Journal
JOURNAL OF NEUROSCIENCE
Volume 42, Issue 38, Pages 7294-7308Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.1776-21.2022
Keywords
basolateral amygdala; critical period; fear conditioning; fragile X syndrome; olfactory learning; synaptic plasticity
Categories
Funding
- National Institutes of Health National Research Service Award Individual Predoctoral Fellowship [F31 MH124277]
- National Institutes of Health [R01 DC000566, R01 NS095311, R37 HD083217]
- National Science Foundation Graduate Research Fellowship [DGE-1553798]
- Universidad de Santiago de Chile, Vicerrectoria de Investigacion, Desarrollo e Innovacion [DICYT 022001CDR]
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Fragile X Syndrome is a common neurodevelopmental disorder associated with intellectual disability, autism spectrum disorders, and anxiety disorders. This study demonstrates that Fmr1KO mice exhibit hyperexcitability in the amygdala during a critical period of development, leading to increased excitatory gain in fear-learning circuits. Additionally, synaptic plasticity is enhanced in the amygdala of Fmr1KO mice. Early intervention with a specific compound improves fear-learning in Fmr1KO mice, suggesting a shift in critical period plasticity in the amygdala.
Fragile X Syndrome is a neurodevelopmental disorder and the most common monogenic cause of intellectual disability, au-tism spectrum disorders, and anxiety disorders. Loss of fragile x mental retardation protein results in disruptions of synaptic development during a critical period of circuit formation in the BLA. However, it is unknown how these alterations impact microcircuit development and function. Using a combination of electrophysiologic and behavioral approaches in both male (Fmr1-/y) and female (Fmr1-/-) mice, we demonstrate that principal neurons in the Fmr1KO BLA exhibit hyperexcitability during a sensitive period in amygdala development. This hyperexcitability contributes to increased excitatory gain in fear -learning circuits. Further, synaptic plasticity is enhanced in the BLA of Fmr1KO mice. Behavioral correlation demonstrates that fear-learning emerges precociously in the Fmr1KO mouse. Early life 4,5,6,7-tetrahydroisoxazolo [5,4-c]pyridin-3ol inter-vention ameliorates fear-learning in Fmr1KO mice. These results suggest that critical period plasticity in the amygdala of the Fmr1KO mouse may be shifted to earlier developmental time points.
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