Julie Lauterborn, PhD
University of CA at Irvine, $40,000

This study complements Dr. Berry-Kravis’s clinical trial of the Ampakine drug CX516. Dr. Lauterborn aims to understand the actions of newer Ampakine compounds which are not yet tested for human use but which are more potent than CX516.

by Julie Lauterborn, 6/2003

Studies in Fragile X mice reveal abnormalities in the shape and number of dendritic spines (where neurons receive input from other neurons), similar to the abnormalities seen in brain cells of humans with Fragile X. In addition, in the Fragile X mouse there is less glutamate receptor protein in the forebrain, suggesting that cognitive deficits in this syndrome may arise from impaired maturation of glutamate spine synapses.

Stimulation of AMPA-class glutamate receptors leads to a normalization of spine shape and stimulates brain neurons to synthesize increased levels of Brain-Derived Neurotrophic Factor (BDNF). BDNF is known to reduce spine number and length, as well as to increase AMPA receptor protein levels. These findings suggest that in Fragile X (and in the mouse model), increases in both AMPA receptor and BDNF signaling may effect changes in synapses that should ameliorate deficits in neurotransmission.

Recently we demonstrated that Ampakines, which increase AMPA receptor function, also increase BDNF expression in normal rodents. The data suggest that Ampakines could be useful therapeutics for dendritic spine abnormalities and cognitive deficits associated with Fragile X. We will test the hypotheses that (1) the regulation of AMPA receptor expression within the cell membrane is similar in Fragile X knockout and wildtype mice and (2) Ampakine facilitation of AMPA receptor function can be used to sustain increases in neuronal BDNF protein content in Fragile X knockout neurons.