Basolateral amygdala hyperexcitability is associated with precocious developmental emergence of fear-learning in Fragile X Syndrome

J Neurosci. 2022 Aug 12;42(38):7294-7308. doi: 10.1523/JNEUROSCI.1776-21.2022. Online ahead of print.

Abstract

Fragile X Syndrome (FXS) is a neurodevelopmental disorder and the most common monogenic cause of intellectual disability, autism spectrum disorders (ASDs) and anxiety disorders. Loss of fragile x mental retardation protein (FMRP) results in disruptions of synaptic development during a critical period (CP) of circuit formation in the basolateral amygdala (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 (PNs) 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 THIP intervention ameliorates fear-learning in Fmr1KO mice. These results suggest that CP plasticity in the amygdala of the Fmr1KO mouse may be shifted to earlier developmental timepoints.SIGNIFICANCE STATEMENTIn these studies we identify early developmental alterations in principal neurons in the FXS BLA. We show that as early as P14, excitability and feed-forward excitation, and synaptic plasticity is enhanced in Fmr1KO lateral amygdala. This correlates with precocious emergence of fear-learning in the Fmr1KO mouse. Early life THIP intervention restores CP plasticity in WT mice and ameliorates fear-learning in the Fmr1KO mouse.