Homeostatic Responses Fail to Correct Defective Amygdala Inhibitory Circuit Maturation in Fragile X Syndrome

Center for Neuroscience Research, Children's National Medical Center, Washington, DC 20010, Department of Anatomy and Neurobiology, Boston University School of Medicine, Boston, Massachusetts 02118, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, and Department of Pharmaceutical Sciences, Skaggs School of Pharmacy, Department of Pediatrics, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 04/2013; 33(17):7548-58. DOI: 10.1523/JNEUROSCI.2764-12.2013
Source: PubMed


Fragile X syndrome (FXS) is a debilitating neurodevelopmental disorder thought to arise from disrupted synaptic communication in several key brain regions, including the amygdala, a central processing center for information with emotional and social relevance. Recent studies reveal defects in both excitatory and inhibitory neurotransmission in mature amygdala circuits in Fmr1(-/y) mutants, the animal model of FXS. However, whether these defects are the result of altered synaptic development or simply faulty mature circuits remains unknown. Using a combination of electrophysiological and genetic approaches, we show the development of both presynaptic and postsynaptic components of inhibitory neurotransmission in the FXS amygdala is dynamically altered during critical stages of neural circuit formation. Surprisingly, we observe that there is a homeostatic correction of defective inhibition, which, despite transiently restoring inhibitory synaptic efficacy to levels at or beyond those of control, ultimately fails to be maintained. Using inhibitory interneuron-specific conditional knock-out and rescue mice, we further reveal that fragile X mental retardation protein function in amygdala inhibitory microcircuits can be segregated into distinct presynaptic and postsynaptic components. Collectively, these studies reveal a previously unrecognized complexity of disrupted neuronal development in FXS and therefore have direct implications for establishing novel temporal and region-specific targeted therapies to ameliorate core amygdala-based behavioral symptoms.

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    • "These socio-emotional deficits are also associated with deficits in neuronal processing of sensory systems. Studies have shown that together with a shift change in development for synaptic formation and plasticity in the amygdala (Kratovac and Corbin, 2013; Vislay et al., 2013), impaired critical plasticity periods for auditory, visual and somatosensory cortex also occurred in FXS (Bureau et al., 2008; Harlow et al., 2010; Till et al., 2012; Van der Molen et al., 2012; Kim et al., 2013). Therefore these studies reveal a role for FMRP in shaping sensory circuits during developmental critical periods when time windows of protein expression are vulnerable to alterations (reviewed in Meredith et al., 2012). "
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