Neutralization of Nogo-A Enhances Synaptic Plasticity in the Rodent Motor Cortex and Improves Motor Learning in Vivo

Abstract

The membrane protein Nogo-A is known as an inhibitor of axonal outgrowth and regeneration in the CNS. However, its physiological functions in the normal adult CNS remain incompletely understood. Here, we investigated the role of Nogo-A in cortical synaptic plasticity and motor learning in the uninjured adult rodent motor cortex. Nogo-A and its receptor NgR1 are present at cortical synapses. Acute treatment of slices with function-blocking antibodies (Abs) against Nogo-A or against NgR1 increased long-term potentiation (LTP) induced by stimulation of layer 2/3 horizontal fibers. Furthermore, anti-Nogo-A Ab treatment increased LTP saturation levels, whereas long-term depression remained unchanged, thus leading to an enlarged synaptic modification range. In vivo, intrathecal application of Nogo-A-blocking Abs resulted in a higher dendritic spine density at cortical pyramidal neurons due to an increase in spine formation as revealed by in vivo two-photon microscopy. To investigate whether these changes in synaptic plasticity correlate with motor learning, we trained rats to learn a skilled forelimb-reaching task while receiving anti-Nogo-A Abs. Learning of this cortically controlled precision movement was improved upon anti-Nogo-A Ab treatment. Our results identify Nogo-A as an influential molecular modulator of synaptic plasticity and as a regulator for learning of skilled movements in the motor cortex.

Nogo-A antibodies enhance axonal repair and remyelination in neuro-inflammatory and demyelinating pathology

“…Dendritic as well as synaptic spine architecture was shown to be influenced by Nogo-A and NgR1 signaling in the hippocampus [74]. Long term potentiation of hippocampal and cortical synapses was increased when Nogo-A or NgR1 were inactivated [75][76][77]. Furthermore, genetic deletion of the Nogo receptor family NgR1, NgR2, and NgR3 revealed an important role of Nogo-A as a brake on synapse formation in development [78].…”

Nogo Receptor 1 Confines a Disinhibitory Microcircuit to the Critical Period in Visual Cortex

“…Four or more days of MD during this interval yields saturating shifts in OD toward the nondeprived eye. In adult mice, longer periods of deprivation are required to shift OD (Sawtell et al, 2003;Fischer et al, 2007a;Morishita and Hensch, 2008;Sato and Stryker, 2008). The OD plasticity in adult mice is smaller in magnitude than during the critical period and operates through distinct mechanisms.…”

“…The OD plasticity in adult mice is smaller in magnitude than during the critical period and operates through distinct mechanisms. Studies using a range of experimental techniques reveal that OD plasticity engages both excitatory and inhibitory neurons in visual cortex (Taha et al, 2002;Gandhi et al, 2008;Stephany et al, 2014).…”

Motivational state, reward value, and Pavlovian cues differentially affect skilled forelimb grasping in rats

“…Even though the dexterity of rodents is limited when compared with primates (Lemon 2008), rodent skilled grasping shows strong similarities to human skilled reaching behavior (Whishaw et al 1992;Sacrey et al 2009;Klein et al 2012a). Skilled grasping protocols require several days of training to reach plateau performance , and were shown to be accompanied by motor cortex plasticity-including increased spine turnover and dendritic branching (Greenough et al 1985;Fu et al 2012), long-term potentiation (LTP) (Rioult-Pedotti et al 1998, 2000Zemmar et al 2014), and major shifts in cortical motor maps (Kleim et al 1998(Kleim et al , 2004. Protein synthesis has been shown to be required for skilled grasping learning and for neuronal plasticity in motor cortex (Kleim et al 2003;Luft et al 2004) and striatum (Wachter et al 2010).…”