Abstract
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.
Highlights
Broad evidence links genetic risk factors with common neurodevelopmental predispositions to psychiatric disorders such as schizophrenia [1], autism spectrum and bipolar disorders [2, 3], and, arguably, depression [4]
None of the analyzed conditional knockout (cKO) strains displayed the thalamocortical deficits of St8sia2−/− mice, but distinct aspects of impaired mammillary bodies (MB) connectivity were detected in Foxb1-Cre;St8sia2f/f as compared to Emx1-Cre; St8sia2f/f animals and allowed us to assess their contributions to psychosis-related behaviors
To validate the conditional recombination of St8sia2 in Foxb1-Cre;St8sia2f/f mice, the presence of the recombined allele was confirmed by genomic PCR, while qPCR analysis revealed a MATERIALS AND METHODS See Supplementary Material for details
Summary
Broad evidence links genetic risk factors with common neurodevelopmental predispositions to psychiatric disorders such as schizophrenia [1], autism spectrum and bipolar disorders [2, 3], and, arguably, depression [4]. Ectopic synapse formation and reduction of basal synaptic transmission in the hippocampus, as well as impaired glutamatergic transmission and synaptic plasticity in the amygdala have been observed [22,23,24] Or combined, these changes may give rise to the cognitive deficits and altered behaviors of St8sia2−/− mice, including impaired working memory and fear learning, deficits in sensorimotor gating, reduced anxiety, increased exploratory and locomotor activity, or reduced social interactions with increased aggression [21,22,23, 25, 26]. As shown recently, increased aggression and impaired fear learning could be reproduced by local silencing of St8sia in the early postnatal amygdala and were assigned to altered glutamatergic synaptic transmission [23]. None of the analyzed cKO strains displayed the thalamocortical deficits of St8sia2−/− mice, but distinct aspects of impaired MB connectivity were detected in Foxb1-Cre;St8sia2f/f as compared to Emx1-Cre; St8sia2f/f animals and allowed us to assess their contributions to psychosis-related behaviors
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