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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FULL STORY ========================================================================== 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.

* RELATED_TOPICS
o Health_&_Medicine
# Nervous_System # Parkinson's_Research # Down_Syndrome
# Birth_Defects
o Mind_&_Brain
# Neuroscience # Brain_Injury # Disorders_and_Syndromes
# Intelligence
* RELATED_TERMS
o Neurobiology o Neural_network o Neuron o Integrated_circuit
o Animal_cognition o Biochemistry o Brain o Sensory_neuron

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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.


========================================================================== 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 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2023/07/230713141945.htm

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