Defining Plasticity and Homeostasis in Fragile X Syndrome

项目摘要

Project Abstract We propose to investigate circuit homeostasis in the developing amygdala in a mouse model of Fragile X Syndrome (FXS) - a pervasive neurodevelopmental disorder (NDD) and a leading monogenic cause of autism. Many NDDs, such as FXS, are characterized by age-dependent symptom onset and regression in early life. Recent evidence, including our own publications, from monogenetic mouse models of NDDs reveal that critical periods of synaptic plasticity are altered in terms of onset, duration and offset. This altered critical period in NDDs is often referred to as a ‘sensitive time window’ – a time regulated window of synaptic impairment. Therefore, the identification of sensitive time windows has implications for understanding brain development and may indicate vulnerable periods for when therapeutic rescue is most effective. We have identified a brief period of enhanced synaptic plasticity in the developing amygdala in the Fmr1 knock out (KO) mouse model of FXS (Vislay et al., JNeurosci 2013). This is akin to a sensitive time window of plasticity in FXS. This discovery was built on our previous observation that inhibitory function is significantly depleted in Fmr1 KOs from postnatal day (P)21) through adult ages. We asked the question, “Are inhibitory circuits defective from birth or do they develop into defective circuits?”. Therefore, we examined the development of inhibitory circuit function during the first three weeks of postnatal development. At P10, when GABAA receptor mediated currents are inhibitory, Fmr1 KOs show decreased inhibitory function. However, surprisingly we observe that there is a homeostatic correction of defective inhibition between P14-16. This increase in inhibitory function is merely transient as this correction ultimately fails to be maintained by the P21 timepoint. By P21, synaptic inhibition falls below that of normal function through adulthood (Olmos-Serrano et al., JNeurosci 2010, Martin et al., JNeurophysiol 2014). We propose this increase in inhibitory function may be a “biomarker” for plasticity and thereby represents a sensitive time window in the developing fragile-x amygdala. In the present proposal, we will identify how this homeostatic fluctuation of inhibition occurs in Fmr1 KOs at key timepoints. The collective goal of these experiments is to determine how fluctuations in inhibitory function affect circuit function, structure, plasticity and behavior. In Specific Aim 1 we will explore this phenomenon with a comprehensive plan of experiments that will first examine how inhibitory circuits are altered in terms of function, connectivity and anatomy. In Specific Aim 2 we will determine how this period of homeostasis affects circuit plasticity and specific behaviors in early postnatal development. In summary, our proposed experiments will provide a clear identification of circuitry changes that alter the synaptic balance of developing circuits in a behaviorally relevant brain region for NDDs.