Homeostatic plasticity is critical for controlling excitability and maintaining synaptic balance for normal circuit development and function. This precise balance between excitation and inhibition (E/I) is essential for maintaining homeostasis during normal development. However, in neurodevelopmental disorders (NDDs) the timing and regulation of critical periods are altered in early postnatal development by aberrant E/I balance. Alterations in cellular and synaptic development during critical periods of circuit formation manifest as the temporal onset of cognitive and behavioral impairments observed in NDDs during the first years of life. Fragile X Syndrome (FXS) is a NDD whose clinical symptomatology includes intellectual disabilities, autism spectrum disorders (ASDs), hyperactivity, and fear and anxiety disorders. However, despite FXS being one of the most well-studied genetically-defined NDDs, there are no currently approved or effective therapies targeted to disease-specific pathophysiology. A critical barrier to the development of effective therapies may be understanding not only how to treat, but when to treat. Thus, defining the synaptic basis of altered critical periods, and how E/I balance affects circuit formation and plasticity in FXS will provide deeper insights into the neurological consequences related to problems with development and maintenance of synaptic function and may suggest new therapeutic strategies in humans. In our studies, we observe periods of homeostatic changes in inhibition in early postnatal development of the amygdala in Fmr1 KO mice. Our published and preliminary data show decreased inhibitory function in the Fmr1 KO mouse model of FXS at postnatal day 10 (P10)) followed by a brief period of enhanced inhibitory function in the developing amygdala between P14-16. Ultimately, this enhanced inhibitory function fails to be maintained and by P21 Fmr1 KO mice again exhibit decreased inhibitory function. This is akin to a sensitive time window of plasticity in FXS. It is our hypothesis that this brief window of enhanced inhibitory function 1) may be a homeostatic response to changes in excitatory neurotransmission and 2) may drive the precocious emergence of fear-learning behaviors. This proposal will seek to understand the functional development of microcircuits within the amygdala and determine if early life pharmacologic intervention can impact the developmental emergence of amygdala-based behaviors. These studies represent a unique, high-impact investigation providing me with foundational training in diverse fields such as NDDs, critical period plasticity, inhibitory interneuron biology, chemosensory systems, and behavioral paradigms. Furthermore, this proposal has translational relevance for early-life intervention in NDDs representing a novel evaluation of pharmacologic interventions which may affect critical period plasticity.
We propose to examine the functional development of amygdala microcircuits necessary for olfactory learning in a mouse model of Fragile X Syndrome (FXS). We will test the hypothesis that temporal changes in excitatory/inhibitory (E/I) balance drive aberrant plasticity in circuits necessary for olfactory learning in FXS. We will also test the hypothesis that changes in inhibitory neurotransmission in early development have distinct behavioral consequences for amygdala-based behaviors.
