Potential mTORC1-dependent mechanisms involved in epileptogenesis and altered social behavior following neonatal seizures.

<p>Neonatal seizures induce intense synaptic activity followed by rapid increases in extracellular glutamate and BDNF levels (within 1 h post-HS; <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0035885#pone-0035885-g004" target="_blank">Figure 4A</a>). Activation of glutamate receptors, including NMDA receptors (NMDARs) and Ca²⁺-permeable AMPA receptors (CP-AMPARs) <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0035885#pone.0035885-Rakhade3" target="_blank">[44]</a>, followed by opening of L-type voltage-gated Ca²⁺ channels (VGCCs), results in increased Ca²⁺ influx. Enhanced expression and function of BDNF activates the membrane-bound tyrosine kinase B receptors (TRKBRs) and, together with Ca²⁺ influx, leads to the recruitment of the PI3K/PDK1/Akt and the Ras/MEK/ERK signaling pathways (within 1–3 h post-HS; <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0035885#pone-0035885-g004" target="_blank">Figure 4B–C</a>). Akt- and ERK-dependent inactivation of Tsc1/Tsc2 complex results in activation of Rheb GTP-ase, and subsequent induction of mTORC1 activity (within 12–24 h post-HS; <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0035885#pone-0035885-g003" target="_blank">Figure 3</a>). In turn, the mTORC1 may inhibit 4EBP1 and enhance the activity of p70S6K at 12 h post-HS, leading to enhanced eIF4E and S6 signaling, and increased protein translation at 24 h post-HS. The negative feedback inhibition between p70S6K and PI3K may account for the time lag between p70S6K and S6 phosphorylation changes. Altered TORC1-dependent translation of synaptic plasticity proteins (such as PSD-95, CamKII, Arc, GluR1) <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0035885#pone.0035885-Schratt1" target="_blank">[40]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0035885#pone.0035885-Bramham1" target="_blank">[91]</a>, among with other important cellular processes regulated by the mTORC1 kinase (autophagy, ribosomal biogenesis and cellular metabolism) <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0035885#pone.0035885-Sengupta1" target="_blank">[92]</a>, may lead to both short-term and long-term neuronal hyperexcitability (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0035885#pone-0035885-g006" target="_blank">Figure 6B</a>), enhancement of synaptic function (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0035885#pone-0035885-g006" target="_blank">Figure 6C-F</a>), epilepsy (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0035885#pone-0035885-g007" target="_blank">Figure 7</a>), and autism-like behaviors (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0035885#pone-0035885-g008" target="_blank">Figure 8</a>). Treatment with the mTORC1 inhibitor rapamycin immediately before and after neonatal seizures reverses both early and late neurological and behavioral consequences (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0035885#pone-0035885-g006" target="_blank">Figures 6</a>–<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0035885#pone-0035885-g007" target="_blank"></a><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0035885#pone-0035885-g008" target="_blank">8</a>).