Transgenic modeling of Ndr2 gene amplification reveals disturbance of hippocampus circuitry and function

Duplications and deletions of short chromosomal fragments are increasingly recognized as the cause for rare neurodevelopmental conditions and disorders. The NDR2 gene encodes a protein kinase important for neuronal development and is part of a microduplication region on chromosome 12 that is associated with intellectual disabilities, autism, and epilepsy. We developed a conditional transgenic mouse with increased Ndr2 expression in postmigratory forebrain neurons to study the consequences of an increased gene dosage of this Hippo pathway kinase on brain circuitry and cognitive functions. Our analysis reveals reduced terminal fields and synaptic transmission of hippocampal mossy fibers, altered hippocampal network activity, and deficits in mossy fiber-dependent behaviors. Reduced doublecortin expression and protein interactome analysis indicate that transgenic Ndr2 disturbs the maturation of granule cells in the dentate gyrus. Together, our data suggest that increased expression of Ndr2 may critically contribute to the development of intellectual disabilities upon gene amplification. [Display omitted] •Transgenic overexpression of Ndr2 in neurons impairs hippocampus-dependent behavior•Ndr2 gene amplification disturbs mossy fiber plasticity and CA3-CA1 network activity•Transgenic Ndr2 attenuates granule cell maturation and mossy fiber growth•Interactome analysis identifies Ndr2-related intracellular signaling pathways Genetics; neuroscience; sensory neuroscience