Figure 4. Inhibiting Shh pathway suppresses epileptogenesis in mouse epilepsy models.

• A–L
  Effects of Cyclo (A–C, n = 14), 5E1 (D–F, n = 16–20), or ablation of Smo in CaMKIIα‐positive neurons (G–I), or ablation of Smo in Aldh1l1‐positive astrocytes (J–L) on the progression of kindling including seizure class (A, D, G, J), evoked electrographic seizure duration (ESD) (B, E, H, K), and the number of stimulations required to reach equivalent seizure intensity (C, F, I, L). In (A–F), Ctrl are vehicle‐treated mice. In (G–I), Ctrl: Smo ^fl/fl induced by tamoxifen; CaMK: Smo ^fl/fl CaMKIIα‐Cre ^ERT2 induced by tamoxifen, n = 14‐20. In (J–L), Ctrl: Smo ^+/fl; Aldh1l1: Smo ^+/fl Aldh1l1‐Cre, n = 19–20.
• M
  Frequency of spontaneous seizures (class 4–5) in mice administrated with Cyclo or vehicle (Ctrl) at 4^th, 6^th, and 8^th week after pilocarpine SE induction. n = 22–23.
• N
  Percentage of mice with class 5 seizures within 8 weeks after pilocarpine SE induction. n = 22–23.
• O
  Schematic diagram depicting a working model for Shh regulation of epileptogenesis. Epileptic activity triggers sequential responses, including Shh release, inhibition of glutamate transporter activity, and increase in extracellular glutamate, leading to epilepsy development.

Data information: Cyclo: 10 mg/kg. 5E1: 900 ng/mouse. Data are mean ± SEM from at least three independent experiments. *P < 0.05; **P < 0.01; ***P < 0.001 vs. Ctrl with Student's t‐test.