MSGID: 1:317/3 64b0cfa4   
   PID: hpt/lnx 1.9.0-cur 2019-01-08   
   TID: hpt/lnx 1.9.0-cur 2019-01-08   
    Boosting certain brain cells diminished hypersensitivity in Fragile X   
   mice    
      
     Date:   
         July 13, 2023   
     Source:   
         University of California - Los Angeles Health Sciences   
     Summary:   
         Study suggests modulating the activity of certain neurons could   
         be an effective approach to restoring circuit function.   
      
      
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   Boosting the activity of inhibitory interneurons in Fragile X mice   
   reduced their hypersensitivity to sensory stimuli, according to a new   
   Neuron study led by UCLA Health researchers.   
      
   Fragile X Syndrome, which is caused by a mutation in a single gene, is the   
   most common inherited form of intellectual disability and autism. Many   
   people with Fragile X are extremely sensitive to sights, sounds, and   
   touch, among other sensory experiences.   
      
   Previous research found Fragile X mice have a lower density of parvalbumin   
   (PV) inhibitory interneurons, the main class of inhibitory neurons in   
   the cerebral cortex -- the region of the brain responsible for sensory   
   processing. These neurons act like a brake on excitatory neurons to help   
   them fire only when necessary.   
      
   Because autism symptoms first appear during the toddler stage and likely   
   reflect changes in the brain that happened earlier, the researchers sought   
   to establish when the reduced activity of PV interneurons was first   
   apparent during brain development in mice -- and whether intervention   
   could help mitigate sensory hypersensitivity.   
      
   Researchers recorded neuronal activity in the brains of young mice during   
   the first two weeks of life. They then sought to influence this activity   
   through a novel drug compound that boosts the firing of PV neurons.   
      
   Researchers found that the density of PV neurons is indeed lower in   
   Fragile X mice compared to controls -- but even in mice as young as six   
   days old. There were also greater numbers of dying PV neurons during   
   early development in Fragile X mice, suggesting that these neurons are   
   dying at a higher rate than what is considered healthy.   
      
   They also found that PV neurons in young Fragile X mice were unable to   
   regulate the activity of excitatory neurons during the first two weeks   
   of development, indicating that these neurons are functionally decoupled   
   during this time. That could explain why researchers were able to restore   
   PV neuron density by boosting PV neuron activity during this period of   
   development but could not restore the activity of excitatory neurons.   
      
   Researchers then administered a novel drug compound aimed at activating   
   PV neurons in Fragile X mice during the third week of development. The   
   treatment restored the ability of excitatory neurons to respond to   
   touch, resembling how they function in healthy controls. It also reduced   
   hypersensitivity to repeated touch, which is similar to what is known   
   as tactile defensiveness in humans with Fragile X.   
      
   While there are no existing treatments for the root cause of Fragile   
   X, there are medications that address symptoms like anxiety, ADHD,   
   or seizures. The new research suggests modulating the activity of PV   
   neurons could be an effective approach to restoring circuit function.   
      
   "Our research is an example of how therapies that target circuit   
   differences in neurodevelopmental conditions, like boosting the activity   
   of inhibitory neurons in the brain, could help mitigate bothersome   
   symptoms such as sensory hypersensitivity," said corresponding   
   author Carlos Portera-Cailliau, MD, PhD, a professor of neurology and   
   neurobiology at the David Geffen School of Medicine at UCLA. Nazim   
   Kourdougli, PhD, a postdoctoral fellow in Portera- Cailliau's lab,   
   is the first author.   
      
   Portera-Cailliau's lab will continue investigating how inhibitory   
   neurons make synapses with excitatory neurons during development, and   
   how the mutation in Fragile X affects this process. It will also test   
   if the same drug compound can ameliorate other behavioral differences   
   in Fragile X mice.   
      
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   Story Source: Materials provided by   
   University_of_California_-_Los_Angeles_Health_Sciences.   
      
   Note: Content may be edited for style and length.   
      
      
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   Journal Reference:   
      1. Nazim Kourdougli, Anand Suresh, Benjamin Liu, Pablo Juarez,   
      Ashley Lin,   
         David T. Chung, Anette Graven Sams, Michael J. Gandal, Vero'nica   
         Marti'nez-Cerden~o, Dean V. Buonomano, Benjamin J. Hall, Ce'dric   
         Mombereau, Carlos Portera-Cailliau. Improvement of sensory deficits   
         in fragile X mice by increasing cortical interneuron activity after   
         the critical period. Neuron, 2023; DOI: 10.1016/j.neuron.2023.06.009   
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   Link to news story:   
   https://www.sciencedaily.com/releases/2023/07/230713141945.htm   
      
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