Abstract
BackgroundFragile X Syndrome is the leading monogenetic cause of autism and most common form of intellectual disability. Previous studies have implicated changes in dendritic spine architecture as the primary result of loss of Fragile X Mental Retardation Protein (FMRP), but recent work has shown that neural proliferation is decreased and cell death is increased with either loss of FMRP or overexpression of FMRP. The purpose of this study was to investigate the effects of loss of FMRP on behavior and cellular activity.MethodsWe knocked down FMRP expression using morpholino oligos in the optic tectum of Xenopus laevis tadpoles and performed a series of behavioral and electrophysiological assays. We investigated visually guided collision avoidance, schooling, and seizure propensity. Using single cell electrophysiology, we assessed intrinsic excitability and synaptic connectivity of tectal neurons.ResultsWe found that FMRP knockdown results in decreased swimming speed, reduced schooling behavior and decreased seizure severity. In single cells, we found increased inhibition relative to excitation in response to sensory input.ConclusionsOur results indicate that the electrophysiological development of single cells in the absence of FMRP is largely unaffected despite the large neural proliferation defect. The changes in behavior are consistent with an increase in inhibition, which could be due to either changes in cell number or altered inhibitory drive, and indicate that FMRP can play a significant role in neural development much earlier than previously thought.
Highlights
Fragile X Syndrome is the leading monogenetic cause of autism and most common form of intellectual disability
Behavioral and electrophysiological experiments were performed on stage 49 tadpoles in which Fragile X Mental Retardation Protein (FMRP) expression was knocked down using a morpholino-antisense oligomer [10] during critical neural proliferation and circuit wiring time periods, referred to as FMRP knock down (KD) tadpoles throughout
Our results show behavioral and electrophysiological deficits that implicate impaired inhibitory circuitry as the primary change resulting from knockdown of FMRP
Summary
Fragile X Syndrome is the leading monogenetic cause of autism and most common form of intellectual disability. Fragile X Syndrome (FXS) is the leading monogenetic cause of autism and most common form of inherited intellectual disability [1,2,3]. The most well understood neuroanatomical marker in FXS is the presence of immature dendritic spines in the cortex [6, 7]. This is thought to occur because FMRP is a RNA binding protein that inhibits protein synthesis downstream of group 1 metabotropic glutamate receptor activation [8], and prevents normal plasticity and synaptic maturation. FMRP disruption prior to synapse formation results in abnormalities that may lead to neurodevelopmental deficits [9], indicating a possible role for FMRP much earlier than initially known
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