SYNGAP1, a synaptic Ras GTPase activating protein deficiency is associated with severe intellectual disability in humans. Zebrafish models of SYNGAP1 syndrome overlaps traits as also observed in humans. Currently at least three isoforms of heterozygous variants of SYNGAP1 has been established in zebrafish model. They display early signs of hyperexcitability as early as day 2 post fertilization (dpf) with lack of conditional learning by 7 dpf. These, mutants also lose the ability to differentiate novel objects with associated poor sleep bouts and episodic seizure.. The condition further progresses with loss of muscle tone, hypotonia which leads to poor swim performance in opposing water current that further develops into aggressive behaviour observed as darting and wall butt activities.
Screening Modalities
Anticonvulsants : Gabapentin 20 ug dosed as oral pellets had short term rescue of episodic seizures. At 20-27ug doses once per day showed significant increased in betterment of sleep bouts in SYNGAP1 Zebrafish Model. However, gabapentin had no significant effect on rescue of motor co-ordination, muscle tone and other pathologies. While the activity of gabapentin had focused on reducing synaptic conductivity density, the impact on muscle tone improvements and therefore overall improvements had been negligible.
Statins: Clinical cases have shown short term positive outcome of statins on SYNGAP1 patients, therefore we investigated Rosuvastatin 1.3 ng once per day through oral pellets. A significant improvement in locomotion, and improvements in swim motion performance in water treadmill was observed in SYNGAP1 Zebrafish Model. However episodic tremors and outcomes on hypotonia were marginal. Behavioural rescue turned to be more negative than without treatment.
Carbonic anhydrase Inhibitor: A delayed but significant improvement in hypotonia, muscle function, episodic seizure for upto 3 weeks post dosing of Methazolamide 0.8ng was observed. Additionally a marginal improvement in learning and delay in aggressive behaviour phenotype was also noted. Hyperexcitability measured through auditory and bright white light stimuli was observed to drop significant from 3 days post dosing until 17 th days afterwards in SYNGAP1 Zebrafish Model.
Rescue strategies could focus on phenotype rescue of pathology and also improvements in physiological function post treatment. Using Pentagrit SYNGAP1 zebrafish model, SNGAP1 isoform modulation could be a path forward to create successful biomarker based clinical candidates.
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