Rtp801 Regulates Motor Cortex Synaptic Transmission and Learning

Abstract

RTP801/REDD1 is a stress-regulated protein whose upregulation is necessary and sufficient to trigger neuronal death in in vitro and in vivo models of Parkinson's and Huntington's diseases and is up regulated in compromised neurons in human postmortem brains of both neurodegenerative disorders. Indeed, in both Parkinson's and Huntington's disease mouse models, RTP801 knockdown alleviates motor-learning deficits. Here, we investigated the physiological role of RTP801 in neuronal plasticity. RTP801 is found in rat, mouse and human synapses. The absence of RTP801 enhanced excitatory synaptic transmission in both neuronal cultures and brain slices from RTP801 knock-out (KO) mice. Indeed, RTP801 KO mice showed improved motor learning, which correlated with lower spine density but increased basal filopodia and mushroom spines in the motor cortex layer V. This paralleled with higher levels of synaptosomal GluA1 and TrkB receptors in homogenates derived from KO mice motor cortex, proteins that are associated with synaptic strengthening. Altogether, these results indicate that RTP801 has an important role modulating neuronal plasticity in motor learning.

RTP801/REDD1 is Involved in Neuroinflammation and Modulates Cognitive Dysfunction in Huntington’s Disease

“…Remarkably, a mild restoration of GluA1 and TrkB.FL synaptic levels was observed, in line with previous results from our group [30,32]. Indeed, the RTP801 total knockout mouse shows increased levels of cortical GluA1 and TrkB.FL, in good correlation with the enhanced synaptic transmission observed in these animals [32], and RTP801 striatal silencing in the R6/1 model enhances the expression of both synaptic proteins in this brain area [30]. On the one hand, AMPAR subunit GluA1 confers calcium permeability to the receptor, promoting the activation of intracellular signaling cascades critical for synaptic transmission and plasticity [58][59][60][61].…”

“…We also confirmed the decreased levels of synaptic markers such as PSD-95, GluA1 AMPAR subunit and TrkB.FL receptor in the R6/1 mouse hippocampus [18,48,49]. Remarkably, a mild restoration of GluA1 and TrkB.FL synaptic levels was observed, in line with previous results from our group [30,32]. Indeed, the RTP801 total knockout mouse shows increased levels of cortical GluA1 and TrkB.FL, in good correlation with the enhanced synaptic transmission observed in these animals [32], and RTP801 striatal silencing in the R6/1 model enhances the expression of both synaptic proteins in this brain area [30].…”

“…RTP801 mediates synaptic transmission and motor learning behavior in physiological conditions. Moreover, RTP801 abrogation increases GluA1 and TrkB levels [32]. RTP801 protein levels are also elevated in Parkinson's disease (PD) [33,34], major depression [35] and Alzheimer's disease (AD) [36].…”