Biology subjects

Bateup, H. S.

Publications and source records attributed to Bateup, H. S..

10 recordsLinked to original sources

bioRxiv2025

mTORC1 activation drives astrocyte reactivity in cortical tubers and brain organoid models of TSC

Tuberous Sclerosis Complex (TSC) is a genetic neurodevelopmental disorder associated with early onset epilepsy, intellectual disability and neuropsychiatric disorders. A hallmark of the disorder is cortical tubers, which are focal malformations of brain development containing dysplastic cells with hyperactive mTORC1 signaling. One barrier to developing therapeutic approaches and understanding the origins of tuber cells is the lack of a model system that recapitulates this pathology. To address this, we established a genetically mosaic cortical organoid system that models a somatic "second-hit" mutation, which is thought to drive the formation of tubers in TSC. With this model, we find that loss of TSC2 cell-autonomously promotes the differentiation of astrocytes, which exhibit features of a disease-associated reactive state. TSC2-/- astrocytes have pronounced changes in morphology and upregulation of proteins that are risk factors for neurodegenerative diseases, such as clusterin and APOE. Using multiplexed immunofluorescence in primary tubers from TSC patients, we show that tuber cells with hyperactive mTORC1 activity also express reactive astrocyte proteins, and we identify a unique population of cells with expression profiles that match those observed in organoids. Together, this work reveals that reactive astrogliosis is a primary feature of TSC that arises early in cortical development. Dysfunctional glia are therefore poised to be drivers of pathophysiology, nominating a potential therapeutic target for treating TSC and related mTORopathies.

neuroscience↗

bioRxiv2024

Gastrin Releasing Peptide Signaling in the Nucleus Accumbens Medial Shell Regulates Neuronal Excitability and Motivation

Neuropeptides are the largest class of neuromodulators. It has been shown that subpopulations of dopamine neurons express mRNA for the neuropeptide Gastrin-releasing peptide (GRP); however, its functional relevance in dopaminergic circuits is unknown. Here, we find that the GRP receptor (GRPR) is present in the nucleus accumbens medial shell (NAc MSh), which is targeted by GRP-expressing midbrain dopamine neurons as well as glutamatergic inputs from the hippocampus and amygdala. We show that the NAc MSh GRPR-positive cells are a subpopulation of D2 receptor-expressing neurons, comprising both classical indirect pathway striatal projection neurons (iSPNs) and eccentric SPNs (eSPNs), which have high intrinsic excitability, and can be activated by GRP in vivo. NAc-specific deletion of Grpr increases motivation in a progressive ratio test, demonstrating that GRPR regulates motivated behaviors. These experiments establish GRP/GRPR signaling as a potent modulator of mesolimbic circuits and advance our understanding of neuropeptide actions in the brain.

neuroscience↗

bioRxiv2024

Cntnap2 loss drives striatal neuron hyperexcitability and behavioral inflexibility

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by two major diagnostic criteria - persistent deficits in social communication and interaction, and the presence of restricted, repetitive patterns of behavior (RRBs). Evidence from both human and animal model studies of ASD suggest that alteration of striatal circuits, which mediate motor learning, action selection, and habit formation, may contribute to the manifestation of RRBs. CNTNAP2 is a syndromic ASD risk gene, and loss of function of Cntnap2 in mice is associated with RRBs. How loss of Cntnap2 impacts striatal neuron function is largely unknown. In this study, we utilized Cntnap2-/- mice to test whether altered striatal neuron activity contributes to aberrant motor behaviors relevant to ASD. We find that Cntnap2-/- mice exhibit increased cortical drive of direct pathway striatal projection neurons (dSPNs). This enhanced drive is likely due to increased intrinsic excitability of dSPNs, which make them more responsive to cortical inputs. We find that Cntnap2-/- mice exhibit spontaneous repetitive behaviors, increased motor routine learning, perseveration, and cognitive inflexibility. Increased corticostriatal drive of the direct pathway may therefore contribute to the acquisition of repetitive, inflexible behaviors in Cntnap2 mice.

neuroscience↗

bioRxiv2023

STAT3 regulates the generation of astroglia inhuman brain organoids with high mTORC1 activity

