Garner Lab Research Areas
Neurodevelopmental Disorders
A new direction for the laboratory has been to link changes in synaptic plasticity to cognitive deficits in individuals with inborn genetic lesions such as Down syndrome and autism. Current efforts are directed towards two goals: 1) understanding the root causes of behavioral and cognitive impairments in individuals with Down syndrome and autism and 2) develop treatment strategies to normalize these indices. To accomplish these goals, we study the characteristics of mouse models that are analogous to the human condition. For example, we routinely use the Ts65Dn mouse (created by Muriel Davisson at the Jackson Laboratories in Bar Harbor, Maine) for our studies of cognitive impairment in Down syndrome.
With regard to our Down syndrome related projects, we are addressing several questions. Does the nervous system of these mice develop normally? For example, do neurons differentiate and form synaptic contacts at normal rates and numbers? Are the circuit properties of neuronal networks in these mice altered and at what developmental stage does this begin to appear?
Our ongoing studies indicate that neuronal differentiation and synaptogenesis is normal in these mice, yet the circuit properties of neuronal networks are subtly altered such that normal synaptic plasticity mechanisms are impaired (Hansen et al., 2007). Of particular note, we find that the balance of excitation and inhibition in the brains of these mice is shifted such that there is too much inhibition.
These studies have lead to new questions, including whether these changes in neuronal excitability and synaptic plasticity lead to alterations in behavior and cognitive performance in these mice and whether drugs that reduce inhibition can normalize cognitive performance. In an elegant study by Fabian Fernandez (at that time a graduate student in the laboratory), we have found that the answer to both of these questions is “yes.” Specifically, he found that Ts65Dn mice, similar to humans with Down syndrome, have reduced hippocampus-dependent cognitive abilities. Moreover, he found that by reducing inhibition in the brains of these mice, with non-competitive GABAA receptor antagonists, Ts65Dn mice perform a variety of memory tasks at levels identical to wild type mice (Fernandez et al., 2007). These results suggest that by subtly reducing inhibition in individuals with Down syndrome, some therapeutic benefit can be achieved (Fernandez and Garner, 2007).
Clearly, translating findings in mice to humans is a challenging endeavor and can take years to achieve. To make this dream a reality, we have expanded our Down syndrome research program to test the safety and efficacy of a number of different drugs in mice with the vision of moving the best and safest drugs into the clinic. These preclinical studies are being performed with Dr. H Craig Heller, a premier sleep scientist here at Stanford. In this work, we have been able to repeat the studies performed by Dr. Fabian Fernandez. Moreover, we could show that at low doses, GABAA receptor drugs can be administered safely, while normalizing cognition.
These fundamental studies have laid the foundation for a clinical trial based on these drugs. With your help, we can make this dream to help children and adults with Down syndrome a reality.
See also
The work described here was supported by grants from the National Institutes of Health, the Nancy Pritzker Foundation, the Hillblom Foundation, the Down syndrome research and treatment foundation (dsrtf.org), the Deutsche Forschungsgemeinschaft (DFG) and US-Israel Binational Science Foundation (BSF) .
