Altered presynaptic function and number of mitochondria in the medial prefrontal cortex of adult Cyfip2 heterozygous mice

Abstract

Variants of the cytoplasmic FMR1-interacting protein (CYFIP) gene family, CYFIP1 and CYFIP2, are associated with numerous neurodevelopmental and neuropsychiatric disorders. According to several studies, CYFIP1 regulates the development and function of both pre- and post-synapses in neurons. Furthermore, various studies have evaluated CYFIP2 functions in the postsynaptic compartment, such as regulating dendritic spine morphology; however, no study has evaluated whether and how CYFIP2 affects presynaptic functions. To address this issue, in this study, we have focused on the presynapses of layer 5 neurons of the medial prefrontal cortex (mPFC) in adult Cyfip2 heterozygous (Cyfip2+/−) mice. Electrophysiological analyses revealed an enhancement in the presynaptic short-term plasticity induced by high-frequency stimuli in Cyfip2+/− neurons compared with wild-type neurons. Since presynaptic mitochondria play an important role in buffering presynaptic Ca2+, which is directly associated with the short-term plasticity, we analyzed presynaptic mitochondria using electron microscopic images of the mPFC. Compared with wild-type mice, the number, but not the volume or cristae density, of mitochondria in both presynaptic boutons and axonal processes in the mPFC layer 5 of Cyfip2+/− mice was reduced. Consistent with an identification of mitochondrial proteins in a previously established CYFIP2 interactome, CYFIP2 was detected in a biochemically enriched mitochondrial fraction of the mouse mPFC. Collectively, these results suggest roles for CYFIP2 in regulating presynaptic functions, which may involve presynaptic mitochondrial changes.

Cell-autonomous reduction of CYFIP2 is insufficient to induce Alzheimer's disease-like pathologies in the hippocampal CA1 pyramidal neurons of aged mice

“…Moreover, CYFIP2 is expressed in neurons of the hippocampal CA3 region as well as of other brain regions that can directly form synaptic connections with CA1 excitatory pyramidal neurons (Han et al 2015 ; Lee SH et al 2020 ). As CYFIP2 regulates axonal and presynaptic development and function (Cioni et al 2018 ; Kim GH et al 2020 ), it is conceivable that both presynaptic and postsynaptic compartments are functionally affected in CA1 pyramidal neurons of Cyfip2 het mice, thereby ultimately leading to synaptic loss. Meanwhile, the postsynapse-specific CYFIP2 reduction in CA1 pyramidal neurons of Cyfip2 cKO mice may be insufficient to induce such changes.…”

“…At the molecular level, CYFIP1 and CYFIP2 have a high amino acid sequence homology and both are involved in the regulation of cellular actin cytoskeleton dynamics as a critical component of the heteropentameric Wiskott–Aldrich syndrome protein family verprolin-homologous protein (WAVE) regulatory complex (WRC) (Lee Y et al 2017 ; Rottner et al 2021 ). Additional functions in neurons, such as regulation of mRNA translation and transport (Napoli et al 2008 ; De Rubeis et al 2013 ; Cioni et al 2018 ), and regulation of mitochondrial function and morphology (Kanellopoulos et al 2020 ; Kim GH et al 2020 ) have also been identified, but unlike actin regulation via the WRC, these functions may be mediated by both shared and distinct interactors of CYFIP1 and CYFIP2, respectively (Lee Y et al 2020 ; Ma et al 2022 ). Collectively, these molecular functions of CYFIP1 and CYFIP2 can contribute to the morphological and functional changes in neuronal synapses observed in both Cyfip1 and Cyfip2 mutant mice (Bozdagi et al 2012 ; Pathania et al 2014 ; Han et al 2015 ; Davenport et al 2019 ; Lee SH et al 2020 ; Zhang et al 2020 ; Kim NS et al 2022 ).…”

Hypoxic Preconditioned Neural Stem Cell-Derived Extracellular Vesicles Contain Distinct Protein Cargo from Their Normal Counterparts

“…The possibility of Rpl34 as a novel prognostic biomarker and therapeutic target for ischemic stroke was also reported previously [ 48 , 49 ]. Noteworthily, other overexpressed proteins such as Cnp, Cyfip1, Cask, and Tubb5 that were also shown to be overexpressed in our proteomics result are found to be involved in neuronal regulation, protection, maturation, and development [ 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 ].…”

Orchestration of synaptic functions by WAVE regulatory complex-mediated actin reorganization

“…Studies on Cyfip1 heterozygous ( Cyfip1 +/- ) mice illustrate the postsynaptic role of Cyfip1, demonstrating altered synapse composition in the hippocampus of these mice, with decreased levels of SynGAP1 (a synaptic Ras GTPase activating protein 1) and GluA1 (an AMPAR [α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor] subunit) and increased levels of mGluR1/5 [metabotropic glutamate receptor 1 and 5], GluN2B (an NMDAR [N-methyl-D-aspartate receptor] subunit), and F-actin 29 , 30 . Cyfip1 also participates in the regulation of presynaptic nerve terminal size and vesicle release probability through its actions on the WRC downstream of Rac1 31 , whereas Cyfip2 regulates presynaptic short-term plasticity through its actions on presynaptic mitochondria in medial prefrontal cortical neurons 32 . However, it remains unclear how Cyfip proteins, which are present at both excitatory and inhibitory synapses, form complexes with Rac1, WAVE1, FMRP, and other proteins to bidirectionally regulate the synaptic E/I ratio.…”