Synaptic destabilization by neuronal Nogo-A

Abstract

Formation and maintenance of a neuronal network is based on a balance between plasticity and stability of synaptic connections. Several molecules have been found to regulate the maintenance of excitatory synapses but nothing is known about the molecular mechanisms involved in synaptic stabilization versus disassembly at inhibitory synapses. Here, we demonstrate that Nogo-A, which is well known to be present in myelin and inhibit growth in the adult CNS, is present in inhibitory presynaptic terminals in cerebellar Purkinje cells at the time of Purkinje cell-Deep Cerebellar Nuclei (DCN) inhibitory synapse formation and is then downregulated during synapse maturation. We addressed the role of neuronal Nogo-A in synapse maturation by generating several mouse lines overexpressing Nogo-A, starting at postnatal ages and throughout adult life, specifically in cerebellar Purkinje cells and their terminals. The overexpression of Nogo-A induced a progressive disassembly, retraction and loss of the inhibitory Purkinje cell terminals. This led to deficits in motor learning and coordination in the transgenic mice. Prior to synapse disassembly, the overexpression of neuronal Nogo-A led to the downregulation of the synaptic scaffold proteins spectrin, spectrin-E and beta-catenin in the postsynaptic neurons. Our data suggest that neuronal Nogo-A might play a role in the maintenance of inhibitory synapses by modulating the expression of synaptic anchoring molecules.

Cutting Edge: TIGIT Has T Cell-Intrinsic Inhibitory Functions

“…Indeed, 2D2 3 TIGIT 2/2 mice showed atypical signs of neurologic dysfunction as early as 28 d after birth (Fig. 3B), and with advancing age all 2D2 3 TIGIT 2/2 mice displayed dyskinesia, ataxia, and a clasping phenotype (9). Some of the 2D2 mice also showed these atypical symptoms.…”

Neuronal Nogo-A upregulation does not contribute to ER stress-associated apoptosis but participates in the regenerative response in the axotomized adult retina

“…This probably toxic overexpression is in line with earlier similar observations. 18,30 The situation in the retina therefore also differs from a model of ALS, where the ablation of the Nogo-A/B gene accelerated the degeneration of ventral motor neuron axons, 15 whereas the systemic absence of Nogo-A slowed the disease, and Nogo-A overexpression in muscle enhanced neuromuscular endplate degeneration. 30 Recent studies showed that the neutralization of Lingo or NgR1, 2 receptor components for Nogo-A, promoted RGC survival after optic nerve transection.…”

“…15 Only few and contradictory observations are available on such a role of Nogo (reticulon 4 (RTN4)) or other RTN proteins, and they rely mostly on in vitro or overexpression experiments. 15,[17][18][19][20][21] We therefore investigated axonal regeneration and survival of RGCs after optic nerve crush in mice with systemic Nogo-A deletion (KO) or neuron-specific knock down using adeno-associated virus vector of serotype 2 (AAV2) that selectively infect RGCs in the retina. For the first time, our work demonstrates that the exogenous increase of neuronal Nogo-A driven by AAV2.Nogo-A, but not the endogenous upregulation of neuronal Nogo-A because of axonal damage enhanced RGC cell loss.…”

Nogo-A Stabilizes the Architecture of Hippocampal Neurons

“…In ngr1 (McGee et al, 2005) and in pirB knock-out mice (Syken et al, 2006), ocular dominance plasticity continues after the end of the critical period, suggesting that NgR1 and PirB signaling contribute to stabilizing the neural circuitry and to temporally limit experiencedependent plasticity. In the mouse cerebellum, overexpression of Nogo-A leads to an age-dependent destabilization and loss of synapses of Purkinje cells (Aloy et al, 2006). Furthermore, NgR1 signaling has been shown to regulate activity-dependent synaptic strength in hippocampal CA1 neurons (Lee et al, 2008).…”