Fragile X syndrome (FXS) is the most common form of inherited intellectual disability and also the single most common known cause of autism. FXS results from an expansion of a CGG repeat sequence in the 5' untranslated region of the gene, which causes hypermethylation, transcriptional silencing, and a resultant loss of expression of the Fragile X mental retardation protein (FMRP). FMRP is a polyribosome associated RNA binding protein that regulates the translation of a large number of messenger RNAs, has roles in mRNA transport, as well as regulating the expression of miRNAs. Altered trajectories for the maturation and stability of synapses have been observed in the cortex of the mouse model of FXS (Fmr1 ko). However, the underlying mechanisms of these alterations in cellular and synaptic development are unknown. One important regulator of cortical development is the inhibitory neurotransmitter GABA. During early development GABA responses in many cortical neurons are excitatory, only maturing to their inhibitory, hyperpolarizing type later. Excitatory effects of GABA have been demonstrated to be important for neuronal proliferation, cell migration, and synaptogenesis. In recent studies we discovered that the regulated development of hyperpolarizing GABA responses is delayed in the cortex of Fmr1 ko mice. We propose that this will lead to an alteration in GABA signaling that contributes to a delay in synaptic and cellular maturation in the cortex. The objectives of this proposal are twofold. The first is to determine how the efficacy of GABA signaling is altered during the critical period, and whether there is a causal link between delayed maturation of GABA signaling and delayed maturation of fast spiking interneurons. The second is to determine whether the underlying mechanism for these changes result from alterations in miRNA expression that normally regulate the transporters underlying the reversal potential for GABA. We will achieve these objectives using two specific aims.
Aim 1 will test whether a commonly used diuretic bumetanide (which acts centrally to inhibit the juvenile chloride cotransporter, NKCC1) can rectify the changes in GABA responses and delayed maturation of fast spiking interneurons.
In Aim 2 using in vitro assays combined with validation in mouse and human derived neurons we will determine whether several candidate miRNAs can regulate expression of the juvenile chloride cotransporter NKCC1, which sets the reversal potential for GABA. These studies will address important knowledge gaps and potentially provide novel insights into developing cures for FXS. Because similar abnormalities of neuron connectivity and synapse maturation are implicated in other childhood brain disorders, it is possible that this research will open new avenues of study in other disorders characterized by autism and intellectual disability.
Fragile X syndrome is a pervasive neurodevelopmental disorder that is the most common form of inherited intellectual disability and autism. Using the mouse model of the disorder and human derived neurons we will determine the extent and mechanisms of altered signaling by the neurotransmitter GABA, and how this results in delays in neuronal maturation
|He, Qionger; Arroyo, Erica D; Smukowski, Samuel N et al. (2018) Critical period inhibition of NKCC1 rectifies synapse plasticity in the somatosensory cortex and restores adult tactile response maps in fragile X mice. Mol Psychiatry :|
|Nomura, Toshihiro; Musial, Timothy F; Marshall, John J et al. (2017) Delayed Maturation of Fast-Spiking Interneurons Is Rectified by Activation of the TrkB Receptor in the Mouse Model of Fragile X Syndrome. J Neurosci 37:11298-11310|