Nogo-A Stabilizes the Architecture of Hippocampal Neurons

Abstract

Although the role of myelin-derived Nogo-A as an inhibitor of axonal regeneration after CNS injury has been thoroughly described, its physiological function in the adult, uninjured CNS is less well known. We address this question in the hippocampus, where Nogo-A is expressed by neurons as well as oligodendrocytes. We used 21 d in vitro slice cultures of neonatal hippocampus where we applied different approaches to interfere with Nogo-A signaling and expression and analyze their effects on the dendritic and axonal architecture of pyramidal cells. Neutralization of Nogo-A by function-blocking antibodies induced a major alteration in the dendrite structure of hippocampal pyramidal neurons. Although spine density was not influenced by Nogo-A neutralization, spine type distribution was shifted toward a more immature phenotype. Axonal complexity and length were greatly increased. Nogo-A KO mice revealed a weak dendritic phenotype resembling the effect of the antibody treatment. To discriminate a possible cellautonomous role of Nogo-A from an environmental, receptor-mediated function, we studied the effects of short hairpin RNA-induced knockdown of Nogo-A or NgR1, a prominent Nogo-A receptor, within individual neurons. Knockdown of Nogo-A reproduced part of the dendritic and none of the spine or axon alterations. However, downregulation of NgR1 replicated the dendritic, the axonal, and the spine alterations observed after Nogo-A neutralization. Together, our results demonstrate that Nogo-A plays a major role in stabilizing and maintaining the architecture of hippocampal pyramidal neurons. Mechanistically, although the majority of the activity of Nogo-A relies on a receptor-mediated mechanism involving NgR1, its cell-autonomous function plays a minor role.

Minocycline but not valproic acid influence the density of NogoA-immunoreactive neurons in the hilus of the dentate gyrus of the rats subjected to intracerebral haematoma

“…During development, Nogo-A influences migration and neurite outgrowth of cortical neurons [31], conducts corticospinal axons growing along the spinal cord, and regulates the progressive restriction of plasticity [8,27]. Few data from studies on adult brains have been published suggesting that NogoA constitutively controls the architecture of neurons in the intact hippocampus (mainly via a receptor mediated mechanisms) [33,44]. Moreover, electrophysiological studies revealed that NogoA or NogoA receptor neutralisation significantly increased the long term potentiation in hippocampal neurons [7].…”

Amino-Nogo-A antagonizes reactive oxygen species generation and protects immature primary cortical neurons from oxidative toxicity

“…9 In the adult CNS, Nogo-A proteins are located at synapse and restrict synaptic plasticity 10 and stabilize the architecture of hippocampal neurons. 11 To date, new findings of neuronal Nogo-A are logically in line with localization of Nogo-A and Nogo-66/NgRmediated signaling; however, concrete evidence for a direct role of amino-Nogo-A in the CNS is not yet available.…”

NogoA restricts synaptic plasticity in the adult hippocampus on a fast time scale

“…It is noteworthy that NogoA/NgR1 are expressed in pyramidal cells of the hippocampus (12), that their expression is regulated by neuronal activity (16,17), and that NgR1 is located at synapses in the adult CNS (18). However, the physiological role of neuronal NogoA in the hippocampus of adult animals has remained largely unexplored (for a review see ref.…”