With $40,000 in funding from FRAXA Research Foundation in 2005, Dr. Karel Svoboda and his team at the Cold Spring Harbor Laboratory imaged neocortical circuits in Fragile X mice to determine the functions of the abnormal dendritic spines found in Fragile X syndrome.
Ingrid Bureau, PhD
FRAXA Postdoctoral Fellow (2005)
Adam Oberlander, PhD
Technician (2005)
by Ingrid Bureau, 6/1/2005
One notable feature of Fragile X syndrome are structural abnormalities of dendritic spines in neocortical pyramidal neurons. Dendritic spines are tiny appendages that stud the surface of most neurons in the cerebral cortex. They are the receiving end of most synapses and as a result they play a pivotal role in the communication between neurons.
In patients with Fragile X syndrome, dendritic spines are unusually abundant and tend to have relatively immature forms. This phenotype is also seen in fmr1 knock-out mice, the dominant animal model of Fragile X syndrome. We do not know, however, whether these structural abnormalities in dendritic spines are related to changes in the structure and function of synaptic circuits in the cerebral cortex. More spines may indicate more abundant and promiscuous connections. Ultimately, intellectual disability syndromes must have a basis in the neural circuits.
We propose to unravel changes in neocortical circuits in fmr1 knock-out mice (the mouse model of Fragile X syndrome). Our studies will be in the barrel cortex, an area in the somatosensory cortex that responds to whisker stimulation. This is a suitable model because FMRP expression is regulated by whisker stimulation. In addition, the barrel cortex is widely used to study the development and plasticity of cortical connectivity. We use laser scanning photo-stimulation to map the pattern of neuronal connectivity in brain slices. This method provides an ‘image’ of functional connectivity impinging onto individual neurons. We will map excitatory synaptic pathways onto neurons from different layers in the barrel cortex of fmr1 knockout mice and compare them to wild-type littermates.
If we discover significant circuit differences in fmr1 knock-out mice, we propose to reintroduce the missing gene in utero directly into specific populations of neurons and determine whether this manipulation is sufficient to correct the defect. Our study may provide a view into circuit mechanisms of Fragile X and provide new tools to study fmr1 biology.
