TABLE 3.
Functional abnormalities of rodent models of ADSHE
| Gene | CRHNA4 | CRHNB2 | |||||||
|---|---|---|---|---|---|---|---|---|---|
| Mutation | c.839C > T (S280F) | c.870_872dupGCT (L291dup: insL) | c.851C > T (S284L) | c.859G > C(V287L) | |||||
| Animal model | (amino‐acid change) | S252F‐KI | S248F‐KI | insL‐KI | S284L‐TG | S286L‐TG | V287L‐TG | V287L‐KI | V286L‐TG |
| Construct validity | CRHNA4‐S280F knock‐in | CRHNA4‐S280F knock‐in | CRHNA‐865‐873insGCT knock‐in | CRHNA4‐S284L transgenic | CRHNA4‐S284L transgenic | CRHNB2‐V287L transgenic | CRHNB2‐V287L knock‐in | CRHNB2‐V287L transgenic | |
| (J1 ES cell line) | (W9.5 ES cell line) | (J1 ES cell line) | (PDGF‐β promotor) | (Chrna4 promotor) | (TET‐OFF system) | (R1 ES cell line) | (PDGF‐β promotor) | ||
| Genetic background | C57BL/6 J | C57BL/6 | C57BL/6 J | Sprague–Dawley rat | Sprague–Dawley rat | FVB | C57BL/6 | Sprague–Dawley rat | |
| 129S4/SvJae | 129S4/SvJae | 129S4/SvJae | |||||||
| Face validity | Background EEG | Increase slow wave | Normal | Increase slow wave | Normal | Normal | Increase slow wave | Normal | |
| Spontaneous epileptic seizure | Motor seizure (wakefulness) | Non | Motor seizure (wakefulness) | ADSHE (NPA, NPD, ENW) during non‐REM | ADSHE (NPA, NPD, ENW) during non‐REM | Frequent ictal discharge (non‐REM > wakefulness) | Non | ADSHE (NPA) during non‐REM | |
| Behaviour | Reduction social interaction time | Disturbances in the normal sleep patterns | |||||||
| Increased activity level in novel environment | Anxiety‐related behaviour (increased activity level in novel environment) | ||||||||
| Predictive validity | Induced seizures | Shorter latencies to onset and longer seizure durations of nicotine‐induced seizure than wild type | Nicotine‐induced EEG‐insensitive DAC | Nicotine (4 mg kg‐1) induced partial seizure but not generalised seizure | Disturbed sleep pattern and circadian rhythm | Nicotine (0.5 and 1 mg kg‐1) induced seizure | |||
| Sub‐proconvulsive dose of picrotoxin (0.1 mg kg‐1) inhibis spontaneous seizures | Normal EEG background during DAC | Less severe nicotine‐induced seizures than wild type | Nicotine‐induced EEG‐insensitive DAC | Shorter latencies to onset and longer seizure durations of nicotine‐induced seizure than wild type | |||||
| Less severe nicotine‐induced seizures than wild type | Almost equal PTZ sensitivity | After DAC, EEG‐sensitive tonic–clonic seizure | |||||||
| Anticonvulsant sensitivity | CBZ inhibits DAC |
CBZ no effect on interictal discharge ZNS and DZP decrease interictal discharge (45%) |
CBZ no effect on interictal discharge ZNS decrease interictal discharge (70%) |
CBZ no effect on seizure frequency and duration, whereas CBZ supresses burst of cultured cortical neurones of V287L‐TG | CBZ no effect on ictal frequency and duration | ||||
| Others | Enhanced GABAergic inhibition induced by nicotine | Impaired reduction of glutamate release during sleep | Silencing V287L‐Chrna4 during embryonic state suppresses seizure severity | Reduced levels of anxiety | |||||
| Impaired synaptic and extrasynaptic GABAergic inhibition induced by nicotine | Silencing V287L‐Chrna4 after seizure onset unaffect seizure severity | Abnormal natural reward | |||||||
| Chronic furosemide administration prevents ADSHE onset | |||||||||
| Reference | [1] | [2] | [1] | [3, 4] | [5–9] | [10, 11] | [12, 13] | [14] | |
References: 1. Klaassen et al. (2006); 2. Teper et al. (2007); 3. Zhu et al. (2008); 4. Yamada et al. (2013); 5. Fukuyama, Fukuzawa, and Okada (2020); 6. K. Fukuyama, Fukuzawa, Okubo et al., (2020); 7. Fukuyama et al., (2020a); 8. Fukuyama et al., (2020b); 9. Fukuyama and Okada (2020); 10. Manfredi et al. (2009); 11. Gullo et al. (2014); 12. Xu et al. (2011); 13. O'neill et al. (2013); 14. Shiba et al. (2015).