Proteasome and Autophagy-Mediated Impairment of Late Long-Term Potentiation (l-LTP) after Traumatic Brain Injury in the Somatosensory Cortex of Mice

Abstract

Traumatic brain injury (TBI) can lead to impaired cognition and memory consolidation.The acute phase (24–48 h) after TBI is often characterized by neural dysfunction in the vicinity ofthe lesion, but also in remote areas like the contralateral hemisphere. Protein homeostasis is crucialfor synaptic long-term plasticity including the protein degradation systems, proteasome andautophagy. Still, little is known about the acute effects of TBI on synaptic long-term plasticity andprotein degradation. Thus, we investigated TBI in a controlled cortical impact (CCI) model in themotor and somatosensory cortex of mice ex vivo-in vitro. Late long-term potentiation (l-LTP) wasinduced by theta-burst stimulation in acute brain slices after survival times of 1–2 days. Proteinlevels for the plasticity related protein calcium/calmodulin-dependent protein kinase II (CaMKII)was quantified by Western blots, and the protein degradation activity by enzymatical assays. Weobserved missing maintenance of l-LTP in the ipsilateral hemisphere, however not in thecontralateral hemisphere after TBI. Protein levels of CaMKII were not changed but, interestingly,the protein degradation revealed bidirectional changes with a reduced proteasome activity and anincreased autophagic flux in the ipsilateral hemisphere. Finally, LTP recordings in the presence ofpharmacologically modified protein degradation systems also led to an impaired synaptic plasticity:bath-applied MG132, a proteasome inhibitor, or rapamycin, an activator of autophagy, bothadministered during theta burst stimulation, blocked the induction of LTP. These data indicate thatalterations in protein degradation pathways likely contribute to cognitive deficits in the acute phaseafter TBI, which could be interesting for future approaches towards neuroprotective treatmentsearly after traumatic brain injury.

Molecular Mechanism and Regulation of Autophagy and Its Potential Role in Epilepsy

“…There is growing evidence for autophagy in LTP and LTD, two major forms of synaptic plasticity. Autophagy activator rapamycin can block late LTP induced by theta burst stimulation in the mouse cortex, leading to impaired synaptic plasticity [ 244 ]. In addition, some evidence suggests that the pharmacological inhibition of neuronal autophagy with Spautin-1 also administers the induction of LTP in CA1, whereas autophagy inhibition with BDNF is found to permit LTP in hippocampal regions [ 224 , 241 ].…”

Homeostatic Roles of the Proteostasis Network in Dendrites

“…Axonal Wallerian degeneration relies on autophagy, and although dendrites can be rapidly dismantled, it does not appear to occur through the same mechanisms as in axons, so autophagy may not be used in dendritic degeneration in the same way (Tao and Rolls, 2011;Yang et al, 2013). In mouse models with induced traumatic brain injuries, proteasomal activity decreased in the general area of injury, while autophagic markers increased; however, there is still some debate as to whether autophagy and UPS are neuroprotective or neurotoxic in cases of dendritic and axonal injury or ischemia (Yang et al, 2013;Feldmann et al, 2019;Gerónimo-Olvera and Massieu, 2019). Though it is still unclear how the two degradative subsystems interact, research indicates that they cooperate with one another in select situations (Yue et al, 2009;Feldmann et al, 2019).…”

“…In mouse models with induced traumatic brain injuries, proteasomal activity decreased in the general area of injury, while autophagic markers increased; however, there is still some debate as to whether autophagy and UPS are neuroprotective or neurotoxic in cases of dendritic and axonal injury or ischemia (Yang et al, 2013;Feldmann et al, 2019;Gerónimo-Olvera and Massieu, 2019). Though it is still unclear how the two degradative subsystems interact, research indicates that they cooperate with one another in select situations (Yue et al, 2009;Feldmann et al, 2019). For comprehensive reviews on UPS-autophagy interactions see Lilienbaum (2013) and Kocaturk and Gozuacik (2018).…”

Synaptic Plasticity in the Injured Brain Depends on the Temporal Pattern of Stimulation

“…Such changes have been observed throughout the brain including in the: hippocampus [28][29][30][31], visual cortex [32][33][34], olfactory cortex [35,36], somatosensory and motor cortices [37][38][39], striatum [40,41] and cerebellum [42,43]. LTP and LTD are also implicated in refinement of synaptic connections during brain development and in functional reorganization of neuronal networks throughout the lifespan [21,[44][45][46][47][48][49][50], after brain injury [51][52][53][54][55][56], and during neuro-rehabilitation for brain injury or disease [57][58][59][60][61][62][63]. It is of interest to learn whether these synaptic plasticity processes may be selectively evoked to facilitate a compensatory re-balancing of the relative strengths of particular synaptic pathways after mTBI and thus become part of the therapeutic toolbox for restoring functionality [64][65][66].…”