Abstracts

Schinzel-Giedion syndrome (SGS) is a rare neurodevelopmental disorder caused by de novo mutations in SET binding protein 1 (SETBP1), leading to pathological protein accumulation. SETBP1 is a multifunctional protein involved in gene regulation and chromatin remodeling.

Although the most debilitating symptom in SGS is epilepsy, the mechanisms of seizure generation remain unexplored. How does SETBP1 accumulation affect the developing brain and contribute to seizure susceptibility?

To explore this, we designed a Cre-dependent conditional mouse model that enables cell type-specific accumulation of mutant human SETBP1.

Whole-brain (Nestin-Cre) mutants showed spontaneous seizures and increased susceptibility to kainic acid (5mg/kg, n=20/group), along with dentate gyrus (DG) hypoplasia. Immunofluorescence (IF) analysis across DG development revealed disrupted granule cell (GC) migration and ectopic differentiation, assessed at the molecular level by MERSCOPE spatial transcriptomics.

While patch clamp recordings revealed GC hyperexcitability due to abnormal short-term facilitation of EPSCs, single-nucleus RNA-sequencing hinted at synaptic abnormalities. Increased excitatory input and immature spine morphology on GC dendrites were then validated by IF and Golgi staining. Electron microscopy revealed vesicle dispersion in presynaptic terminals, implicating disrupted synaptic dynamics.

To confirm the contribution of excitatory neurons, we generated an excitatory-specific mutant (Emx1-Cre), which showed DG hypoplasia and GC hyperexcitability but lacked seizure vulnerability (n=10/group). Although the combination of structural and functional defects could create the perfect seizure-prone milieu, this seems not to be sufficient to establish the epileptic phenotype, suggesting a beneficial buffering role of the unaffected interneurons. Optogenetics and IF revealed enhanced interneuron-mediated inhibition, supporting a homeostatic plasticity mechanism.

Conversely, inhibitory-specific (Gad2-Cre) mutants showed neither structural defects nor seizure vulnerability (n=10/group), indicating interneuron impairment alone is insufficient to trigger the pathology.

Our findings show that SGS-related epilepsy results from a “constructive interference” between excitatory and inhibitory dysfunctions within the hippocampal circuitry. Impairment of either population alone is instead insufficient to overcome brain resilience against seizure initiation. We hypothesize that this concept may extend to other seizure-associated neurodevelopmental disorders caused by genes not classically linked to epilepsy (like SETBP1).