Yale University Archives • Fragile X Research

Novel Modulators of Potassium Channels to Treat Fragile X

FRAXA Research Foundation 2015 Grants • 2016 Grants • 2017 Grants • Disease Mechanisms • Kaczmarek, Leonard • Research Grant with Results • Treatment Targets • Yale University January 2, 2019April 2, 2019Autifony Therapeutics, autism, glutamate, hypersensitivity, ion channel, mGluR, mGluR5, mRNAs, potassium channels, sound

With funding from FRAXA over 2015-2017, the Yale University team of Leonard Kaczmarek, PhD showed that the firing patterns of auditory neurons in response to repeated stimulation is severely abnormal in Fragile X mice. Based on these results, they are collaborating with the UK-based company Autifony to develop advanced compounds which may reverse these deficits.

Inhibitors of STEP as a Novel Treatment of Fragile X Syndrome

FRAXA Research Foundation 2006-2010 Grants • 2011 Grants • 2014 Grants • 2015 Grants • Completed Research Grant • Disease Mechanisms • Lombroso, Paul • Research Grant with Results • Treatment Targets • Yale University February 26, 2015May 16, 2018AMPA, AMPAkines, autism, glutamate, LTD (Long-term depression), mRNAs, STEP (STriatal-Enriched protein tyrosine Phosphatase)

With a $349,000 grant from FRAXA Research Foundation from 2008-2015, Dr. Paul Lombroso and his team at Yale University researched if inhibiting STEP could reduce behavioral abnormalities in Fragile X syndrome. Results published.

Bcl-xL Inhibition as a Therapeutic Strategy for Fragile X Syndrome

FRAXA Research Foundation 2013 Grants • 2014 Grants • Completed Research Grant • Disease Mechanisms • FRAXA Research Grants • Jonas, Elizabeth • Levy, Richard • Treatment Targets • Yale University September 12, 2014April 25, 2018autism

Scientists have found increases in the numbers of neurons in brain regions of autistic children, suggesting a problem in developmental programmed cell death pathways. One of the most important effectors of neuronal survival during brain development is the “anti-cell death” protein Bcl-xL. While the normal function of Bcl-xL is to maintain a healthy number of neurons and synapses, over-expressed Bcl-xL can cause an overabundance of synaptic connections. This may be happening in Fragile X.

Potassium Channel Modulators to Treat Fragile X

FRAXA Research Foundation 2012 Grants • 2013 Grants • 2014 Grants • Kaczmarek, Leonard • Research Grant with Results • Treatment Targets • Yale University January 7, 2014June 13, 2019hypersensitivity, potassium channels, sound

With $246,000 in funding from FRAXA over 2012-2014, the Yale University team of Leonard Kaczmarek, PhD, showed that loss of FMRP leads to an increased Kv3.1 potassium currents and decreased Slack potassium currents in neurons. Both of these changes impair timing of action potentials in auditory neurons (and likely others throughout the brain). The team also found that the firing pattern of neurons in response to repeated stimulation is severely abnormal in Fragile X mice. Based on these results, they are collaborating with the UK-based company Autifony to develop and test advanced compounds which may reverse these deficits.

The Slack Potassium Ion channel as a Therapeutic Target for Fragile X Syndrome

FRAXA Research Foundation 2006-2010 Grants • Completed Research Grant • Kaczmarek, Leonard • Treatment Targets • Yale University June 8, 2011August 2, 2018potassium channels, sound

A paper on this work has been published in Journal of Neuroscience on 2010 August 4: Fragile X mental retardation protein is required for rapid experience-dependent regulation of the potassium channel Kv3.1b by Leonard Kaczmarek, PhD and Jack Kronengold, PhD Our laboratory has investigated how the excitability of neurons becomes modified in the absence of the FMRP protein. We have found that the levels of two potassium channels, termed Slack and Kv3.1 are altered in mice that lack this protein. We have made significant progress in identifying novel pharmacological activators of the Slack potassium channel for potential therapeutic intervention in FXS individuals. The Slack potassium channel is widely expressed in the brain. Using neurons of the central auditory system, our laboratory has demonstrated that Slack is required for accurate timing of action potentials in response to synaptic stimuli. This channel is activated by the FMRP protein through a direct association

The Slack Potassium Ion channel is a Therapeutic Target for Fragile X

FRAXA Research Foundation 2006-2010 Grants • 2011 Grants • Kaczmarek, Leonard • Treatment Targets • Yale University January 7, 2011January 9, 2019glutamate, mRNAs, potassium channels, sound

With a $282,000 funding from FRAXA Research Foundation, Dr. Leonard Kaczmarek and colleagues explored association of Slack channels with the Fragile X protein (FMRP).

Electrophysiological, Biochemical and Immunohistochemical Characterization of Kv3.1 in Auditory Brainstem Nuclei in the Fragile X Knockout Mouse

FRAXA Research Foundation 2006-2010 Grants • Kaczmarek, Leonard • Treatment Targets • Yale University January 9, 2007January 9, 2019autism, hypersensitivity, mGluR, mGluR5, sound

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).

Structure of FMRP

FRAXA Research Foundation 2001-2005 Grants • Completed Research Grant • Disease Mechanisms • Regan, Lynne • Yale University February 27, 2002August 2, 2018mRNAs

With a $68,000 grant from FRAXA Research Foundation from 2001-2002, Dr. Lynne Regan at Yale University studied different protein shapes and how they contributed towards different functions for Fragile X syndrome. Results published.