Overview
Development, integration and function of newborn neurons in the adult brain
Our laboratory focuses on two debilitating and potentially related diseases; epilepsy and autism. Epilepsy is the most common disease associated with autism, and therefore it is likely that the two disorders share common etiologies. Unfortunately, neither preventatives nor cures exist for either disease. To address this problem, our research seeks to elucidate the basic mechanisms underling the development of these diseases. By understanding how these diseases come about in the first place, we can begin to develop new and more effective treatments.
Diseases affecting the developing brain have proven to be among the most devastating and difficult to treat ailments faced by children today. Many of these diseases can be hard to diagnose, lack effective treatments, and become progressively worse with time. Further hampering treatment efforts, developing neurons are extremely vulnerable to a wide range of insults. Their growth can be disrupted directly by the disease process, secondarily as normal brain regions fail to develop properly due to abnormal activity in the affected brain region, and even as unwanted side affects from medications needed to control debilitating symptoms, such as seizures. One brain region that is particularly vulnerable is the hippocampal dentate gyrus. These neurons are among the last to be generated in the brain, and in fact, are one of the few populations of neurons produced in the adult brain. The late production of these neurons is likely related to the important role they play in later developing skills, such as language, cognition and memory. Their late production, however, may also render them vulnerable to brain insults occurring late in development. Indeed, impaired granule cell function is implicated in a host of diseases, including epilepsy and autism.
Aberrant integration of granule cells may underlie the development of epilepsy
In the epileptic brain, hippocampal dentate granule cells develop aberrant excitatory connections with other dentate granule cells. These aberrant connections create "short circuits" in the brain which are believed to contribute to hyperexcitability and seizures. Continued accrual of these abnormalities may underlie progression of the disease. Recent work from our laboratory has demonstrated that in adult epilepsy models, newborn granule cells underlie the formation of many of these short circuits (Walter et al., 2007). Ongoing studies seek to confirm (or refute) the pro-epileptogenic role of these newly-generated neurons, and to elucidate the mechanisms regulating the aberrant integration of these new cells. Elucidating the structural and functional changes required for epileptogenesis will reveal novel drug targets that will enable us to develop new therapies to treat, and hopefully cure, epilepsy.
Disrupted granule cell integration in the autistic brain
The pathological changes leading to the development of autism are still unclear. Autistic children do, however, exhibit significant structural abnormalities in the hippocampus, suffer from impairments in a variety of hippocampal-dependant tasks, including language development, and surprisingly, frequently have epilepsy. Indeed, up to 30% of children with severe forms of autism also have epilepsy, raising the possibility that the two diseases share a common etiology. To explore this possibility, we are examining the impact of disrupting postnatal granule cell development on the acquisition of autistic-like phenotypes and seizures. Determining whether and how disrupted granule cell integration contributes to the pathogenesis of autism will help to focus research efforts and provide insights into possible treatments.
Approach
We utilize a variety of techniques to examine the development of newborn neurons in the brain, including models of epilepsy and autism, confocal microscopy, immunohistochemistry, electrophysiology, organotypic slice culture, labeling of neurons with fluorescent proteins using in vitro and transgenic approaches, and genetic manipulations of target proteins. The laboratory is also equipped to do real-time imaging of living neurons in cell and organotypic cultures.
Our laboratory participates in the Neuroscience Graduate Program the Molecular and Developmental Biology Graduate Program, and the Physician Scientist Training Program. We also offer programs for training clinicians (both fellows and residents) in basic neuroscience research. Inquiries from interested trainees are always welcome.
Neurodevelopmental Disease Research Laboratory Members
- Stefanie Bronson, Graduate Student, Program in Neuroscience
- Brian Murphy, Graduate Student, Program in Neuroscience
- Raymond Pun, PhD, Research Associate
- Cynthia Walter, BA, Research Assistant
Selected References
Danzer, S.C. (2008) Postnatal and adult neurogenesis in the development of human disease. The Neuroscientist, in press.
Danzer, S.C., Kotloski, R.J., Walter, C., Hughes, M. and McNamara, J.O. (2008) Altered morphology of hippocampal dentate granule cell presynaptic and postsynaptic terminals following conditional deletion of TrkB. Hippocampus, in press.
Walter, C., Murphy, B.L., Pun, R.Y.K., Spieles-Engemann, A.L. and S.C. Danzer (2007) Pilocarpine-induced seizures cause selective time-dependent changes to adult-generated hippocampal dentate granule cells. Journal of Neuroscience, 27(28):7541-52.
Danzer, S.C. and McNamara, J.O. (2004) Localization of BDNF to distinct terminals of mossy fiber axons implies regulation of both excitation and feedforward inhibition of CA3 pyramidal cells. Journal of Neuroscience 24: 11346-11355.
Danzer, S.C., Pan, E., Nef, S., Parada, L.F., McNamara, J.O. (2004) Altered Regulation of BDNF Protein in Hippocampus Following Slice Preparation. Neuroscience 126(4):859-69.
Danzer, S.C., He, X.P. and McNamara, J.O. (2004) Ontogeny of Seizure-Induced Increases in BDNF Immunoreactivity and TrkB Receptor Activation in Rat Hippocampus. Hippocampus 14: 345-355.
Danzer, S.C., Crooks, K.R.C., Lo, D.C. and McNamara, J.O. (2002) Increased basal dendrites and axonal branching of BDNF-transfected dentate granule cells in hippocampal explant cultures. Journal of Neuroscience 22: 9754-9763.
Danzer, S.C., McMullen, N.T., and Rance, N.E. (1998) Dendritic Growth of Arcuate Neuroendocrine Neurons Following Orchidectomy in Adult Rats. Journal of Comparative Neurology, 390: 234-246.
"The ultimate goal of all science is the spiritual and material well being of all humanity"
Karl Heinrich Emil Koch, MD, 1840
