Epileptiform activity influences theta-burst induced LTP in the adult hippocampus: a role for lipid raft dynamics in early metaplasticity

Abstract

Non-epileptic seizures are identified as a common epileptogenic trigger. Early metaplasticity following seizures may contribute to epileptogenesis by abnormally altering synaptic strength and homeostatic plasticity. We now studied how in vitro epileptiform activity triggers early changes in CA1 long-term potentiation (LTP) induced by theta-burst stimulation (TBS) in rat hippocampal slices and the involvement of lipid rafts in these early metaplasticity events. Two forms of epileptiform activity (EA) were induced: 1) interictal-like EA triggered by withdrawal of Mg2+ and K+ elevation to 6mM in the superfusion medium or 2) ictal-like EA induced by bicuculine (10 μM) delivery. LTP induced 30 min post EA was impaired, an effect more pronounced after ictal-like EA. LTP recovered to control levels 60 min post interictal-like EA but was still impaired 60 min after ictal-like EA. The synaptic molecular events underlying this altered LTP were investigated 30 min post EA. Synaptosomes isolated from parallel slices showed enhanced AMPA GluA1 Ser831 phosphorylation but decreased Ser 845 phosphorylation and a marked decrease in GluA1/GluA2 ratio. A marked decrease in flotillin-1 and caveolin-1 levels concomitantly with a moderate increase in PSD-95 and marked increase in gephyrin levels. Altogether, EA differentially influences hippocampal CA1 LTP thorough regulation of GluA1/GluA2 levels and AMPA GluA1 phosphorylation suggesting altered LTP post-seizures may be a relevant target of antiepileptogenic therapies. In addition, this metaplasticity is also associated with marked alterations in classic and synaptic lipid raft markers, suggesting these may also constitute promising targets in epileptogenesis prevention.

Regulation of depressive‐like behaviours by palmitoylation: Role of AKAP150 in the basolateral amygdala

“…In addition, protein palmitoylation was changed along with the alteration of neuronal activity, for example, blocking synaptic activity rapidly induces PSD‐95 palmitoylation and mediates synaptic clustering of PSD‐95 and associated AMPA‐type glutamate receptors (Noritake et al, 2009). In contrast, AKAP150 palmitoylation and its association with synaptic lipid raft increased following seizure activity in vivo (Carvalho‐Rosa et al, 2023), and such findings indicated that neuronal activity bidirectionally modulates protein palmitoylation in the BLA. However, what is the possible explanation for the difference between anxiety and depression in protein palmitoylation?…”

Mismatch novelty exploration training shifts VPAC1 receptor‐mediated modulation of hippocampal synaptic plasticity by endogenous VIP in male rats

“…For studying changes in VPAC 1 receptor expression that could be relevant for synaptic plasticity, we used hippocampal synaptosomes, thus avoiding probing VPAC 1 receptors in other cell types, like microglia (Cunha‐Reis et al., 2021), that could mask small variations occurring in synaptic contacts. Hippocampal synaptosomes were isolated from the hippocampal tissue of trained animals within 3–5 days after training completion as previously described (Carvalho‐Rosa et al., 2023). Briefly, the hippocampi of CTR, HT, FT, and NT 6‐ to 7‐week‐old rats were collected in sucrose solution (320 mM Sucrose, 1 mg/mL BSA, 10 mM HEPES e 1 mM EDTA, pH 7,4) containing protease (complete, mini, EDTA‐free Protease Inhibitor Cocktail, Sigma) and phosphatase (1 mM PMSF, 2 mM Na 3 VO 4 , and 10 mM NaF) inhibitors, homogenized with a Potter‐Elvejham apparatus and the hippocampal homogenates were centrifuged at 3000 g for 10 min at 4°C; the supernatant was then centrifuged at 14,000 g for 12 min at 4°C and the pellet resuspended in 3 mL of a Percoll 45% (v/v) in modified aCSF.…”