Alcino J. Silva

After spending three years in the Tonegawa laboratory, Silva set up his own laboratory at Cold Spring Harbor Laboratory in Long Island, New York, a research institute then run by James Watson, best known as the co-discoverer of the structure of DNA in 1953 with Francis Crick.

Initially, the Silva laboratory focused its studies on molecular and cellular mechanisms of hippocampal learning and memory.

For example, Rousudan Bourtchuladze led a project in the Silva laboratory that uncovered a role for the transcription factor CREB in the stability of hippocampal long term potentiation and long-term memory.

This was the first report of a genetic manipulation that affected the stability of synaptic plasticity and specifically long-.

but not short-term memory.

Other notable studies of memory mechanisms in the early years of the Silva laboratory in Cold Spring Harbor included the discovery that hippocampal pre-synaptic short-term plasticity mechanisms have a role in hippocampal learning and memory.

This early work with hippocampal mutations that affected long term potentiation and learning & memory became the basis for a large literature that now has definitively implicated stable changes in synaptic plasticity in the hippocampal CA1 region in hippocampal dependent learning and memory.

Alcino J. Silva (born April 9, 1961) is a Portuguese-American neuroscientist who was the recipient of the 2008 Order of Prince Henry and elected as a fellow of the American Association for the Advancement of Science in 2013 for his contributions to the molecular cellular cognition of memory, a field he pioneered with the publication of two articles in Science in 1992.

Silva is a Distinguished Professor of neurobiology, psychiatry and psychology at the David Geffen School of Medicine at UCLA, director of the Integrated Center for Learning and Memory at UCLA, and the Founding President of the Molecular and Cellular Cognition Society.

He is former scientific director of the Division of Intramural Research Programs at the National Institute of Mental Health, having also served as member of the Board of Regents of the University of Minho, Portugal.

Silva was born in Portugal in 1961, but spent his early years in Luanda, Angola.

He left Africa when he was 12 and in Portugal he went through the Carnation Revolution of 1974.

He arrived in the United States in 1978, attended Rutgers University, where he studied biology and philosophy and worked in the Drosophila laboratory of William Sofer.

After that he pursued graduate studies in human genetics at the University of Utah.

There, he worked with Raymond White, one of the pioneers of modern human genetics.

His graduate work showed that epigenetic patterns of DNA methylation can be polymorphic and that they are inherited in a Mendelian fashion.

During his graduate studies he became intrigued by the inner processes of science, and organized yearly graduate symposia where leading scientists shared their insights on this subject.

It was in Utah that he realized that he could combine his passion for biology with his interest in epistemology.

It was also in Utah, while working with Mario Capecchi, that he had the idea of bringing the newly developed mouse gene targeting approaches to studies of memory.

Capecchi shared the Nobel prize with Martin Evans and Oliver Smithies for the development of gene targeting strategies in mice.

While at a meeting in Cold Spring Harbor Laboratory, Silva heard from Peter Mombaerts (now at the Max Planck Institute for Biophysics) that Susumu Tonegawa at MIT was interested in Neuroscience (Tonegawa had taken a Neuroscience course at CSHL in 1987), and that his lab was trying to set up gene targeting to study the immunology T-cell receptors they had cloned.

So, he wrote to Tonegawa and proposed to target genes expressed postnatally in the cerebellum to study cerebellar memory.

At the time the Tonegawa laboratory at MIT was focused exclusively in immunology.

Susumu Tomegawa was awarded a Nobel Prize in 1987 for his discovery of the genetic mechanism that produces antibody diversity.

Silva joined the Tonegawa laboratory in early fall of 1988.

After attending a Society for Neuroscience symposium (Toronto, 1988), organized by John Lisman on mechanisms of hippocampal plasticity, Silva decided to study hippocampal-dependent memory formation.

The compelling properties of calcium calmodulin kinase II, one of the topics discussed in that symposium, and a model by John Lisman proposing a key role for that kinase in hippocampal learning and memory, persuaded Silva to refocus his project in the Tonegawa laboratory on the role of the alpha calcium calmodulin kinase II in hippocampal synaptic plasticity and learning & memory.

The two articles he published in Science as a post-doctural fellow in Susumu Tonegawa's laboratory were the first to combine molecular genetic techniques with electrophysiological analyses and behavioral studies.

This interdisciplinary integration of molecular, electrophysiological and behavioral approaches, fostered by transgenic techniques, has become a mainstay of neuroscience studies.

In 1998, the Silva laboratory moved to the Department of Neurobiology at the UCLA School of Medicine.

There, the laboratory bridged their growing involvement in animal models of cognitive disorders with clinical studies.

Additionally, UCLA's large and highly collaborative neuroscience community was an ideal environment for the interdisciplinary studies that characterized work in the Silva laboratory.

The Silva laboratory became more involved in studying molecular and cellular mechanisms responsible for cognitive deficits in genetic neurodevelopmental disorders.

In the late nineties, cognitive deficits associated with this class of disorders were thought to be caused by genetic disruptions of brain development Animal model studies of Neurofibromatosis type I (NF1) in the Silva lab suggested that the learning and memory deficits associated with NF1 mutations are caused by changes in synaptic plasticity mechanisms in adults.

Accordingly, a project led by Rui M. Costa in the Silva Lab demonstrated that the electrophysiological, and more importantly the behavioral deficits, caused by NF1 mutations could be reversed in adults by manipulations that corrected the molecular signaling deficits associated with these mutations.

This discovery, and a series of later studies in many laboratories worldwide, have demonstrated the surprising efficacy of adult interventions in reversing cognitive phenotypes in animal models of neurodevelopmental disorders.

Following the NF1 studies published in 2002 by the Silva laboratory, other findings that reported adult rescue of neurodevelopment disorders include, for example, animal studies of Lhermitte-Duclos disease and Rubinstein-Taybi syndrome in 2003, Fragile X syndrome in 2005, Down syndrome in 2007, Rett syndrome and Angelman syndrome in 2007, and Tuberous Sclerosis in 2008.

Weidong Li and Steven Kushner led a team in the Silva lab that developed a treatment for the cognitive deficits associated with an animal model of Neurofibromatosis type I (NF1).

They discovered that Lovastatin, a statin that crosses the blood–brain barrier, at a dose that does not affect control mice, rescues the Ras/MAPK signaling, synaptic plasticity and behavioral deficits of mice with a NF1 mutation.

Statins decrease the levels of isoprenyls, lipid groups that are required for the isoprenylation and activity of Ras, a signaling molecule normally regulated by the protein encoded by the NF1 gene.