Dendrites form the primary receptive surface for synaptic connections, but key questions still remain about how dendrite field size, geometry and synaptic density are regulated. In the context of development, data obtained from addressing these questions would be immediately relevant to a wide array of human neurodevelopmental disorders. Further, mechanisms of initial morphogenesis of postsynaptic structure are thought to have mechanistic parallels between later experience-dependent plasticity associated with memory and recovery from brain injury. Here, we focus on the role of the astroglia cell, a newly-recognized partner in synapse formation, in regulating neuron development. Proposed experiments exploit primary cultures of dissociated hippocampal neurons as a bioassay to detect the influence of astrocytes on synaptic formation between developing neurons. Our preliminary data confirm previous reports from retinal ganglion cell culture that soluble factors released by astroglia regulate synapse formation. We also have evidence that astroglial secretions inhibit dendritic growth in a manner that may shift neurons from an intrinsic program of branch formation to an extrinsically-mediated readiness for synapses.
In Specific Aim 1, we will manipulate neuron-glia interactions, comparing conditions that model the in vivo state of physical contact to a co-culture condition that allows only soluble signals from glia to reach neurons.
Aim 2 uses markers of pre- and postsynaptic specializations to determine if astroglia differentially affect maturation of these compartments in excitatory vs. inhibitory neurons. Guided by the data of Aims 1 and 2, Specific Aim 3 will test individual glial signals with over-expression and RNAi knock-down experiments.
The proposed studies characterize the relationship between glial cells and synapse development. There is a diverse array of postnatal neurodevelopmental disorders (mental retardation, Rhett's syndrome, autism) as well as many genetically-determined disorders (e.g. Down's and Fragile X) that are poorly understood at the cell biological level, but clearly associated with abnormal synapse formation. Previous studies have focused exclusively on neurons, but the active role of glial in regulating neuron maturation can no longer be denied. The proposed work will advance our understanding of the mechanisms by which glial cells influence synapse formation, to further our understanding of normal and pathological neural development.
| Wallace, Christopher S; Withers, Ginger S; Farnand, Alex et al. (2011) Evidence that angiogenesis lags behind neuron and astrocyte growth in experience-dependent plasticity. Dev Psychobiol 53:435-42 |
| Withers, Ginger S; Wallace, Christopher S; Gibbs, Elizabeth M et al. (2011) Synapses on demand require dendrites at the ready: how defining stages of dendritic development in vitro could inform studies of behaviorally driven information storage in the brain. Dev Psychobiol 53:443-55 |
