With $80,000 in funding from FRAXA over several years, the Yale University team of Leonard Kaczmarek, PhD showed that loss of FMRP leads to an increased Kv3.1 potassium currents. This change impairs timing of action potentials in auditory neurons (and likely others throughout the brain).
Individuals with Fragile X Syndrome exhibit extreme sensitivity to auditory stimuli. The debilitating behavioral symptoms associated with “sensory overload” interfere with attention, learning, language development and social interactions and are likely due to changes in synaptic connections in the auditory circuitry.
Studies have shown that the Fragile X knockout mouse also exhibits abnormal sensitivity to auditory stimuli including hyper reactivity and the induction of audiogenic seizures by acoustic stimulation. While audiogenic seizures have not been reported in Fragile X patients, the onset and manifestation of autistic behavior in these individuals has been directly correlated with auditory hypersensitivity. The source of the audiogenic seizures is believed to be due to increased excitation in auditory nuclei and not to an overall increase in brain excitability.
A paper in Cell by Darnell et al. (2001) has identified the mRNA for the voltage gated potassium (K+) channel, Kv3.1, as a candidate “binding target” for the Fragile X Protein (FMRP). The absence of FMRP in the Fragile X knockout mouse would be expected to result in the altered regulation of Kv3.1 which is critical for normal synaptic function. The goals of this project are to determine the changes in expression of Kv3.1 in auditory neurons of the Fragile X knockout mouse. The Kv3.1 channel, which belongs to the Kv3 family of voltage-dependent K+ channels, is found at particularly high levels in neurons of auditory nuclei. The biophysical properties of the Kv3.1 channel impart a “fast spiking” (FS) phenotype to neurons that need to fire repetitively at high frequencies, in response to high frequency stimuli. Moreover, the response to all sound frequencies is dependent on a precise tonotopic expression of Kv3.1 in neurons of the auditory nuclei. Disruption of this auditory space code, or map, by altered regulation of Kv3.1, would be expected to interfere with auditory processing in auditory nuclei of the brain stem and in the auditory cortex.
We have identified a new FMRP-interacting protein which is widely expressed in neurons in many parts of the brain. We are currently examining its function in the auditory brainstem and how this is likely to be misregulated in Fragile X and Autism Spectrum Disorder individuals.
Our project now includes not only studies of the Kv3.1 channel but of the newly discovered protein as well. Because of the exciting discoveries centered around the mGluR theory of Fragile X, we have added studies involving the inferior colliculus, a brain region which expresses high levels of mGluR5. Fortuitously, we can study all these components simultaneously in neurons of the auditory brainstem.