Rapid Turnover of Cortical NCAM1 Regulates Synaptic Reorganization after Peripheral Nerve Injury

Abstract

Peripheral nerve injury can induce pathological conditions that lead to persistent sensitized nociception. Although there is evidence that plastic changes in the cortex contribute to this process, the underlying molecular mechanisms are unclear. Here, we find that activation of the anterior cingulate cortex (ACC) induced by peripheral nerve injury increases the turnover of specific synaptic proteins in a persistent manner. We demonstrate that neural cell adhesion molecule 1 (NCAM1) is one of the molecules involved and show that it mediates spine reorganization and contributes to the behavioral sensitization. We show striking parallels in the underlying mechanism with the maintenance of NMDA-receptor- and protein-synthesis-dependent long-term potentiation (LTP) in the ACC. Our results, therefore, demonstrate a synaptic mechanism for cortical reorganization and suggest potential avenues for neuropathic pain treatment.

Protein Kinase C Lambda Mediates Acid-Sensing Ion Channel 1a-Dependent Cortical Synaptic Plasticity and Pain Hypersensitivity

“…Cannula implantation and drug microinjection. Cannulation and microinjection were performed as described previously (Wang et al, 2011;Ko et al, 2018). Animals were anesthetized and placed in a stereotaxic frame (RWD Life Science).…”

“…The fEPSPs recorded at the remaining microelectrodes were amplified by a 64-channel amplifier, displayed on the monitor screen, and stored on the hard disk of a microcomputer for offline analysis. For LTP induction, after the baseline synaptic responses were stabilized for at least 30 min, a theta burst stimulation (TBS) protocol (5 bursts at 5 Hz, repeated 5 times at 10 s intervals, 4 pulses at 100 Hz for each burst) was delivered with the stimulation intensity eliciting 40%-60% of the maximum response (Li et al, 2010;Song et al, 2017;Ko et al, 2018). For LTD induction, stable baseline responses were recorded for at least 20 min before delivery of the low-frequency stimulation (LFS) protocol (1 Hz, 900 pulses) (Liu and Zhuo, 2014).…”

“…Synaptic plasticity in ACC is considered one of the most critical mechanisms underlying the transition of pain from acute to chronic (Luo et al, 2014;Bliss et al, 2016). Peripheral inflammatory or neuropathic pain elicits dramatic plastic changes in synaptic transmission and morphology of ACC neurons (Zhao et al, 2006;Ko et al, 2018), whereas blocking or erasing aberrant cingulate plasticity produces significant analgesic effects in animals (Li et al, 2010;Wang et al, 2011).…”

Hemispheric asymmetry in the human brain and in Parkinson’s disease is linked to divergent epigenetic patterns in neurons

“…The genes with the most significant aging changes in hemispheric asymmetry in PD were then ranked based on consistency across the discovery and replication cohorts. Among the top genes, there were calcium/calmodulindependent protein kinase 2 (CAMK2B), histone deacetylase 4 (HDAC4), and NCAM1, which have established roles in synaptic plasticity, neurotransmitter release, neurodevelopment, memory, and locomotor activity, as well as endothelin-converting enzyme-1 (ECE1), which degrades α-synuclein pathology [56][57][58][59][60] (Fig. 4d).…”

Epigenetic contributions to hemisphere asymmetry in healthy brain, aging, and Parkinson’s disease

“…3c and 3d; Supplementary Data 7). In particular, the neuronal cell adhesion molecule 1 (NCAM1), which regulates neuronal development, synaptogenesis, cell-cell interactions, and synaptic plasticity 50 , was central to the abnormalities in the symptom-dominant PD hemisphere ( Fig. 3d).…”