4th International Conference on Neurology and Brain Disorders

September 09-11, 2021

September 09 -11, 2021 | Virtual Event
INBC 2017

Lynda El-Hassar

Speaker at International Conference on Neurology and Brain Disorders 2017 - Lynda El-Hassar
Yale School of Medicine, United States
Title : Modulators of Kv3 channels regulate firing rate and temporal accuracy of auditory brainstem neurons in a mouse model of Fragile X syndrome

Abstract:

Fragile X syndrome (FXS) is the most common form of inherited intellectual disability. In common with autism, FXS is characterized by hypersensitivity to many types of sensory stimuli, including environmental sounds. Our previous work has shown that mice lacking the gene for FMRP (Fmr1-/y or Fragile X mice) have abnormally elevated levels of Kv3.1 potassium currents (“high threshold” K+ currents) and significantly decreased levels of Na+-activated K+ currents in auditory brainstem neurons in the medial nucleus of the trapezoid body (MNTB). Both of these changes in K+ currents are predicted to increase the firing rate of the postsynaptic neurons and to substantially degrade the accuracy of timing of action potentials. Consistent with this, we have found that the firing pattern of MNTB neurons in response to stimulation is severely abnormal in Fragile X mice. The threshold for action potential generation is significantly reduced in Fragile X mice over that in wild type mice. Moreover, in contrast to MNTB neurons from wild type animals, sustained depolarization triggers repetitive firing rather a single action potential at the onset of a stimulus pulse. We have also found that wave IV of the Auditory Brainstem Response (ABR) recorded in vivo is significantly enhanced in Fragile X mice, suggesting that loss of FMRP alters central processing of auditory signals. Based on these results we are now testing, in Fragile X mice, the physiological effects of potential therapeutic compound, AUT2, which modulate the activity of Kv3 family channels in cell lines. We found that, in Fragile X mice, AUT2 improved the accuracy of timing of action potentials in response to repetitive stimulation, presumably by shifting the activation curve of high threshold potassium currents to hyperpolarizing potentials, thereby increasing the low threshold potassium currents and restoring the accuracy and the timing of action potentials.

Audience take away:

  • This work will help provide alternative strategies to cure symptoms of fragile syndrome.
  • The results presented here will help the audience to think about alternative mechanisms to rescue deficits observed in brain disorders.
  • This is typically the type of research that could be useful for teaching as it illustrates how deficit in a single protein can alter neuronal function through different pathways and mechanisms.
  • This work can create collaborations with pharmaceutical companies in order to develop clinical trials.

Ultimately, this finding suggests that pharmaceutical modulation of Kv3.1 currents represents a novel avenue for manipulation of neuronal excitability, and has the potential for therapeutic benefit in the treatment of hearing disorders.

Biography:

Lynda El-Hassar is a research scientist working currently at Yale School of Medicine in the Neurobiology and Pharmacology departments. As electrophysiologist in brain slices of rodents, she focuses her research on the functional reorganization of voltage-gated potassium channels, ionotropic and metabotropic glutamatergic receptors involved in neurological disorders such as Epilepsy, Schizophrenia abd Fragile X syndrome.

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