Johns Hopkins Researchers at Society For Neuroscience Annual Meeting
GETTING TO THE ROOT OF MENTAL ILLNESS
--Gene combined with viral infection could predispose toward several major mental disorders
Program #96.1, Poster #EE91; South Hall A; Saturday, Oct. 17, 1-2 p.m.
Using mice that carry a human gene variant previously linked to schizophrenia, Johns Hopkins researchers have found a connection between viral infection during gestation and adult behavior reminiscent of several major mental disorders, including depression and autism.
The mice used in the study, led by Bagrat Abazyan, M.D., postdoctoral fellow in the laboratory of Johns Hopkins associate professor Mikhail Pletnikov, M.D., Ph.D., were bred to carry a mutant version of the hDISC1 gene. The gene’s name is an acronym for “disrupted in schizophrenia 1.” The mutated version of the gene was discovered nearly a decade ago in a large Scottish family with an unusually high incidence of schizophrenia.
Previous studies have linked viral infections, such as the flu, during gestation with increased risk of schizophrenia later in life, so Abazyan and his colleagues decided to combine both DISC1 and viral infection to see how these factors together might affect behavior. The researchers injected pregnant mice carrying offspring with the variant of hDISC1 linked to schizophrenia with a synthetic nucleic acid that simulates immune activation produced by viral infection. Other pregnant mice carrying hDISC1 offspring were injected only with saline. After the offspring were born and grew into adulthood, the scientists administered a battery of behavioral tests.
In a test where the mice were forced to swim in a pool, those whose mothers had the simulated viral infection spent more time floating, a behavior widely thought to mimic depression in people, than the saline-exposed offspring. In another test, where mice were encouraged to explore the enclosed or open arms of a maze shaped like a “plus” sign elevated high off the ground, the simulated virus-exposed mice spent more time than the saline-exposed ones in enclosed arms of the maze, a behavior thought to signify anxiety. In a third test, where the mice had a choice between spending time with another mouse or inanimate objects, the simulated virus-exposed mice spent more time with objects than the saline-exposed mice, a behavior thought to mimic antisocial behavior in humans. Importantly, these behavioral effects were not present in other offspring that didn’t carry the mutant DISC1 gene, even if they were exposed to the same synthetic nucleic acid during gestation.
Abazyan notes that these findings suggest that the interaction between genes and viral infections might be responsible for many varieties of mental illness, not just schizophrenia. “The long-term goal is learning more about this interaction so that, eventually, we might be able to prevent these types of mental illness in people,” he says.
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RECEPTORS, SYNAPSES AND MEMORIES: RICHARD HUGANIR, PH.D.
Special Lecture; McCormick Place: Hall B1 Sunday, Oct. 18, 2009, 8:30 a.m.- 9:40 a.m.
Richard Huganir’s earliest work on memory and learning date precisely to 1970 when he carefully filled a 12th grade science notebook with handwritten data, documenting an ambitious investigation involving goldfish that was entitled: “Memory and Protein Synthesis.”
Fast-forward 20 years, and this retrospective lecture by Huganir begins in earnest. Now the director of the Solomon Snyder Department of Neuroscience at the Johns Hopkins University School of Medicine, Huganir will discuss the generation of a “forgetful” mouse. In this animal model, phosphorylation sites in the brain’s major excitatory receptors were mutated in order to better understand the mechanisms that regulate so-called “AMPA” receptors, which mediate about 70 percent of synaptic transmission in the brain. His team directly linked modification of receptor function to plasticity, learning, and memory retention and, in addition, detected defects in the emotional memories of these forgetful rodents.
More recently, Huganir’s lab has created a mouse with the opposite mutation: one that mimicks constant phosphorylation, in which the AMPA receptor is always primed. Huganir anticipates this will result in an animal that is smart but anxious as well as prone to drug addiction.
In addition to investigating plasticity in the hippocampal region of the brain, which is involved in memory encoding and spatial learning, Huganir’s lab has probed plasticity in the cerebellum, which is responsible for fine motor control and motor learning.
Huganir’s overview will span decades of brain research and include discussion of his study published earlier this year revealing how his team watched florescent-tagged receptors strengthen synapses — in essence, how they watched learning in real time.
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SPEEDING DISCOVERY: THE NOSE KNOWS
Program #118.10, Room S404; Sunday, Oct 18, 2009, 10:15 a.m. -10:30 a.m.
Trying to understand neurological disease by studying cells in a dish is limited by the availability of the right cells. For years, researchers have relied on postmortem human brains as a source for schizophrenia-affected neurons. Now, Johns Hopkins researchers have developed a novel method via nasal biopsies of schizophrenia patients, establishing a faster way to make neurons in a dish for further study.
