Active Research Projects
- Balancing Excitation and Inhibition
- Restoring Neuronal Pathways
- Neurotransmitter Restoration
- New Technology, New Insights
- Sleep and Cognition
- Down Syndrome and Alzheimer’s Disease
- Drug Discovery
- Measuring the Efficacy of Potential Treatments
- The Down Syndrome Cognition Project (DSCP)
Balancing Excitation and Inhibition
Our initial grants funded new research that explored neural circuits that are involved with learning and memory. It is known that circuit actions are influenced by both excitatory and inhibitory inputs. In mouse models of Down syndrome it has been determined that the excitatory and inhibitory inputs are imbalanced in the hippocampus, an area of the brain critical for learning and memory processes. More specifically, in mouse models of DS an excess inhibition has been detected, a feature that appears to reduce the ability of circuits to change as part of the learning process. These findings continue to be the basis for a number of research projects that seek to restore an effective balance and improve learning and memory in Down syndrome.
LuMind RDS-supported researchers at Stanford University are continuing to study the multiple subtypes of GABA-A receptors. GABA is a small neurotransmitter molecule that is responsible for inhibition within neural circuits. Researchers at Stanford previously demonstrated that by blocking GABA-A receptors it is possible to restore excitatory and inhibitory balance in the neural circuits in the hippocampus and significantly improve learning and memory in a mouse model for Down syndrome. The scientists (Drs. Craig Heller, Craig Garner and colleagues) at Stanford are continuing to improve understanding of the potential for a GABA-A receptor-mediated therapy by defining the distinct properties and pharmacological sensitivities of the GABA-A subtypes.
LuMind RDS-supported researchers at UCSD have also been studying the excitatory and inhibitory imbalance in mouse models for Down syndrome and the accompanying structural and functional changes. These researchers have shown that the functional changes, including impairment of learning and memory, can be significantly overcome by blocking both GABA-B receptors and GIRK2 potassium channels in inhibitory neurons. GIRK2 potassium channels also specifically modulate neurotransmission, and are encoded by a human chromosome 21 gene which is over-expressed in mouse models for Down syndrome.
Researchers at Johns Hopkins University are also studying the process by which excitatory and inhibitory inputs to the hippocampus can be balanced to support learning and memory. Drs. Paul Worley and Connie Smith-Hicks are investigating additional alternative approaches to restore the balance at a level similar to that found in a typical hippocampus.
As a significant part of the LuMind RDS Research Strategy to engage pharmaceutical companies in advancing new effective and safe therapies, LuMind RDS’s research leadership initiated ongoing discussions and work with Roche, a major international pharmaceutical company, several years ago. In September, 2011, Roche announced the initiation of a Phase 1 clinical trial of a new investigational drug to evaluate the safety and tolerability of a molecule designed to address the cognitive and behavioral deficits associated with Down syndrome. This new investigational drug is being assessed for its ability to address the excitatory and inhibitory imbalance by targeting the GABAergic system through a specific GABA-A receptor subtype.
Dr. Roger Reeves’ lab at Johns Hopkins University has determined that a certain population of cerebellar neurons is compromised due to a decreased response to the SHH growth factor. Using a compound, SAG, that mimics the effects of SHH, in a mouse model for Down syndrome, these LuMind RDS-supported researchers were able to normalize the development of the cerebellum and restore function in a key learning and memory test of the hippocampus in these mice. This improvement had a surprising range of positive effects on brain function. Ongoing studies are further investigating the positive effects of SAG in the mouse model for Down syndrome.
Dr. William Mobley of UC San Diego and Dr. Ahmad Salehi of the VA Palo Alto Health Care System identified that LC neurons, which are a principal site for the synthesis of the neurotransmitter norepinephrine with input to the hippocampus, degenerate in mouse models of Down syndrome and Alzheimer’s disease and result in reduction in levels of norepinephrine and associated neurotransmission. The shortage of norepinephrine results in an inability to process sensory and navigational information. By administering two different potential drug compounds that restored norepinephrine levels, contextual learning and memory was also significantly restored. Additional investigation and testing of the two drug compounds and others continues.
