Ray Turner’s laboratory focuses on the mechanisms underlying long-term potentiation (LTP) at the mossy fiber-granule cell synapse and strategies to restore circuit and behavioral functions using the Fmrp1 knockout mouse model of fragile X syndrome.
Turner’s laboratory previously showed that LTP involves modulation of a complex between Cav3 calcium and Kv4 potassium channels (Cav3-Kv4) that reduces A-type potassium currents to enhance granule cell excitability. Recent unpublished studies in Turner’s laboratory have demonstrated that the FMRP protein is an integral component of the Cav3-Kv4 complex and that LTP of the mossy fiber input is absent in Fmrp mutant mice. Importantly, Turner’s group has found that infusing a short (aa 1-298) fragment of FMRP into granule cells restores Cav3-Kv4 modulation and rescues mossy fiber-evoked LTP. Moreover, introduction of a tat-FMRP(298) construct into P60 Fmrp mutant mice reduces hyperactivity in an open field assay.
Turner’s team is currently working on optimizing peptide concentration and infusion timeframes for further assessments of tat-FMRP(298)’s effects on synaptic plasticity rescue and on its ability to reduce aberrant behaviors in Fmrp mutant mice. Turner’s group will determine the distribution of tat-FMRP(298) in the cerebellum and other brain regions over time post-injection and the effects on mossy fiber LTP will be examined through in vitro granule cell patch recordings in tissue slices from Fmrp mutant mice and wild-type controls (FVB/S129 background). Potential toxicity effects from the tat-FMRP(298) will be assessed using dissociated cell cultures and fluorescence-activated cell sorting (FACS) analysis and live-dead cell kits. The effects of tat-FMRP(298) injection will be tested against a range of behaviors in Fmrp mutant mice, including the open field assay, ultrasonic vocalizations and cerebellar-relevant motor tests. Together, these experiments will provide insights into the possible use of tat-FMRP(298) as a potential therapeutic approach to reinstate FMRP function at the cellular and behavioral level in fragile X syndrome.
