Oligodendrocyte- and Neuron-Specific Nogo-A Restrict Dendritic Branching and Spine Density in the Adult Mouse Motor Cortex

Abstract

Nogo-A has been well described as a myelin-associated inhibitor of neurite outgrowth and functional neuroregeneration after central nervous system (CNS) injury. Recently, a new role of Nogo-A has been identified as a negative regulator of synaptic plasticity in the uninjured adult CNS. Nogo-A is present in neurons and oligodendrocytes. However, it is yet unclear which of these two pools regulate synaptic plasticity. To address this question we used newly generated mouse lines in which Nogo-A is specifically knocked out in (1) oligodendrocytes (oligoNogo-A KO) or (2) neurons (neuroNogo-A KO). We show that both oligodendrocyte- and neuron-specific Nogo-A KO mice have enhanced dendritic branching and spine densities in layer 2/3 cortical pyramidal neurons. These effects are compartmentalized: neuronal Nogo-A affects proximal dendrites whereas oligodendrocytic Nogo-A affects distal regions. Finally, we used two-photon laser scanning microscopy to measure the spine turnover rate of adult mouse motor cortex layer 5 cells and find that both Nogo-A KO mouse lines show enhanced spine remodeling after 4 days. Our results suggest relevant control functions of glial as well as neuronal Nogo-A for synaptic plasticity and open new possibilities for more selective and targeted plasticity enhancing strategies.

Loss of Nogo-A, encoded by the schizophrenia risk gene Rtn4, reduces mGlu3 expression and causes hyperexcitability in hippocampal CA3 circuits

“…As the mice used in this study had global deletion of Nogo-A, we cannot rule-out possible effects from altered glia cells. Indeed, a recently study by Zemmar et al[ 41 ] showed that both neuronal and oligodendrocyte-localized Nogo-A regulate dendritic branching in cortical neurons. Interestingly, the two had compartmentalized effects, with oligodendrocytic Nogo-A regulating distal dendrites and neuronal Nogo-A modulating more proximal dendrites.…”

The Extracellular Environment of the CNS: Influence on Plasticity, Sprouting, and Axonal Regeneration after Spinal Cord Injury

“…Importantly, anti-NogoA antibody treatment also demonstrated that in an uninjured system, inhibition of the Nogo pathway induced sprouting of CA3 fibers [ 86 ]. In a study by Zemmar and colleagues, mouse lines in which Nogo-A was knocked out in either oligodendrocytes or neurons revealed enhanced dendritic branching and spine formation, suggesting that both sources of Nogo-A contribute to synaptic development and plasticity [ 87 ].…”

Limiting Neuronal Nogo Receptor 1 Signaling during Experimental Autoimmune Encephalomyelitis Preserves Axonal Transport and Abrogates Inflammatory Demyelination

“…It is then plausible that either: (1) the limitation of myelin debris enriched with Nogo-A, initiating signaling through the NgR1-dependent phosphorylation of CRMP2 (inflammatorymediated demyelination and secondary axonal damage; outside-in axonopathy), preserves axons or; (2) limiting the phosphorylation of CRMP2 within the axon prevents myelin from degenerating (inside-out axonal damage; secondary demyelination) and abrogates the cycle of inflammatory cell infiltration within the CNS. These outside-in versus inside-out mechanisms of axonopathy still require investigation, particularly because Nogo-A is also highly expressed in axons and may play an active role in driving degeneration during neuroinflammation (Ineichen et al, 2017;Zemmar et al, 2018). Although neuronal Nogo-Adependent signaling downstream to CRMP2 has not been well defined but has been identified in the regulation of axonal transport (Joset et al, 2010).…”