| |
 L. Kaczmarek |
Leonard K. Kaczmarek, PhD
Principal Investigator
Jack Kronengold, PhD
Postdoctoral Fellow
Yale University School of Medicine
FRAXA Awards:
$40,000 in 2007
$40,000 in 2006
by Leonard Kaczmarek and Jack Kronengold, updated 4/2007
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 Mental Retardation 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.
more FRAXA research reports
