Biology subjects

Masana, M.

Publications and source records attributed to Masana, M..

4 recordsLinked to original sources

bioRxiv2020

Hippocampal Egr1-dependent neuronal ensemblesnegatively regulate motor learning

Motor skills learning is classically associated with brain regions including cerebral and cerebellar cortices and basal ganglia. Less is known about the role of the hippocampus in the acquisition and storage of motor skills. Here we show that mice receiving a long-term training in the accelerating rotarod display marked transcriptional changes in the striatum and hippocampus when compared with short-term trained mice. We identify Egr1 as a modulator of gene expression in the hippocampus during motor learning. Using mice in which neural ensembles are permanently labeled in an Egr1 activity-dependent fashion we identify ensembles of Egr1-expressing pyramidal neurons in CA1 activated in short- and long-term trained mice in the rotarod task. When Egr1 is downregulated or these neuronal ensembles are depleted, motor learning is improved whereas their chemogenetic stimulation impairs motor learning performance. Thus, Egr1 organizes specific CA1 neuronal ensembles during the accelerating rotarod task that limit motor learning.

neuroscience↗

bioRxiv2020

RTP801 Is A Key Modulator For Motor Learning

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 Parkinsons and Huntingtons diseases and is up regulated in compromised neurons in human postmortem brains of both neurodegenerative disorders. Indeed, in both Parkinsons and Huntingtons 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.

neuroscience↗

bioRxiv2020

M2 Cortex-Dorsolateral striatum stimulation reverses motor symptoms and synaptic deficits in Huntington's Disease

Huntingtons disease (HD) is a neurological disorder characterized by motor disturbances. HD pathology is most prominent in the striatum, the central hub of basal ganglia. The cortex is the main striatal afference and progressive cortico-striatal disconnection characterizes HD. We mapped cortico-striatal dysfunction in HD mice to ultimately modulate the activity of selected cortico-striatal circuits to ameliorate motor symptoms and recover synaptic plasticity. Multimodal MRI in vivo suggested prominent functional network deficits in fronto-striatal compared to motor-striatal pathways, which were accompanied by reduced glutamate levels in the striatum of HD mice. Moreover, optogenetically-stimulated glutamate release from fronto-striatal terminals was reduced in HD mice and electrophysiological responses in striatal neurons were blunted. Remarkably, repeated M2 Cortex-dorsolateral striatum optogenetic stimulation normalized motor behavior in HD mice and evoked a sustained increase of synaptic plasticity. Overall, these results reveal that the selective stimulation of fronto-striatal pathways can become an effective therapeutic strategy in HD.

neuroscience↗

bioRxiv2020

SYNAPTIC RTP801 CONTRIBUTES TO MOTOR LEARNING DYSFUNCTION IN HUNTINGTON DISEASE

RTP801/REDD1 is a stress responsive protein that mediates mutant huntingtin (mhtt) toxicity in cellular models and is up regulated in Huntingtons disease (HD) patients putamen. Here, we investigated whether RTP801 is involved in motor impairment in HD by affecting striatal synaptic plasticity. Ectopic mhtt was over expressed in cultured rat primary neurons. The protein levels of RTP801 were assessed in homogenates and crude synaptic fractions from human postmortem HD brains and mouse models of HD. Striatal RTP801 expression was knocked down with adeno-associated viral particles containing a shRNA in the R6/1 mouse model of HD and motor learning was then tested. Ectopic mhtt elevated RTP801 in synapses of cultured neurons. RTP801 was also up regulated in striatal synapses from HD patients and mouse models. Knocking down RTP801 in the R6/1 mouse striatum prevented motor learning impairment. RTP801 silencing normalized the Ser473 Akt hyperphosphorylation by downregulating Rictor and it induced synaptic elevation of calcium permeable GluA1 subunit and TrkB receptor levels, suggesting an enhancement in synaptic plasticity. These results indicate that mhtt-induced RTP801 mediates motor dysfunction in a HD murine model, revealing a potential role in the human disease. These findings open a new therapeutic framework focused on the RTP801/Akt/mTOR axis.

neuroscience↗