Activation of the CREB/c-Fos Pathway during Long-Term Synaptic Plasticity in the Cerebellum Granular Layer

Abstract

The induction of long-term potentiation and depression (LTP and LTD) is thought to trigger gene expression and protein synthesis, leading to consolidation of synaptic and neuronal changes. However, while LTP and LTD have been proposed to play important roles for sensori-motor learning in the cerebellum granular layer, their association with these mechanisms remained unclear. Here, we have investigated phosphorylation of the cAMP-responsive element binding protein (CREB) and activation of the immediate early gene c-Fos pathway following the induction of synaptic plasticity by theta-burst stimulation (TBS) in acute cerebellar slices. LTP and LTD were localized using voltage-sensitive dye imaging (VSDi). At two time points following TBS (15 min and 120 min), corresponding to the early and late phases of plasticity, slices were fixed and processed to evaluate CREB phosphorylation (P-CREB) and c-FOS protein levels, as well as Creb and c-Fos mRNA expression. High levels of P-CREB and Creb/c-Fos were detected before those of c-FOS, as expected if CREB phosphorylation triggered gene expression followed by protein synthesis. No differences between control slices and slices stimulated with TBS were observed in the presence of an N-methyl-D-aspartate receptor (NMDAR) antagonist. Interestingly, activation of the CREB/c-Fos system showed a relevant degree of colocalization with long-term synaptic plasticity. These results show that NMDAR-dependent plasticity at the cerebellum input stage bears about transcriptional and post-transcriptional processes potentially contributing to cerebellar learning and memory consolidation.

LTD at amygdalocortical synapses as a novel mechanism for hedonic learning

“…There was a significant decrease in the number of c-Fos and EGR1 positive neurons following CTA ( Fig. 1d-f; c-Fos, control: 128.13 ± 9.46 positive nuclei/0.1mm 2 , N = 6, CTA: 82.21 ± 11.73 positive nuclei/0.1mm 2 , N = 6 rats, p < 0.01; EGR1, control: 175.90 ± 15.65 positive nuclei/0.1mm 2 , N = 6, CTA: 133.03 ± 10.10 positive nuclei/0.1mm 2 , N = 6, p < 0.05), suggesting that taste/malaise association decreased GC neurons activity, consistent with previous reports testing neuronal activity 2,12 and showing changes in markers for plasticity 10,13 .…”

Brainstem Nuclei Associated with Mediating Apnea-Induced Respiratory Motor Plasticity

“…However, these studies do not identify why LC neurons are activated in the LTF group, but not in the “No LTF” group; this would be the subject of future studies. But, as presented and interpreted, our data are consistent with previously studies showing that increases in c-Fos expression can be used to identify cells associated with inducing other forms of plasticity, such as granule cells and their role in mediating long-term potentiation (LTP) in the cerebellum 35 , or parvalbumin basket cells and their role in regulating plasticity 36 .…”

LTD at amygdalocortical synapses as a novel mechanism for hedonic learning

“…The decrease in the number of IEG-labeled neurons following CTA suggests that the associative learning between taste and malaise induced plastic changes in this region of GC, but does not indicate which form of plasticity these changes represent ( Inberg et al, 2013 ; Gandolfi et al, 2017 ). Indeed, the effect could result from changes to the intrinsic properties of GC neurons, affecting their overall excitability and input/output function.…”

“…Current thinking associates learning with an increase in synaptic efficacy ( Bliss and Collingridge, 1993 ; Rogan et al, 1997 ; Dityatev and Bolshakov, 2005 ), and changes in molecular markers for plasticity following CTA have been interpreted as indication of LTP expression ( Shema et al, 2007 ; Gal-Ben-Ari and Rosenblum, 2011 ). However, many of the molecular mechanisms involved in CTA ( Berman and Dudai, 2001 ; Gal-Ben-Ari and Rosenblum, 2011 ; Guzman-Ramos and Bermudez-Rattoni, 2012 ) can be engaged by both LTP and LTD ( Yilmaz-Rastoder et al, 2011 ; Gandolfi et al, 2017 ; Li and Pozzo-Miller, 2019 ). Additional evidence in support of the interpretation that CTA should potentiate BLA input to GC came from studies based on BLA activation with drug infusions or tetanic electrical stimulation during CTA learning.…”