Table 1.
Overview and comparison of phenotypes and treatments in mouse models for four different RASopathies.
| Phenotype | Mouse Model | Costello Syndrome (CS) | Neurofibromatosis Type 1 (NF1) | Noonan Syndrome (NS)10 | Legius syndrome (LS)11 |
|---|---|---|---|---|---|
| Gene | HRAS | NF1 | PTPN11 | SPRED1 | |
| Mutation | HRAS G12V/G12V | NF +/− | Ptpn11 D61G/+ | SPRED1 −/− | |
| pERK level | Strongly increased# | Moderately increased8, 24, 31 | Moderately-strongly increased | Normal-slightly increased | |
| Behavior | |||||
| Morris Water Maze | Impaired#, 17 | Impaired8, 24, 25, 31 | Impaired | Impaired | |
| Contextual fear conditioning | Normal#, 1, 17 | Impaired8, 24 | Impaired | ||
| Rotarod | Normal#, 17 | Impaired25, 54 | Normal | ||
| Neuronal function | |||||
| LTP (TBS induced) | Normal# | Impaired ↓8, 24, 25, 31 | Impaired ↓ | Impaired ↓ | |
| LTD | mGluR-LTD ↓# | LFS-LTD ↑ | |||
| Inhibitory function (s/m/eIPSCs)* | Normal# | Increased8, 24, 25 | Normal | ||
| Excitatory function (s/mEPSCs) | Normal# | Normal24, 25 | Increased | ||
| I/O at strong stimulation | Normal# | Impaired8, 24 | Normal | Impaired | |
| Short term/PPF | Normal# | Normal8, 25 | Normal | ↑ | |
| Ih current | Normal25 | ↓25 | |||
| Brain morphology | |||||
| Craniofacial features | Abnormal#, 2 | Normal8, 25 | Abnormal52 | ||
| Gross brain morphology | Abnormal#; Normal39, ** | ||||
| Cell size/Cell number | Increased#, 4/Increased39, * | ||||
| Treatment: Lovastatin | |||||
| Treatment | 10 mg/kg, IP, adult mice, 3 days before the first training day, and then daily during behavioral training#, 9, 31 | ||||
| pERK level normalized? | No | Yes | Yes | ||
| Behavioral deficit rescued? | No | Yes | Yes | ||
| LTP rescued? | (No phenotype) | Yes | Yes | ||
| Treatment: MEK-inhibitor | |||||
| Drug | PD0325901# | PD03259019 | SL327 | ||
| Treatment | 2 mg/kg, IP, adult mice, 3 days before the first training day, and then daily during behavioral training | 5 mg/kg, oral gavage, daily administration to lactating females for the treatment of P0.5– P18 mice | 32 mg/kg, IP, adult mice, daily during behavioral training | ||
| pERK level normalized? | Yes | Yes9 | Yes | ||
| Behavioral deficit rescued? | No | Yes | |||
| Brain morphology rescued? | No | Yes9 | |||
| Neuronal function rescued? | Yes (mGlur-LTD)# (U0126, 1 µM) | Yes (mIPSC)24, (U0126, 10 µM) | Yes (LTP) (SL327, 1 µM) | ||
Abbreviations: TBS – theta burst stimulation; LFS - low frequency stimulation, ↑ - significant increase; ↓ - significant decrease; Normal - no difference observed; “−” – no rescue observed; “+” – rescue observed; LTD – long-term depression; LTP – long-term potentiation; I/O – input/output; pERK – phosphorylated ERK; IP – Intra peritoneal injection; s-, m-, e E/IPSCs – spontaneous-, miniature- or evoked- excitatory (E)/inhibitory (I) postsynaptic currents; * - mIPSCs recordings in high KCl concentration (12,5 mM); ** - young animals, E14-P7; #- current study.