During brain development, neural progenitor cells first produce neurons, then astrocytes and other glial cell types, which provide important trophic support and shape neuronal development and function. Intrinsic genetic programs interact with extracellular signals to control progenitor fate, resulting in temporally segregated periods of neurogenesis and gliogenesis. Animal models have implicated STAT3 as an important driver of astrogenesis; however, the signaling pathways that control glial differentiation during human brain development are less well understood. Prior work demonstrated that constitutive activation of mTORC1 signaling in human brain organoid models resulted in the precocious generation of glial-lineage cells. In this study, we tested whether mTORC1 acts via STAT3 to control astrogenesis in brain organoids. We show that knockdown of STAT3 reduces astrogenesis in wild-type organoids and in organoids with constitutively high mTORC1 signaling caused by deletion of the negative regulator TSC2. However, mTORC1 is not required for cytokine-induced activation of STAT3 and expression of the astrocytic protein GFAP. Together, these results show that mTORC1 acts through STAT3 to control astroglia production in human brain organoid models, but that mTOR signaling is dispensable for STAT3-driven astrogenesis. Summary statementDeb et al, use human brain organoid models to show a requirement for STAT3 downstream of mTORC1 in regulating astrogliogenesis during early human brain development.

neuroscience↗

bioRxiv2021

Dopamine neuron morphology and output are differentially controlled by mTORC1 and mTORC2

The mTOR pathway is an essential regulator of cell growth and metabolism. Midbrain dopamine neurons are particularly sensitive to mTOR signaling status as activation or inhibition of mTOR alters their morphology and physiology. mTOR exists in two distinct multiprotein complexes termed mTORC1 and mTORC2. How each of these complexes affect dopamine neuron properties and whether they act together or independently is unknown. Here we investigated this in mice with dopamine neuron-specific deletion of Rptor or Rictor, which encode obligatory components of mTORC1 or mTORC2, respectively. We find that inhibition of mTORC1 strongly and broadly impacts dopamine neuron structure and function causing somatodendritic and axonal hypotrophy, increased intrinsic excitability, decreased dopamine production, and impaired dopamine release. In contrast, inhibition of mTORC2 has more subtle effects, with selective alterations to the output of ventral tegmental area dopamine neurons. As mTOR is involved in several brain disorders caused by dopaminergic dysregulation including Parkinsons disease and addiction, our results have implications for understanding the pathophysiology and potential therapeutic strategies for these diseases.

neuroscience↗

bioRxiv2021

Raptor downregulation rescues neuronal phenotypes in mouse models of Tuberous Sclerosis Complex

Tuberous Sclerosis Complex (TSC) is a neurodevelopmental disorder caused by mutations in the TSC1 or TSC2 genes, which encode proteins that negatively regulate mTOR complex 1 (mTORC1) signaling. Current treatment strategies focus on mTOR inhibition with rapamycin and its derivatives. While effective at improving some aspects of TSC, chronic rapamycin inhibits both mTORC1 and mTORC2 and is associated with systemic side-effects. It is currently unknown which mTOR complex is most relevant for TSC-related brain phenotypes. Here we used genetic strategies to selectively reduce neuronal mTORC1 or mTORC2 activity in mouse models of TSC. We find that reduction of the mTORC1 component Raptor, but not the mTORC2 component Rictor, rebalanced mTOR signaling in Tsc1 knock-out neurons. Raptor reduction was sufficient to improve several TSC-related phenotypes including neuronal hypertrophy, macrocephaly, impaired myelination, network hyperactivity, and premature mortality. Raptor downregulation represents a promising potential therapeutic intervention for the neurological manifestations of TSC.

neuroscience↗

bioRxiv2020

A multimodal cell census and atlas of the mammalian primary motor cortex

We report the generation of a multimodal cell census and atlas of the mammalian primary motor cortex (MOp or M1) as the initial product of the BRAIN Initiative Cell Census Network (BICCN). This was achieved by coordinated large-scale analyses of single-cell transcriptomes, chromatin accessibility, DNA methylomes, spatially resolved single-cell transcriptomes, morphological and electrophysiological properties, and cellular resolution input-output mapping, integrated through cross-modal computational analysis. Together, our results advance the collective knowledge and understanding of brain cell type organization: First, our study reveals a unified molecular genetic landscape of cortical cell types that congruently integrates their transcriptome, open chromatin and DNA methylation maps. Second, cross-species analysis achieves a unified taxonomy of transcriptomic types and their hierarchical organization that are conserved from mouse to marmoset and human. Third, cross-modal analysis provides compelling evidence for the epigenomic, transcriptomic, and gene regulatory basis of neuronal phenotypes such as their physiological and anatomical properties, demonstrating the biological validity and genomic underpinning of neuron types and subtypes. Fourth, in situ single-cell transcriptomics provides a spatially-resolved cell type atlas of the motor cortex. Fifth, integrated transcriptomic, epigenomic and anatomical analyses reveal the correspondence between neural circuits and transcriptomic cell types. We further present an extensive genetic toolset for targeting and fate mapping glutamatergic projection neuron types toward linking their developmental trajectory to their circuit function. Together, our results establish a unified and mechanistic framework of neuronal cell type organization that integrates multi-layered molecular genetic and spatial information with multi-faceted phenotypic properties.

