough of the Year honors by Science. Control of the Mars rovers has shifted between National Aeronautics and Space Administration’s JPL-Caltech and Cornell’s Space Sciences Building.

Further, Cornell researchers discovered the rings around the planet Uranus, and Cornell built and operated the telescope at Arecibo Observatory located in Arecibo, Puerto Rico until 2011, when they transferred the operations to SRI International, the Universities Space Research Association and the Metropolitan University of Puerto Rico [Universidad Metropolitana de Puerto Rico].

The Automotive Crash Injury Research Project was begun in 1952. It pioneered the use of crash testing, originally using corpses rather than dummies. The project discovered that improved door locks; energy-absorbing steering wheels; padded dashboards; and seat belts could prevent an extraordinary percentage of injuries.

In the early 1980s, Cornell deployed the first IBM 3090-400VF and coupled two IBM 3090-600E systems to investigate coarse-grained parallel computing. In 1984, the National Science Foundation began work on establishing five new supercomputer centers, including the Cornell Center for Advanced Computing, to provide high-speed computing resources for research within the United States. As a National Science Foundation center, Cornell deployed the first IBM Scalable Parallel supercomputer.

In the 1990s, Cornell developed scheduling software and deployed the first supercomputer built by Dell. Most recently, Cornell deployed Red Cloud, one of the first cloud computing services designed specifically for research. Today, the center is a partner on the National Science Foundation XSEDE-Extreme Science Engineering Discovery Environment supercomputing program, providing coordination for XSEDE architecture and design, systems reliability testing, and online training using the Cornell Virtual Workshop learning platform.

Cornell scientists have researched the fundamental particles of nature for more than 70 years. Cornell physicists, such as Hans Bethe, contributed not only to the foundations of nuclear physics but also participated in the Manhattan Project. In the 1930s, Cornell built the second cyclotron in the United States. In the 1950s, Cornell physicists became the first to study synchrotron radiation.

During the 1990s, the Cornell Electron Storage Ring, located beneath Alumni Field, was the world’s highest-luminosity electron-positron collider. After building the synchrotron at Cornell, Robert R. Wilson took a leave of absence to become the founding director of DOE’s Fermi National Accelerator Laboratory, which involved designing and building the largest accelerator in the United States.

Cornell’s accelerator and high-energy physics groups are involved in the design of the proposed ILC-International Linear Collider(JP) and plan to participate in its construction and operation. The International Linear Collider(JP), to be completed in the late 2010s, will complement the CERN Large Hadron Collider(CH) and shed light on questions such as the identity of dark matter and the existence of extra dimensions.

As part of its research work, Cornell has established several research collaborations with universities around the globe. For example, a partnership with the University of Sussex(UK) (including the Institute of Development Studies at Sussex) allows research and teaching collaboration between the two institutions.