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

Abstract

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 pre- 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 knockout and rescue mice, we further reveal that Fragile X Mental Retardation Protein (FMRP) function in amygdala inhibitory microcircuits can be segregated into distinct pre- 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.

Bryostatin-1 Restores Hippocampal Synapses and Spatial Learning and Memory in Adult Fragile X Mice

“…Potential therapeutics, therefore, include mGluR inhibitors (Vinueza Veloz et al, 2012), GABAergic enhancers (D'Hulst andKooy, 2007;Olmos-Serrano et al, 2010;Paluszkiewicz et al, 2011;Heulens et al, 2012), and inhibitors of GSK-3b (Yuskaitis et al, 2010;Guo et al, 2012). Because intellectual ability, as well as retardation (Wang et al, 2012) involves multiple players in signal processing, bryostatin-1-like agents, for their multitargeting actions, may represent a more effective class of therapeutics than agents that target a single factor in this complex pathologic process (Vislay et al, 2013).…”

Altered Neuronal and Circuit Excitability in Fragile X Syndrome

“…Despite this, the functionally characterized alterations in phasic GABA A -mediated transmission are quite modest and may be regionally restricted. Both the frequency and amplitude of miniature IPSCs and spontaneous IPSCs are reduced in the mature amygdala (Olmos-Serrano et al, 2010), as well as during development (Vislay et al, 2013). However, in the subiculum and L2/3 of somatosensory cortex there are no reported alterations in postsynaptic GABA signaling (Curia et al, 2009; Paluszkiewicz et al, 2011).…”

Rescue of Synaptic Phenotypes and Spatial Memory in Young Fragile X Mice

“…Bryostatin-1-like agents enhance the synthesis of proteins required for memory processing and synaptic repair/ synaptogenesis, reduce Ab formation through activation of a-secretase and increase Ab degradation via the endothelinconverting enzyme, and are antiapoptotic. Since intellectual ability, as well as retardation (Wang et al, 2012), involves multiple players in signal processing, these agents with multitargeting actions (Sun et al, 2015) may represent a more effective class of therapeutics than agents that target a single factor in this complex pathologic process (Vislay et al, 2013).…”