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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 long-term 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.

SUBMITTER: Lee KY

PROVIDER: S-EPMC8490988 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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

Lee Kwan Young KY Zhu Jiuhe J Cutia Cathryn A CA Christian-Hinman Catherine A CA Rhodes Justin S JS Tsai Nien-Pei NP

EMBO reports 20210803 10

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 long-term synaptic potentiation (L-LTP) at Schaffer coll ...[more]

PMID: 34342389

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Project description:ObjectiveThis study attempted to validate the effects of neonatal estradiol in ameliorating the spasms in the prenatally betamethasone-primed N-methyl-d-aspartate (NMDA) model of infantile spasms in rats as shown previously in a mouse Arx gene knock-in expansion model of infantile spasms.MethodsNeonatal rats prenatally exposed to betamethasone (on day 15 of pregnancy) were treated with subcutaneous 40 ng/g estradiol benzoate (EB) between postnatal days (P)3-P10 or P0-P5. A synthetic estrogen analogue, diethylstilbestrol, was used between P0 and P5 (2 μg per rat, s.c.). On P12, P13, and P15, the rats were subjected to NMDA-triggered spasms, and latency to onset and number of spasms were evaluated. Rats with EB on P3-P10 were tested after spasms in the open field, novel object recognition, and elevated plus maze to determine effects of treatment on behavior. Additional rats with P3-P10 or P0-P5 EB were investigated for γ-aminobutyric acid (GABA)ergic neurons (glutamate decarboxylase [GAD]67 expression) in the neocortex. As a positive control, a group of rats received either subcutaneous adrenocorticotropic hormone (ACTH) (2 × 0.3 mg/kg on P12 and 3 × 0.3 mg/kg on P13 and P14) or vehicle after the first episode of spasms on P12.ResultsNeither EB treatment nor diethylstilbestrol consistently affected expression of spasms in this model, although we found a significant increase in GAD67-immunopositive cells in the neocortex after P3-P10 and P0-P5 EB treatment, consistent with a study in mice. Behavioral tests showed increase in lateralization in male rats treated with P3-P10 EB, a behavioral trait usually associated with female sex. Diethylstilbestrol treatment in male rats resulted in arrested pubertal descent of testes. ACTH had robust effects in suppressing spasms.SignificanceTreatment of infantile spasms (IS) using neonatal EB may be justified in those cases of IS that present with detectable deficits in GABAergic neurons. In other types of IS, the efficacy of neonatal EB and its analogues is not supported.

Dataset Information

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

Publications

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

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