SYNGAP1 Developmental and Epileptic Encephalopathy
Developmental and Epileptic Encephalopathies (DEEs)
Proper brain development requires precise levels of synaptic proteins. The consequences of synaptic protein abundance dysregulation are devastating neurologic disorders including Developmental and Epileptic Encephalopathies (DEEs). Precisely how SYNGAP1 mutations result in phenotypes is unclear, however, in published data, The Holder Lab discovered that complete deficiency of SynGAP in human neurons causes precocious and exuberant neuronal network firing. Additionally, our published data indicate cultured engineered human neurons completely deficient for SYNGAP1 have increased excitability and network connectivity.
The Holder Lab is working to identify candidate therapeutic approaches for this devastating epileptic encephalopathy.
SHANK3 and Phelan-McDermid syndrome
Haploinsufficiencies
Work done in rodent models of SYNGAP1 haploinsufficiency have revealed a critical function of the encoded protein in neurodevelopment. Mice harboring two mutant copies of Syngap1 have an early post-natal lethality. Mice heterozygous for a null allele develop multiple behavioral abnormalities in adulthood including hyperactivity, learning and memory deficits, sensory perception issues and reduced seizure threshold. Fortunately, post-developmental restoration of normal SynGAP abundance in Syngap1 heterozygous mice rescues select phenotypes. Unfortunately, although this shows improvement in mice, it’s not directly translatable into human patients.
The Holder Lab is working with human neurons to replicate these results in a potential therapy that is translatable to humans.
Neuropsychiatric gene discovery
Cultured Human Neurons
The Holder Lab characterized induced Pluripotent Stem Cells (iPSCs) with homozygous loss-of function mutations in SYNGAP1 developed in collaboration with Gavin Rumbaugh’s Lab. We evaluated two mutant iPSCs that have homozygous loss-offunction mutations in exon 7 resulting in frameshift and >90% loss of SynGAP protein as well as two isogenic wild-type iPSC lines. Loss of SynGAP in these engineered human neurons results in larger neurons than isogenic wild-type controls. These larger neurons also have stronger synapses with elevated amplitude of miniature Excitatory PostSynaptic Currents (mEPSCs). The stronger synapses of these neurons are associated with increased number of excitatory synapses as determined by PSD95 and GluA1 immunostaining.
