Synaptic protein changes after a chronic period of sensorimotor perturbation in adult rats: a potential role of phosphorylation/O‐GlcNAcylation interplay

Abstract

In human, a chronic sensorimotor perturbation (SMP) through prolonged body immobilization alters motor task performance through a combination of peripheral and central factors. Studies performed on a rat model of SMP have shown biomolecular changes and a reorganization of sensorimotor cortex through events such as morphological modifications of dendritic spines (number, length, functionality). However, underlying mechanisms are still unclear. It is well known that phosphorylation regulates a wide field of synaptic activity leading to neuroplasticity. Another post‐translational modification that interplays with phosphorylation is O‐GlcNAcylation. This atypical glycosylation, reversible, and dynamic, is involved in essential cellular and physiological processes such as synaptic activity, neuronal morphogenesis, learning, and memory. We examined potential roles of phosphorylation/O‐GlcNAcylation interplay in synaptic plasticity within rat sensorimotor cortex after a SMP period. For this purpose, sensorimotor cortex synaptosomes were separated by sucrose gradient, in order to isolate a subcellular compartment enriched in proteins involved in synaptic functions. A period of SMP induced plastic changes at the pre‐ and post‐synaptic levels, characterized by a reduction in phosphorylation (synapsin1, α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazoleproprionic acid receptors (AMPAR) GluA2) and expression (synaptophysin, PSD‐95, AMPAR GluA2) of synaptic proteins, as well as a decrease in MAPK/ERK42 activation. Expression levels of O‐GlcNAc transferase/O‐GlcNAcase enzymes was unchanged but we observed a specific reduction of synapsin1 O‐GlcNAcylation in sensorimotor cortex synaptosomes. The synergistic regulation of synapsin1 phosphorylation/O‐GlcNAcylation could affect pre‐synaptic neurotransmitter release. Associated with other pre‐ and post‐synaptic changes, synaptic efficacy could be impaired in somatosensory cortex of SMP rat. Thus, phosphorylation/O‐GlcNAcylation interplay appears to be involved in synaptic plasticity by finely regulating neural activity.

Catalytic deficiency of O-GlcNAc transferase leads to X-linked intellectual disability

“…In agreement with previous studies implying a requirement for OGT function in normal neuron differentiation, morphology, and health (27, 37, 92–94), abnormal OGT activity in 3HA-OGT N567K cells resulted in reduced neurite outgrowth. These data suggest a possible mechanistic link between the mutation and the microcephaly and neurodevelopmental cognitive impairments observed in the patients.…”

Isoflurane Rapidly Modifies Synaptic and Cytoskeletal Phosphoproteomes of the Supraoptic Nucleus of the Hypothalamus and the Cortex

“…We next performed western blots to validate these observations using commercially available phospho-antibodies against phosphosites with changes in response to isoflurane that had been previously used in the literature: SYN1 S67-p [15,23,24], MAP2 T1625-p [25][26][27], and CAMK2A T286-p [28][29][30]. We investigated the phosphosites SYN1 S67-p and MAP2 T1625-p that showed a Log2FC of 1.76 (FDR = 4.32E-03) and of 1.06 (FDR = 2.45E-03), respectively, in the CC, as well as antibodies against SYN and MAP proteins.…”

Sensorimotor Perturbation Induces Late and Transient Molecular Synaptic Proteins Activation and Expression Changes

“…A previous study has highlighted many synaptic changes after a 14-day period of SMP (Fourneau et al 2018). We observed changes in activation and expression of presynaptic proteins involved in the trafficking and release of synaptic vesicles (synapsin 1, synaptophysin) and postsynaptic proteins (PSD-95 or the GluA2 subunit of AMPAR).…”