Drug fights hard-to-treat depression by targeting brain receptors in a new way

A first-of-its-kind antidepressant drug discovered by a Northwestern University professor and now tested on adults who have failed other antidepressant therapies has been shown to alleviate symptoms within hours, have good safety and produce positive effects that last for about seven days from a single dose. 

The novel therapeutic targets brain receptors responsible for learning and memory — a very different approach from existing antidepressants. The new drug and others like it also could be helpful in treating other neurological conditions, including schizophrenia, bipolar disorder, anxiety and Alzheimer’s disease.

The results of the phase IIa clinical trial were presented (Dec. 6) at the 51st Annual Meeting of the American College of Neuropsychopharmacology in Hollywood, Fla.

Also this week a paper reporting some of the background scientific research that provided the foundation for the clinical development of GLYX-13 was published by the journal Neuropsychopharmacology.

The compound, called GLYX-13, is the result of more than two decades of work by Joseph Moskal, research professor of biomedical engineering at Northwestern’s McCormick School of Engineering and Applied Science and director of the University’s Falk Center for Molecular Therapeutics.

New research investigates how the common ‘cat parasite’ gets into the brain

The Toxoplasma gondii parasite causes toxoplasmosis. The parasite is common and infects between 30 and 50 per cent of the global population. It also infects animals, especially domestic cats. Human infection is contracted by eating poorly cooked (infected) meat and handling cat feces. Toxoplasmosis first appears with mild flu-like symptoms in adults and otherwise healthy people before entering a chronic and dormant phase, which has previously been regarded as symptom-free. But when the immune system is weakened toxoplasmosis in the brain can be fatal. The fetus can be infected through the mother and because of this risk, pregnant women are recommended to avoid contact with cat litter boxes. Surprisingly, several studies in humans and mice have suggested that even in the dormant phase, the parasite can influence increasing risk taking and infected people show higher incidence of schizophrenia, anxiety and depression, which are broader public health concerns.

In their recent study Fuks et al. showed for the first time how the parasite enters the brain and increases the release of a neurotransmitter called GABA (gaba-Aminobutyric acid), that, amongst other effects, inhibits the sensation of fear and anxiety. In one laboratory experiment, human dendritic cells were infected with toxoplasma. After infection, the cells, which are a key component of the immune defense, began actively releasing GABA), In another experiment on live mice, the team was able to trace the movement of infected dendritic cells in the body after introducing the parasite into the brain, from where it spread and continued to affect the GABA system.

"For toxoplasma to make cells in the immune defense secrete GABA was as surprising as it was unexpected, and is very clever of the parasite," says Antonio Barragan, researcher at the Center for Infectious Medicine at Karolinska Institute and the Swedish Institute for Communicable Disease Control. "It would now be worth studying the links that exist between toxoplasmosis, the GABA systems and major public health threats."

Discovery of pathway leading to depression reveals new drug targets

Scientists have identified the key molecular pathway leading to depression, revealing potential new targets for drug discovery, according to research led by King’s College London’s Institute of Psychiatry. The study, published in Neuropsychopharmacology, reveals for the first time that the ‘Hedgehog pathway’ regulates how stress hormones, usually elevated during depression, reduce the number of brain cells.

Depression affects approximately 1 in 5 people in the UK at some point in their lives. The severity of symptoms can range from feelings of sadness and hopelessness to, in the most severe cases, self-harm or suicide. Treatment for depression involves either medication or talking treatment, or usually a combination of the two.

Recent studies have demonstrated that depression is associated with a reduction in a brain process called ‘neurogenesis’- the ability of the brain to produce new brain cells. However, the pathway responsible for this process has, until now, remained unknown.

In this study, Dr Christoph Anacker from the Centre for the Cellular Basis of Behaviour (CCBB) at King’s Institute of Psychiatry and his team studied human stem cells, which are the source of new cells in the human brain, to investigate the effect of stress hormones on brain cell development. The study was funded by the National Institute for Health Research Biomedical Research Centre for Mental Health at the South London and Maudsley NHS Foundation Trust and King’s College London and the Medical Research Council UK.

Stress hormones, such as cortisol, are generally elevated in stress and depression. The team studied stem cells in a laboratory and found that high concentrations of cortisol damaged these stem cells and reduced the number of newborn brain cells. They discovered that a specific signalling mechanism in the cell, the ‘Hedgehog pathway’, is responsible for this process. Then, using an animal model, the team confirmed that exposure to stress inhibited this pathway in the brain.

Finally, in order to test the findings, the researchers used a compound called purmorphamine, which is known to stimulate the Hedgehog pathway. They found that by using this drug, they were able to reverse the damaging effects of stress hormones, and normalise the production of new brain cells.

The many maps of the brain

Your brain has at least four different senses of location – and perhaps as many as 10. And each is different, according to new research from the Kavli Institute for Systems Neuroscience, at the Norwegian University of Science and Technology.

The findings, published in the 6 December 2012 issue of Nature, show that rather than just a single sense of location, the brain has a number of “modules” dedicated to self-location. Each module contains its own internal GPS-like mapping system that keeps track of movement, and has other characteristics that also distinguishes one from another.

