Compromised mammillary body connectivity and psychotic symptoms in mice with di- and mesencephalic ablation of ST8SIA2.

Altered long-range connectivity is a common finding across neurodevelopmental psychiatric disorders, but causes and consequences are not well understood. Genetic variation in ST8SIA2 has been associated with schizophrenia, autism, and bipolar disorder, and St8sia2-/- mice show a number of related neurodevelopmental and behavioral phenotypes. In the present study, we use conditional knockout (cKO) to dissect neurodevelopmental defects and behavioral consequences of St8sia2 deficiency in cortical interneurons, their cortical environment, or in the di- and mesencephalon. Neither separate nor combined cortical and diencephalic ablation of St8sia2 caused the disturbed thalamus-cortex connectivity observed in St8sia2-/- mice. However, cortical ablation reproduced hypoplasia of corpus callosum and fornix and mice with di- and mesencephalic ablation displayed smaller mammillary bodies with a prominent loss of parvalbumin-positive projection neurons and size reductions of the mammillothalamic tract. In addition, the mammillotegmental tract and the mammillary peduncle, forming the reciprocal connections between mammillary bodies and Gudden's tegmental nuclei, as well as the size of Gudden's ventral tegmental nucleus were affected. Only mice with these mammillary deficits displayed enhanced MK-801-induced locomotor activity, exacerbated impairment of prepulse inhibition in response to apomorphine, and hypoanxiety in the elevated plus maze. We therefore propose that compromised mammillary body connectivity, independent from hippocampal input, leads to these psychotic-like responses of St8sia2-deficient mice.

Cell-autonomous impact of polysialic acid-producing enzyme ST8SIA2 on developmental migration and distribution of cortical interneurons.

In humans, variations in the polysialic acid-producing enzyme ST8SIA2 and disturbances in the cortical inhibitory system are associated with neurodevelopmental psychiatric disorders such as schizophrenia and autism. In mice, the ST8SIA2-dependent formation of polysialic acid during embryonic development is crucial for the establishment of interneuron populations of the medial prefrontal cortex. However, the spatial pattern and the neurodevelopmental mechanisms of interneuron changes caused by loss of ST8SIA2 function have not been fully characterized. Here, we use immunohistochemical analysis to demonstrate that densities of parvalbumin-positive interneurons are not only reduced in the medial prefrontal cortex, but also in the adjacent motor and somatosensory cortices of St8sia2-deficient male mice. These reductions, however, were confined to the rostral parts of the analyzed region. Mice with conditional knockout of St8sia2 under the interneuron-specific Lhx6 promoter, but not mice with a deletion under the Emx1 promoter that targets cortical excitatory neurons and glia, largely recapitulated the area-specific changes of parvalbumin-positive interneurons in the anterior cortex of St8sia2-/- mice. Live imaging of interneuron migration in slice cultures of the developing cortex revealed a comparable reduction of directional persistence accompanied by increased branching of leading processes in slice cultures obtained from St8sia2-/- embryos or from embryos with interneuron-specific ablation of St8sia2. Together, the data demonstrate a cell-autonomous impact of ST8SIA2 on cortical interneuron migration and the distribution of parvalbumin-positive interneurons in the anterior cortex. This provides a neurodevelopmental mechanism for how dysregulation of ST8SIA2 may lead to disturbed inhibitory balance as observed in schizophrenia and autism.