neuroscience↗

bioRxiv2020

Generation of a DAT-Flp mouse line for intersectional genetic targeting of dopamine neuron subpopulations

Dopamine neurons project to diverse regions throughout the brain to modulate various brain processes and behaviors. It is increasingly appreciated that dopamine neurons are heterogeneous in their gene expression, circuitry, physiology, and function. Current approaches to target dopamine neurons are largely based on single gene drivers, which either label all dopamine neurons, or mark a sub-set but concurrently label non-dopaminergic neurons. Here we establish a novel mouse line in which Flp recombinase is knocked-in to the endogenous Slc6a3 (dopamine active transporter, DAT) locus. DAT-Flp mice can be used with various Cre-expressing mouse lines to efficiently and selectively label dopaminergic subpopulations using Cre/Flp-dependent intersectional strategies. We demonstrate the utility of this approach by crossing DAT-Flp mice with NEX-Cre mice, to specifically label Neurod6-expressing dopamine neurons that project to the nucleus accumbens medial shell. DAT-Flp mice represent a novel tool, which will help parse the diverse functions mediated by dopaminergic circuits.

neuroscience↗

bioRxiv2019

Loss of Tsc1 from striatal direct pathway neurons impairs endocannabinoid-LTD and enhances motor routine learning

Tuberous Sclerosis Complex (TSC) is a neurodevelopmental disorder in which patients frequently present with autism spectrum disorder (ASD). A core diagnostic criterion for ASD is the presence of restricted, repetitive behaviors, which may result from abnormal activity in striatal circuits that mediate motor learning, action selection and habit formation. Striatal control over motor behavior relies on the coordinated activity of two subtypes of principle neurons, direct pathway and indirect pathway spiny projection neurons (dSPNs or iSPNs, respectively), which provide the main output of the striatum. To test if altered striatal activity is sufficient to cause changes to motor behavior in the context of TSC, we conditionally deleted Tsc1 from dSPNs or iSPNs in mice and determined the consequences on synaptic function and motor learning. We find that mice with loss of Tsc1 from dSPNs, but not iSPNs, have enhanced motor routine learning in the accelerating rotarod task. In addition, dSPN Tsc1 KO mice have impaired endocannabinoid-mediated long-term depression (eCB-LTD) at cortico-dSPN synapses in the dorsal striatum. Consistent with a loss of eCB-LTD, disruption of Tsc1 in dSPNs, but not iSPNs, results in a strong enhancement of corticostriatal synaptic drive. Together these findings demonstrate that within the striatum, dSPNs show selective sensitivity to Tsc1 loss and indicate that enhanced cortical activation of the striatal direct pathway is a potential contributor to altered motor behaviors in TSC.

neuroscience↗

bioRxiv2017

Widespread translational remodeling during human neuronal differentiation

Faithful cellular differentiation requires precise coordination of changes in gene expression. However, the relative contributions of transcriptional and translational regulation during human cellular differentiation are unclear. Here, we induced forebrain neuronal differentiation of human embryonic stem cells (hESCs) and characterized genomewide RNA and translation levels during neurogenesis. We find that thousands of genes change at the translation level across differentiation without a corresponding change in RNA level. Specifically, we identify mTOR complex 1 signaling as a key driver for elevated translation of translation-related genes in hESCs. In contrast, translational repression in active neurons is mediated by transcript 3' UTRs, through regulatory sequences. Together, our findings identify a functional role for the dramatic 3' UTR extensions that occur during brain development, and provide insights to interpret genetic variants in post-transcriptional control factors that influence neurodevelopmental disorders and diseases.

cell biology↗