New technologies recently developed at Stanford University, array tomography and optogenetics, are being utilized by Drs. Craig Heller’s and Craig Garner’s labs to study structure and function of neural circuits in mouse models of Down syndrome. Array tomography permits studies of anatomy and protein expression at high resolution in brain slices. The lab’s initial studies are focused in the hippocampus on proteins that are expressed at synapses, the site of connection between neurons. Optogenetic technology allows specific experimental control of neural activity. This technology is being used to investigate sleep and circadian rhythm functions.
LuMind RDS-supported researcher Dr. Jon Pierce-Shimomura, at the University of Texas, Austin, have been investigating the high-throughput development of new animal models for Down syndrome using C. elegans, a major, long-standing experimental laboratory organism, together with a novel high-throughput screening system to evaluate neurobiological function, mechanisms, behaviors and drugs as well as identify potential novel therapeutic targets and drugs. Recently, Dr. Pierce-Shimomura together with an engineering colleague at the University of Texas, Austin, were also awarded a NIH Director’s Transformative Research Grant, for approximately $3 million in funding over 5 years, to extend and further the development of the new high-throughput screening technology for neurodegenerative conditions, including Down syndrome.
LuMind RDS-supported researchers at Stanford University are investigating and characterizing abnormalities in sleep structure and its related brain rhythms in mouse models of Down syndrome. The studies are directed at determining if normalizing sleep structure improves learning and memory.
It is generally known that there is a high incidence of sleep apnea in the Down syndrome population. Drs. Lynn Nadel and Jamie Edgin of the University of Arizona are examining a possible correlation of cognitive status and abilities with sleep apnea and disturbances in individuals with Down syndrome.
The APP protein, which is the product of a gene on human chromosome 21, contributes to the degeneration of specific neuronal circuits important for learning and memory. This same neuronal degeneration is also a characteristic feature of Alzheimer’s disease. Dr. Mobley and his colleagues at UCSD are continuing to investigate the genetic, molecular and cellular mechanisms that lead to learning and memory difficulties, including association with Alzheimer’s disease and to test small molecules and compounds that would reduce the level of the APP protein in mice and lead to the improvements in cognition and halt neurodegeneration of affected neuronal circuits.
Previous LuMind RDS-funded studies have identified promising candidates for pharmacotherapy in Down syndrome. The following drugs, compounds and molecules are in various stages of investigation in mouse models of DS to determine efficacy, dosage amount, dosage frequency and routes of administration:
- Pentylenetetrazol or PTZ – for reducing inhibition in neural circuits and restore cognitive function
- L-DOPS – to restore the ability to process sensory and navigational information
Drs. Lynn Nadel and Jamie Edgin of the University of Arizona have developed and are continuing to refine and validate and optimizing the Arizona Cognitive Test Battery (ACTB). This battery of tests offers the ability to more specifically assess the efficacy of interventions in eventual clinical trials. Current enhancements to the test battery include increased correlation with the cognitive tests on mice, extending battery tests to younger and older age groups, addition of tests for speech and communication improvement, and identification of potential biomarkers for cognitive function. This will improve the predictability and evaluation of drug efficacy in moving testing in mice through to human trials.
The Down Syndrome Cognition Project (DSCP) benefits from a “Virtual Network” which includes investigators at Johns Hopkins University, Emory University, University of Arizona, Kennedy Krieger Institute, the Mind Institute, UC, Davis, National Children’s Medical Center in Washington, DC, University of Pittsburgh, Oregon Health and Science University, and the Waisman Center/University of Wisconsin. The formally networked group, now including 10 research investigators, is investigating the genetic basis for the high degree of variability in the cognitive ability of different persons with Down syndrome. The project utilizes the new Arizona Cognitive Test Battery. In addition, the collection of DNA samples and cognitive profiles from individuals with Down syndrome and their parents will provide the basis for genetic analyses to identify targets for potential therapeutic interventions.
The bio-banking infrastructure (for the DNA samples) and secure database (for medical record information) provide important elements that can contribute to a national Down syndrome registry. The Virtual Network also represents a series of potential test sites for clinical trials.