“Nasal biopsies are more efficient than the standard skin biopsy for use in conventional methods of generating induced pluripotent stem cells,” saysAkira Sawa, M.D., Ph.D., director of the program in molecular psychiatry at Johns Hopkins. “Our process takes two weeks, compared to the 12 months it might take to generate cells otherwise.”
Taking a tiny bit of skin tissue from inside of the nose, the researchers then grow that sample of cells in a dish. Nasal biopsies, unlike standard skin biopsies taken from an arm, contain neural stem cells, which, according to Sawa, grow more easily in a dish and thus provide more cells to work with. The team then separates the neural cells from the other cells in the biopsy with molecular tricks that they plan to patent.
“Critics have suggested that neuronal cells grown from the nose are not the same as those isolated from the brain,” says Sawa. “But we’ve tested them and they share many of the same markers and respond similarly to stimulation.”
The team hopes that these cells will be used by many to study conditions like schizophrenia, mood disorders, and other neuropsychiatric disorders, and provide a system to tease apart molecular mechanisms underlying the disease as well as response to drugs and potential treatments.
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NERVE TRANSPLANTS AS POSSIBLE TREATMENT FOR ALS-RELATED FOR ALS-RELATED RESPIRATORY FAILURE
Program #327.2, Poster G1; South Hall A, Monday, Oct. 19, 2009, 9 a.m. - 10 a.m.
Because the inability to breathe is an ultimate cause of death of patients with ALS, Johns Hopkins scientists are targeting the diaphragm as a therapeutic target by transplanting stem cells directly into rats’ cervical spinal cords, precisely where the motor neurons that control this respiratory muscle are located.
“We are transplanting stem cells that will become astrocytes because these cells play an important role in maintaining the health of motor neurons,” says Angelo Lepore, Ph.D., a postdoctoral fellow in the lab of Nicholas Maragakis, M.D., associate professor of neurology, Johns Hopkins University School of Medicine.
The team showed that transplanting rat-derived stem cells into the rodents’ cervical spinal cords helped slow down the decline of diaphragm function and therefore extended survival in the rat model of ALS. Their findings show that a targeted delivery of stem cells to the cervical spinal cord is a promising therapeutic strategy because even the partial rescue of motor neurons resulted in a decreased loss of respiratory function.
“I think that we first need to examine the potential of human-derived cells following transplantation before we can say whether this strategy will work in human patients,” Lepore says. “While the initial results are promising, a number of key experiments must be conducted before this therapy is translated to the clinic, including testing the efficacy of a similar class of human stem cells.”
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GINGKO DELIVERS STRIKE FOR STROKE
--Ancient herbal remedy keeps blood flowing in brain
Program #332.16, Poster #I37; South Hall A; Monday, Oct. 19, 11 a.m. – 12 a.m.
Gingko biloba has long been used as a remedy for a variety of ailments, from allergies to leg cramps to dementia. While many of these claims haven’t panned out in clinical trials, some evidence has shown that this herb could help stem stroke damage. Now, Johns Hopkins scientists have an explanation for this herb’s success in stroke: In a mouse model, gingko appears to help restore blood flow in the brain.
Sylvain Doré, Ph.D., associate professor of anesthesiology/critical care medicine and pharmacology and molecular sciences, and Zahoor Shah, Ph.D., a former instructor at Johns Hopkins who is now an assistant professor at the University of Toledo, pretreated some mice for seven days with a standardized extract of gingko or with a placebo. The researchers then simulated a stroke by blocking a major artery in the rodents’ brains. The team monitored blood flow before, during, and after the simulated stroke. They found that mice who received the gingko extract had significantly greater blood flow through the artery for at least 90 minutes after the stroke ended than mice who received the placebo.
The team also found that gingko delivered after a stroke can offer some therapeutic protection. Mice that weren’t pretreated with gingko but were fed the extract four hours after the simulated stroke had more than 20 percent less brain damage and fewer behavioral deficits than mice fed a placebo after the stroke.
Doré notes that in his previous studies, he’s shown that gingko extract appears to increase cell content of heme oxygenase-1, a protein that appears to protect nerves and has metabolites that dilate blood vessels. “For many herbal extracts, the benefits are anecdotal, but we’re narrowing down the basis for gingko’s success in protecting against stroke damage, at least in preclinical models,” he says. He and his team are currently working on defining which ingredients in gingko extract are responsible for this effect.