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 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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ABSTRACT: Resilience and adaptation in the face of early genetic or environmental risk has become a major interest in child psychiatry over recent years. However, we still remain far from an understanding of how developing human brains as a whole adapt to the diffuse and widespread atypical synaptic function that may be characteristic of some common developmental disorders. The first part of this paper discusses four types of whole-brain adaptation in the face of early risk: redundancy, reorganization, niche construction, and adjustment of developmental rate. The second part of the paper applies these adaptation processes specifically to autism. We speculate that key features of autism may be the end result of processes of early brain adaptation, rather than the direct consequences of ongoing neural pathology.Development and Psychopathology 05/2015; 27(02):425-442. DOI:10.1017/S0954579415000073 · 4.89 Impact Factor
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ABSTRACT: Many neurological disorders, including neurodevelopmental disorders, report hypersynchrony of neuronal networks. These alterations in neuronal synchronization suggest a link to the function of inhibitory interneurons. In Fragile X Syndrome (FXS), it has been reported that altered synchronization may underlie hyperexcitability, cognitive dysfunction and provide a link to the increased incidence of epileptic seizures. Therefore, understanding the roles of inhibitory interneurons and how they control neuronal networks is of great importance in studying neurodevelopmental disorders such as FXS. Here, we present a review of how interneuron populations and inhibition are important contributors to the loss of excitatory/inhibitory balance seen in hypersynchronous and hyperexcitable networks from neurodevelopmental disorders, and specifically in FXS.Frontiers in Cellular Neuroscience 08/2014; 8:245. DOI:10.3389/fncel.2014.00245 · 4.18 Impact Factor
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ABSTRACT: During sensitive and critical periods, the brain undergoes significant plasticity from the level of individual synapses and neuronal networks up to the level of behaviour. Both sensitive and critical periods during neurotypical development of the young animal provide a framework to the early temporally-regulated modifications that occur in the nervous system. In neurodevelopmental disorders (NDD), notably autistic syndromes and intellectual disability, children exhibit developmental delays in motor, social and sensory processes and often miss key developmental milestones. In corresponding genetic NDD mouse models, recent data reveal temporally-regulated and in some cases, transient impairments in many neuronal and behavioural phenotypes during development. However, the mechanisms underlying these impairments in NDDs and their potential links with neurobiological mechanisms governing neurotypical development are not fully investigated. This article highlights the potential for the use of known critical and sensitive periods during vertebrate development to investigate and advance our understanding of the neural bases underlying impairments in these developmental disorders of the nervous system. Copyright © 2014. Published by Elsevier Ltd.Neuroscience & Biobehavioral Reviews 12/2014; 50. DOI:10.1016/j.neubiorev.2014.12.001 · 10.28 Impact Factor