Opposing excitatory and inhibitory synaptic pathologies drive ZC4H2-associated intellectual disability.

ZC4H2 L66H/y and ZC4H2 R213W/y knockin mice show comparable cognitive deficits despite opposite synaptic pathologies driven by enhanced GABA A R degradation versus increased AMPAR stability.

• Why it matters: Patients with mutations in the same gene are often grouped and treated similarly, even though their synaptic dysfunction—and likely therapy response—may differ in direction.
• What they did: The study tested two ZC4H2 mutations in knockin mice and assessed synaptic transmission/plasticity, then used muscimol or perampanel to probe mechanism-specific rescue.
• The result: Muscimol specifically rescues ZC4H2 L66H/y deficits, while the AMPAR antagonist perampanel rescues ZC4H2 R213W/y deficits, supporting pathomechanism-based stratification for targeted therapy.

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