Infantile spasms‐linked Nedd4‐2 mediates hippocampal plasticity and learning via cofilin signaling

Abstract

Individuals affected by infantile spasms (IS), such as those carrying mutations in an IS-linked gene, neural precursor cell expressed developmentally downregulated gene 4-like (Nedd4-2), exhibit developmental delays and learning disabilities, but the underlying mechanism is unknown. Using conditional Nedd4-2 knockout mice, we uncover that Nedd4-2 functions to maintain the excitatory synapses in hippocampal neurons and allows for late-phase longterm synaptic potentiation (L-LTP) at Schaffer collateral synapses in the hippocampus. We also find that Nedd4-2 is required for multiple forms of hippocampus-dependent learning and memory. Mechanistically, we show that loss of Nedd4-2 leads to a decrease in actin polymerization caused by reduced phosphorylation of the actin depolymerizing protein cofilin. A cell-permeable peptide promoting phosphorylation of endogenous cofilin in Nedd4-2 knockout neurons restores the number of hippocampal excitatory synapses and hippocampal L-LTP and partially restores hippocampus-dependent learning in mice. Taken together, our results reveal a novel mechanism underlying IS-associated learning disabilities and may provide information for future therapeutic strategies for IS.

Hyperfunction of post-synaptic density protein 95 promotes seizure response in early-stage aβ pathology

“…To test this, we first measured the synapse numbers in WT primary cortical neurons upon treatment with Aβ 1-42 or the scrambled peptide for 2 h. Neurons were fixed, permeabilized, and immunostained with Synapsin-I, PSD-95, and MAP2 to label presynaptic, postsynaptic, and dendritic compartments, respectively. The number of synapses was measured by quantifying the number of colocalized pre- and postsynaptic puncta, as we performed previously (Lee et al, 2021 ; Lizarazo et al, 2022 ). As shown in Fig.…”

Amyloid beta induces Fmr1‐dependent translational suppression and hyposynchrony of neural activity via phosphorylation of eIF2α and eEF2

“…Because multiple studies have demonstrated the role of Fmr1 in suppressing synapse numbers, in part through translational suppression (Comery et al, 1997; Huebschman et al, 2020; Pfeiffer et al, 2010; Tsai et al, 2017; Zang et al, 2013), we asked whether Fmr1 participates in Aβ42‐induced loss of synapses. To answer this question, we performed immunocytochemistry to quantify synapse numbers in WT and Fmr1 KO cortical neuron cultures treated with Aβ42 or a control peptide for 24 h. Following the treatments, the neurons were fixed and stained for the presynaptic marker synapsin‐I and the postsynaptic marker postsynaptic density protein 95 (PSD‐95) to measure colocalization of pre‐ and postsynaptic puncta, as we have done recently (Lee et al, 2021). As shown, while the basal levels of PSD‐95 and Synapsin‐I were not significantly different between WT and Fmr1 KO neurons (Figure ), in comparison to the control peptide, Aβ42 induced a reduction in synapse number in WT cultures but this reduction was not observed in Fmr1 KO cultures (Figure 2b).…”

“…Immunocytochemistry was done as previously described (Lee et al, 2021). In brief, primary neurons were cultured on poly‐ d ‐lysine‐coated coverslips.…”

“…participates in Aβ42-induced loss of synapses. To answer this question, we performed immunocytochemistry to quantify synapse numbers in WT and Fmr1 KO cortical neuron cultures treated with Aβ42 or a control peptide for 24 h. Following the treatments, the neurons were fixed and stained for the presynaptic marker synapsin-I and the postsynaptic marker postsynaptic density protein 95 (PSD-95) to measure colocalization of pre-and postsynaptic puncta, as we have done recently(Lee et al, 2021). As shown, while the basal levels of PSD-95 and Synapsin-I were not significantly different between WT and Fmr1 KO neurons (FigureS2), in comparison to the control peptide, Aβ42 induced a reduction in synapse number in WT cultures F I G U R E 2 Amyloid beta inducesFmr1-dependent hyposynchrony of neural network activity and reduction of synapse number.…”