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.
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.
"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). "
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] ABSTRACT: Many neurodevelopmental disorders (NDDs) are characterized by age-dependent symptom onset and regression, particularly during early postnatal periods of life. The neurobiological mechanisms preceding and underlying these developmental cognitive and behavioral impairments are, however, not clearly understood. Recent evidence using animal models for monogenic NDDs demonstrates the existence of time-regulated windows of neuronal and synaptic impairments. We propose that these developmentally-dependent impairments can be unified into a key concept: namely, time-restricted windows for impaired synaptic phenotypes exist in NDDs, akin to critical periods during normal sensory development in the brain. Existence of sensitive time-windows has significant implications for our understanding of early brain development underlying NDDs and may indicate vulnerable periods when the brain is more susceptible to current therapeutic treatments.
Trends in Neurosciences 04/2012; 35(6):335-44. DOI:10.1016/j.tins.2012.03.005 · 13.56 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Brain function and behavior undergo significant plasticity and refinement, particularly during specific critical and sensitive periods. In autistic and intellectual disability (ID) neurodevelopmental disorders (NDDs) and their corresponding genetic mouse models, impairments in many neuronal and behavioral phenotypes are temporally regulated and in some cases, transient. However, the links between neurobiological mechanisms governing typically normal brain and behavioral development (referred to also as "neurotypical" development) and timing of NDD impairments are not fully investigated. This perspective highlights temporal patterns of synaptic and neuronal impairment, with a restricted focus on autism and ID types of NDDs. Given the varying known genetic and environmental causes for NDDs, this perspective proposes two strategies for investigation: (1) a focus on neurobiological mechanisms underlying known critical periods in the (typically) normal-developing brain; (2) investigation of spatio-temporal expression profiles of genes implicated in monogenic syndromes throughout affected brain regions. This approach may help explain why many NDDs with differing genetic causes can result in overlapping phenotypes at similar developmental stages and better predict vulnerable periods within these disorders, with implications for both therapeutic rescue and ultimately, prevention.
Frontiers in Systems Neuroscience 10/2013; 7:75. DOI:10.3389/fnsys.2013.00075
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