Aug 2026· Proceedings of the National Academy of Sciences of the United States of America· Vol 123 35, pp.
e2606900123
· 0 citations· 48 references
Medicine
TL;DR
These findings identify ankyrin-G as a molecular bridge between excitatory neuronal activity, synaptic structure, and myelin-associated protein expression, revealing a pathway by which ANK3 variants may contribute to neuropsychiatric disease.
Abstract
ANK3, encoding the scaffolding protein ankyrin-G, is a major risk gene for bipolar disorder and schizophrenia, but its cellular and circuit-level mechanisms remain poorly defined. Here, we demonstrate that deletion of Ank3 in forebrain excitatory neurons-either prenatally (Ank3-/-:Emx1-Cre) or in adolescence (Ank3-/-:CaMKIIα-Cre) leads to convergent behavioral phenotypes in adulthood, including hyperactivity, reduced anxiety-like behavior, and decreased depression-like responses. Calcium imaging in cultured neurons and acute brain slices revealed that ankyrin-G loss reduces both spontaneous and evoked neuronal activity. Quantitative proteomic profiling of membrane-enriched cortical fractions uncovered widespread remodeling of the synaptic proteome, including upregulation of the kinase Taok2 and unexpected downregulation of myelin basic protein (Mbp), a structural component of oligodendrocyte-derived myelin. Importantly, chronic lithium treatment, known to reverse behavioral abnormalities in Ank3-deficient mice, also restored Mbp expression. Together, our findings identify ankyrin-G as a molecular bridge between excitatory neuronal activity, synaptic structure, and myelin-associated protein expression, revealing a pathway by which ANK3 variants may contribute to neuropsychiatric disease.
The results suggest that β-catenin deficiency in forebrain excitatory neurons leads to fear conditioning impairment, which could be contributed by the diminished excitatory synaptic transmission in PFC resulting from disrupted synaptic gene expression.
Luis Gustavo Hernandez Carballo, Rachel Senek, Ksenia Novototskaya-Vlasova et al.· Brain Communications· 0 citations
Rett syndrome (RTT) is a severe X-linked neurodevelopmental disorder caused by loss-of-function mutations in the MECP2 gene and characterized by profound impairments in neuronal maturation and synaptic connectivity. Increasing evidence indicates that astrocyte dysfunction contributes to RTT pathogenesis through non-cell-autonomous mechanisms, although the molecular pathways underlying defective astrocyte-neuron communication are only partially understood. Astrocytes are the primary source of cholesterol in the brain and support neuronal maturation and synaptic function by supplying cholesterol through ApoE-containing lipoproteins. Although alterations in brain cholesterol metabolism have been reported in RTT, the underlying cellular mechanisms and their functional consequences remain poorly investigated. Here, we studied cholesterol homeostasis in Mecp2 knock-out (KO) astrocytes and its impact on neuron-astrocyte communication. Mecp2 KO astrocytes exhibited reduced nuclear localization of the transcriptional regulator Srebp2, together with the downregulation of genes involved in cholesterol biosynthesis and transport. These molecular alterations were associated with intracellular cholesterol and desmosterol accumulation, reduced Abca1 expression and defective ApoE lipidation, despite preserved ApoE expression and cholesterol secretion. Importantly, similar alterations were detected in acutely isolated astrocytes and in the cerebral cortex of Mecp2 deficient mice, demonstrating that impaired cholesterol homeostasis extends beyond in vitro models. Functionally, cholesterol supplementation of astrocyte-conditioned medium rescued the synaptic defects induced in wild-type neurons by Mecp2 KO astrocytes. Moreover, cholesterol treatment restored pre- and post-synaptic density, as well as axon initial segment length in Mecp2 heterozygous (HET) neurons. Together, these findings identify defective astrocyte-to- neuron cholesterol trafficking as a key mechanism contributing to neuronal dysfunction in RTT and suggest that strategies aimed at restoring cholesterol functional availability might represent a promising therapeutic avenue for RTT.
Francesca M. Postogna, Noemi Giancroce, C. Cabasino et al.· bioRxiv· 0 citations
In mice with conditional Arid1b haploinsufficiency in excitatory neurons, an increase in the rate of synaptic connectivity between excitatory neurons and reduced strength of excitatory synapses to parvalbumin (PV)-expressing inhibitory interneurons is found.
Alec H. Marshall, Meretta A. Hanson, Danielle J. Boyle et al.· Experimental Neurology· 0 citations
Results suggest that Adgrd1 plays a key role in maintaining hippocampal resilience and regulating motivational behaviors through integrated molecular and circuit-level mechanisms.
Inés Martínez-Soria, Pol Picón-Pagès, A. P. Pérez González et al.· bioRxiv· 0 citations
This study indicates that KIF2C may regulate microtubule dynamics to control deep-layer cortical neuron number and organization and modulate neuronal projections and signaling pathways and provides a foundation for understanding the role of KIF2C in neural development.
Germline heterozygous TCF4 LOF, which models PTHS, does not appear to significantly affect the astrocyte lineage at the cell population level, and germline heterozygous Tcf4 LOF did not result in misallocation of ventrally derived astrocytes into the dorsal cortex.
Sarain Stump, Joseph F. Bohlen, BaDoi N. Phan et al.· Neuroglia· 0 citations
