4E-BP2–dependent translation in parvalbumin neurons controls epileptic seizure threshold

Abstract

The mechanistic/mammalian target of rapamycin complex 1 (mTORC1) integrates multiple signals to regulate critical cellular processes such as mRNA translation, lipid biogenesis, and autophagy. Germline and somatic mutations in mTOR and genes upstream of mTORC1, such as PTEN, TSC1/2, AKT3, PIK3CA, and components of GATOR1 and KICSTOR complexes, are associated with various epileptic disorders. Increased mTORC1 activity is linked to the pathophysiology of epilepsy in both humans and animal models, and mTORC1 inhibition suppresses epileptogenesis in humans with tuberous sclerosis and animal models with elevated mTORC1 activity. However, the role of mTORC1-dependent translation and the neuronal cell types mediating the effect of enhanced mTORC1 activity in seizures remain unknown. The eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) and 2 (4E-BP2) are translational repressors downstream of mTORC1. Here we show that the ablation of 4E-BP2, but not 4E-BP1, in mice increases the sensitivity to pentylenetetrazole (PTZ)- and kainic acid (KA)–induced seizures. We demonstrate that the deletion of 4E-BP2 in inhibitory, but not excitatory neurons, causes an increase in the susceptibility to PTZ-induced seizures. Moreover, mice lacking 4E-BP2 in parvalbumin, but not somatostatin or VIP inhibitory neurons exhibit a lowered threshold for seizure induction and reduced number of parvalbumin neurons. A mouse model harboring a human PIK3CA mutation that enhances the activity of the PI3K-AKT pathway (Pik3caH1047R-Pvalb) selectively in parvalbumin neurons shows susceptibility to PTZ-induced seizures. Our data identify 4E-BP2 as a regulator of epileptogenesis and highlight the central role of increased mTORC1-dependent translation in parvalbumin neurons in the pathophysiology of epilepsy.

DEPDC5-dependent mTORC1 signaling mechanisms are critical for the anti-seizure effects of acute fasting

“…We found the expression and sensitivity of 4EBP1 to be low. It is also suggested that 4EBP2, not 4EBP1, controls mTORC1 signaling, at least in parvalbumin-positive neurons (Sharma et al, 2021). Although our results are largely consistent with prior studies, the differences may be due to methodological or cell-type differences.…”

Genetic expression of 4E-BP1 in juvenile mice alleviates mTOR-induced neuronal dysfunction and epilepsy

“…Furthermore, while our data underscore that many alterations can be rescued by c4E-BP1 CA expression, it should not be inferred that dysregulated 4E-BP1 activity alone causes seizures. A recent study showed that ablation of 4E-BP2, but not 4E-BP1, reduces the threshold to chemoconvulsant-induced seizures in mice, although neither resulted in spontaneous seizures (Sharma et al, 2021). Interestingly, the effects on seizure threshold were specific to 4E-BP2 deletion in parvalbumin inhibitory neurons and not in other inhibitory or excitatory neurons in the hippocampus.…”

PARVing the Way to Cap Translation for Seizure Control

“…4 In a tours de force employing 11 different mouse lines, Sharma and colleagues recently shed more light on molecular and cellular mediators of mTOR-related regulation of brain excitability. 5 They provided support for neuronal mTORC1 signaling as a driver of brain excitability while at the same time emphasizing the importance of neuronal subtype.…”