Dataset Information

Cyfip2 controls the acoustic startle threshold through FMRP, actin polymerization, and GABA_B receptor function.

ABSTRACT: Animals process a constant stream of sensory input, and to survive they must detect and respond to dangerous stimuli while ignoring innocuous or irrelevant ones. Behavioral responses are elicited when certain properties of a stimulus such as its intensity or size reach a critical value, and such behavioral thresholds can be a simple and effective mechanism to filter sensory information. For example, the acoustic startle response is a conserved and stereotyped defensive behavior induced by sudden loud sounds, but dysregulation of the threshold to initiate this behavior can result in startle hypersensitivity that is associated with sensory processing disorders including schizophrenia and autism. Through a previous forward genetic screen for regulators of the startle threshold a nonsense mutation in Cytoplasmic Fragile X Messenger Ribonucleoprotein (FMRP)-interacting protein 2 (cyfip2) was found that causes startle hypersensitivity in zebrafish larvae, but the molecular mechanisms by which Cyfip2 establishes the acoustic startle threshold are unknown. Here we used conditional transgenic rescue and CRISPR/Cas9 to determine that Cyfip2 acts though both Rac1 and FMRP pathways, but not the closely related FXR1 or FXR2, to establish the acoustic startle threshold during early neurodevelopment. To identify proteins and pathways that may be downstream effectors of Rac1 and FMRP, we performed a candidate-based drug screen that indicated that Cyfip2 can also act acutely to maintain the startle threshold branched actin polymerization and N-methyl D-aspartate receptors (NMDARs). To complement this approach, we used unbiased discovery proteomics to determine that loss of Cyfip2 alters cytoskeletal and extracellular matrix components while also disrupting oxidative phosphorylation and GABA receptor signaling. Finally, we functionally validated our proteomics findings by showing that activating GABA_B receptors, which like NMDARs are also FMRP targets, restores normal startle sensitivity in cyfip2 mutants. Together, these data reveal multiple mechanisms by which Cyfip2 regulates excitatory/inhibitory balance in the startle circuit to control the processing of acoustic information.

SUBMITTER: Deslauriers JC

PROVIDER: S-EPMC10769380 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Cyfip2 controls the acoustic startle threshold through FMRP, actin polymerization, and GABA<sub>B</sub> receptor function.

Deslauriers Jacob C JC Ghotkar Rohit P RP Russ Lindsey A LA Jarman Jordan A JA Martin Rubia M RM Tippett Rachel G RG Sumathipala Sureni H SH Burton Derek F DF Cole D Chris DC Marsden Kurt C KC

bioRxiv : the preprint server for biology 20240205

Animals process a constant stream of sensory input, and to survive they must detect and respond to dangerous stimuli while ignoring innocuous or irrelevant ones. Behavioral responses are elicited when certain properties of a stimulus such as its intensity or size reach a critical value, and such behavioral thresholds can be a simple and effective mechanism to filter sensory information. For example, the acoustic startle response is a conserved and stereotyped defensive behavior induced by sudden ...[more]

PMID: 38187577

Similar Datasets

Project description:Latency of the acoustic startle response is the time required from the presentation of startling auditory stimulus until the startle response is elicited and provides an index of neural processing speed. Latency is prolonged in subjects with schizophrenia compared to controls in some but not all studies and is 68-90% heritable in baseline startle trials. In order to determine the genetic association with latency as a potential inroad into genetically based vulnerability to psychosis, we conducted a gene-based study of latency followed by an independent replication study of significant gene findings with a single-nucleotide polymorphism (SNP)-based analysis of schizophrenia and control subjects. 313 subjects from an urban population of low socioeconomic status with mixed psychiatric diagnoses were included in the gene-based study. Startle testing was conducted using a Biopac M150 system according to our published methods. Genotyping was performed with the Omni-Quad 1M or the Omni Express BeadChip. The replication study was conducted on 154 schizophrenia subjects and 123 psychiatric controls. Genetic analyses were conducted with Illumina Human Omni1-Quad and OmniExpress BeadChips. Twenty-nine SNPs were selected from four genes that were significant in the gene-based analysis and also associated with startle and/or schizophrenia in the literature. Linear regressions on latency were conducted, controlling for age, race, and diagnosis as a dichotomous variable. In the gene-based study, 2,870 genes demonstrated the evidence of association after correction for multiple comparisons (false discovery rate < 0.05). Pathway analysis of these genes revealed enrichment for relevant biological processes including neural transmission (p = 0.0029), synaptic transmission (p = 0.0032), and neuronal development (p = 0.024). The subsequent SNP-based replication analysis revealed a strong association of onset latency with the SNP rs901561 on the neuregulin gene (NRG1) in an additive model (beta = 0.21, p = 0.001), indicating that subjects with the AA and AG genotypes had slower mean latency than subjects with GG genotype. In conclusion, startle latency, a highly heritable measure that is slowed in schizophrenia, may be a useful biological probe for genetic contributions to psychotic disorders. Our analyses in two independent populations point to a significant prediction of startle latency by genetic variation in NRG1.

Dataset Information

Cyfip2 controls the acoustic startle threshold through FMRP, actin polymerization, and GABA_B receptor function.

Publications

Cyfip2 controls the acoustic startle threshold through FMRP, actin polymerization, and GABA<sub>B</sub> receptor function.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

Cyfip2 controls the acoustic startle threshold through FMRP, actin polymerization, and GABAB receptor function.

Publications

Cyfip2 controls the acoustic startle threshold through FMRP, actin polymerization, and GABA<sub>B</sub> receptor function.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Cyfip2 controls the acoustic startle threshold through FMRP, actin polymerization, and GABA_B receptor function.