"We have at least four senses of location," says Edvard Moser, director of the Kavli Institute. "Each has its own scale for representing the external environment, ranging from very fine to very coarse. The different modules react differently to changes in the environment. Some may scale the brain’s inner map to the surroundings, others do not. And they operate independently of each other in several ways."

This is also the first time that researchers have been able to show that a part of the brain that does not directly respond to sensory input, called the association cortex, is organized into modules. The research was conducted using rats.

Johns Hopkins Surgeons Implant First Brain ‘Pacemaker’ for Alzheimer’s Disease in United States as Part of a Clinical Trial Designed to Slow Memory Loss

Researchers at Johns Hopkins Medicine in November surgically implanted a pacemaker-like device into the brain of a patient in the early stages of Alzheimer’s disease, the first such operation in the United States. The device, which provides deep brain stimulation and has been used in thousands of people with Parkinson’s disease, is seen as a possible means of boosting memory and reversing cognitive decline.

The surgery is part of a federally funded, multicenter clinical trial marking a new direction in clinical research designed to slow or halt the ravages of the disease, which slowly robs its mostly elderly victims of a lifetime of memories and the ability to perform the simplest of daily tasks, researchers at Johns Hopkins say. Instead of focusing on drug treatments, many of which have failed in recent clinical trials, the research focuses on the use of the low-voltage electrical charges delivered directly to the brain. There is no cure for Alzheimer’s disease.

As part of a preliminary safety study in 2010, the devices were implanted in six Alzheimer’s disease patients in Canada. Researchers found that patients with mild forms of the disorder showed sustained increases in glucose metabolism, an indicator of neuronal activity, over a 13-month period. Most Alzheimer’s disease patients show decreases in glucose metabolism over the same period.

The first U.S. patient in the new trial underwent surgery at The Johns Hopkins Hospital, and a second patient is scheduled for the same procedure in December. The surgeries at Johns Hopkins are being performed by neurosurgeon William S. Anderson, M.D.

The surgery involves drilling holes into the skull to implant wires into the fornix on either side of the brain. The fornix is a brain pathway instrumental in bringing information to the hippocampus, the portion of the brain where learning begins and memories are made, and where the earliest symptoms of Alzheimer’s appear to arise. The wires are attached to a pacemaker-like device, the “stimulator,” which generates tiny electrical impulses into the brain 130 times a second. The patients don’t feel the current, says Paul B. Rosenberg, M.D., an associate professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine, and site director of the trial’s Johns Hopkins location. 

Mammalian brain knows where it’s at

A new study in the journal Neuron suggests that the brain uses a different region than neuroscientists had thought to associate objects and locations in the space around an individual. Knowing where this fundamental process occurs could help treat disease and brain injury as well as inform basic understanding of how the brain supports memory and guides behavior.

“Understanding how and where context is represented in the brain is important,” said study senior author Rebecca Burwell, professor of psychology and neuroscience at Brown University. “Context, or the place in which events occur, is the hallmark of episodic memory, but context is more than a place or a location. This room, for example, has a window, furniture, and other objects. You walk into a room and all that information helps you remember what happened there.”

Pinpointing where the brain puts together objects and places to form a context could also matter for treating traumatic brain injuries or neuropsychiatric diseases, such as schizophrenia and depression, that involve that part of the brain, said Burwell, who is also affiliated with the Brown Institute for Brain Science.

“We know that contextual representations are disrupted in mental disorders, particularly schizophrenia and depression,” Burwell said. “Individuals with these disorders have trouble using context to plan actions or choose appropriate behaviors.”

After 100 Years, Understanding the Electrical Role of Dendritic Spines

It’s the least understood organ in the human body: the brain, a massive network of electrically excitable neurons, all communicating with one another via receptors on their tree-like dendrites. Somehow these cells work together to enable great feats of human learning and memory. But how?

Researchers know dendritic spines play a vital role. These tiny membranous structures protrude from dendrites’ branches; spread across the entire dendritic tree, the spines on one neuron collect signals from an average of 1,000 others. But more than a century after they were discovered, their function still remains only partially understood.

A Northwestern University researcher, working in collaboration with scientists at the Howard Hughes Medical Institute (HHMI) Janelia Farm Research Campus, has recently added an important piece of the puzzle of how neurons “talk” to one another. The researchers have demonstrated that spines serve as electrical compartments in the neuron, isolating and amplifying electrical signals received at the synapses, the sites at which neurons connect to one another.

The key to this discovery is the result of innovative experiments at the Janelia Farm Research Campus and computer simulations performed at Northwestern University that can measure electrical responses on spines throughout the dendrites.

A paper about the findings, “Synaptic Amplification by Dendritic Spines Enhances Input Cooperatively,” was published November 22 in the journal Nature.

“This research conclusively shows that dendritic spines respond to and process synaptic inputs not just chemically, but also electrically,” said William Kath, professor of engineering sciences and applied mathematics at Northwestern’s McCormick School of Engineering, professor of neurobiology at the Weinberg College of Arts and Sciences, and one of the paper’s authors.