Time‐dependent changes in the mouse hippocampal synaptic membrane proteome after contextual fear conditioning

Abstract

A change in efficacy of hippocampal synapses is critical for memory formation. So far, the molecular analysis of synapses during learning has focused on small groups of proteins, whereas the dynamic global changes at these synapses have remained unknown. Here, we analyzed the temporal changes of the mouse hippocampal synaptic membrane proteome 1 and 4 h after contextual fear learning, comparing two groups; (1) a fear memory forming "delayed-shock" group and (2) a fear memory-deficient "immediate-shock" group. No changes in protein expression were observed 1 h after conditioning between the two experimental groups. However, 423 proteins were significantly regulated 4 h later of which 164 proteins showed a temporal regulation after a delayed shock and 273 proteins after the stress of an immediate shock. From the proteins that were differentially regulated between the delayed- and the immediate-shock groups at 4 h, 48 proteins, most prominently representing endocytosis, (amphiphysin, dynamin, and synaptojanin1), glutamate signaling (glutamate [NMDA] receptor subunit epsilon-1, disks large homolog 3), and neurotransmitter metabolism (excitatory amino acid transporter 1, excitatory amino acid transporter 2, sodium- and chloride-dependent GABA transporter 3) were regulated in both protocols, but in opposite directions, pointing toward an interaction of learning and stress. Taken together, this data set yields novel insight into diverse and dynamic changes that take place at hippocampal synapses over the time course of contextual fear-memory learning.

Strain Differences in Presynaptic Function

“…However, with Rab3A expression (triple knock-out) there was no apparent decrease in evoked responses. We compared our dataset with observed regulation of hippocampal synaptic membrane proteins 4 h after contextual fear conditioning (plasticity related to learning) (30). It is of interest to note that we found overlap between datasets in six (out of seven) exocytosis proteins that were differentially expressed in DBA mice.…”

Posttraumatic stress disorder: A metabolic disorder in disguise?

“…Fear conditioning in rodents results in alterations of serotonin and norepinephrine in the hippocampus and prefrontal cortex (Wilson et al, 2014a) and altered metabolism of dopamine and acetylcholine (Okada et al, 2015), both characteristics of PTSD pathophysiology in humans. Animal models have also implicated alterations in the transcriptome of the amygdala in underlying neuronal plasticity (Ponomarev et al, 2010) and changes in hippocampal plasticity via proteomic alterations (Rao-Ruiz et al, 2015). Similar to the HPA axis dysregulation in PTSD, fear conditioning in rodents has been linked to prefrontal GR activity (Reis et al, 2015) and FKBP5 expression (Chakraborty et al, 2015).…”

Gpr158 deficiency impacts hippocampal CA1 neuronal excitability, dendritic architecture, and affects spatial learning

“…Previously, we have observed Gpr158 strongly upregulated in the hippocampus synaptic membrane fraction after stress of an immediate shock (Rao-Ruiz et al, 2015). The stress-responsiveness of Gpr158 was further illustrated by its rapid and robust increase in expression upon glucocorticoid stimulation either in vitro (Patel et al, 2013), or in vivo (Sutton et al, 2018).…”