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

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.

Normative mammillary body volumes: From the neonatal period to young adult

“…While it is well-known that the MBs are sensitive to thiamine deficiency, their sensitivity to hypoxia-ischemia has become more apparent, as shown by the prevalence of MB pathology in hypoxic-ischemic encephalopathy ( Molavi et al, 2019 ; Lequin et al, 2021 ). In addition to acquired injury, MB pathology has also been associated with psychiatric and neurodevelopmental disorders ( Küçükerden et al, 2022 ; Briess et al, 1998 ; Bernstein et al, 2012 ). To better understand the contribution of MB neuropathology in these diverse conditions, it is necessary to have a detailed structural knowledge of the MBs in normal populations.…”

Construction of complex memories via parallel distributed cortical–subcortical iterative integration

“…Functional hippocampal output requires that it receives theta pattern input from the medial septum, dependent on arousal-related reticular and cerebellar input via areas such as SuM [ 61 ]. The passage of the resultant hippocampal output through the MB appears to depend on similar arousal-related inputs from the dorsal and ventral tegmental nuclei [ 96 - 98 ]. Thus SuM/MB would provide arousal and interoceptive information to boost and bias iterative processing, while prefrontal cortex would contain the cell assemblies that the process enhances; with increased signal/noise ratio with each iteration.…”

“…The extended Papez circuits, including the MBs and/or the anterior thalamic nuclei have been implicated in several neurological disorders that are associated with memory impairments, e.g., Korsakoff syndrome, Alzheimer’s disease, Down syndrome, and hypoxic-ischaemic encephalopathy [ 115 , 116 ]. However, there is also increasing evidence for a role for the medial diencephalon in psychiatric and neurodevelopmental disorders [ 117 - 119 ], where memory impairments are present but also emotional dysregulation. Given the role we attribute to the supramammillary and mammillary areas in Papez circuit processing we think it is time for a closer look into overlaps between memory and emotion across mnemonic, neurodevelopmental, and psychiatric disorders.…”

News and Views on Polysialic Acid: From Tumor Progression and Brain Development to Psychiatric Disorders, Neurodegeneration, Myelin Repair and Immunomodulation

“…To further dissect neurodevelopmental defects and behavioral consequences of St8sia2 deficiency, mice with conditional knockout (cKO) of St8sia2 in cortical interneurons ( Lhx6-Cre;St8sia2 f/f ) were compared to mice with cKO in the cortical environment ( Emx1-Cre;St8sia2 f/f ), in the di- and mesencephalon ( Foxb1-Cre;St8sia2 f/f ), or both ( Foxb1-Cre;Emx1-Cre;St8sia2 f/f ) ( Küçükerden et al, 2022 ). Unexpectedly, disturbed thalamocortical connectivity could not be observed in any of these cKO lines.…”

“…Assessed behavioral traits are (i) increased sensitivity of the locomotor response to the psychotropic drug MK-801 (hyperlocomotion), (ii) exacerbated apomorphine-induced impairment of prepulse inhibition of the acoustic startle response (impaired PPI), (iii) reduced anxiety in the elevated plus maze (hypoanxiety), and (iv) impaired spatial working memory in a delayed nonmatch-to-place T-maze task. Data compiled from Küçükerden et al (2022) . (B) Scheme of neurogenesis, occurrence of polySia and doublecortin, and expression of polySTs in the dentate gyrus of the hippocampal formation.…”