The development of MGE-derived cortical interneurons: An Lhx6 tale

2021 ◽  
Author(s):  
Ourania Christodoulou ◽  
Ioannis Maragkos ◽  
Vassiliki Antonakou ◽  
Myrto Denaxa
Keyword(s):  
Cortical Neurons ◽  
Pyramidal Neurons ◽  
Current Knowledge ◽  
Neuronal Cell ◽  
Inhibitory Interneurons ◽  
Medial Ganglionic Eminence ◽  
Ganglionic Eminence ◽  
Research Activity ◽  
Cortical Interneurons ◽  
Functional Features

The cerebral cortex contains two main neuronal cell populations, the excitatory pyramidal neurons and the inhibitory interneurons, which constitute 20-30% of all cortical neurons. Cortical interneurons are characterized by a remarkable morphological, molecular and functional diversity. A swathe of research activity in the last 20 years aimed to determine how cortical interneurons acquire their mature cellular and functional features, identified a number of transcription factors that function at different stages of interneuron development. Here, we review all current knowledge concerning the multiple functions of the “master regulator” LIMHomeodomain transcription factor Lhx6; a gene expressed in the medial ganglionic eminence of the basal telencephalon that controls the development of somatostatin and parvalbumin expressing interneurons.

scholarly journals Nf1deletion results in depletion of theLhx6transcription factor and a specific loss of parvalbumin+cortical interneurons

2020 ◽  
Vol 117 (11) ◽  
pp. 6189-6195 ◽  
Author(s):  
Kartik Angara ◽  
Emily Ling-Lin Pai ◽  
Stephanie M. Bilinovich ◽  
April M. Stafford ◽  
Julie T. Nguyen ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Mek Inhibitor ◽  
Gabaergic Interneurons ◽  
Medial Ganglionic Eminence ◽  
Ganglionic Eminence ◽  
Specific Loss ◽  
Developmental Milestone ◽  
Cortical Interneurons ◽  
Dose Dependent Decrease ◽  
Dose Dependent

Neurofibromatosis 1 (NF1) is caused by mutations in theNF1gene, which encodes the protein, neurofibromin, an inhibitor of Ras activity. Cortical GABAergic interneurons (CINs) are implicated in NF1 pathology, but the cellular and molecular changes to CINs are unknown. We deleted mouseNf1from the medial ganglionic eminence, which gives rise to both oligodendrocytes and CINs that express somatostatin and parvalbumin.Nf1loss led to a persistence of immature oligodendrocytes that prevented later-generated oligodendrocytes from occupying the cortex. Moreover, molecular and cellular properties of parvalbumin (PV)-positive CINs were altered by the loss ofNf1, without changes in somatostatin (SST)-positive CINs. We discovered that loss ofNf1results in a dose-dependent decrease inLhx6expression, the transcription factor necessary to establish SST+and PV+CINs, which was rescued by the MEK inhibitor SL327, revealing a mechanism whereby a neurofibromin/Ras/MEK pathway regulates a critical CIN developmental milestone.

scholarly journals Consistent cross-modal identification of cortical neurons with coupled autoencoders

2020 ◽  
Author(s):  
Rohan Gala ◽  
Agata Budzillo ◽  
Fahimeh Baftizadeh ◽  
Jeremy Miller ◽  
Nathan Gouwens ◽  
...  
Keyword(s):  
Cortical Neurons ◽  
Neuronal Cell ◽  
Cell Types ◽  
Modal Identification ◽  
Large Patch ◽  
Multimodal Data ◽  
Optimization Framework ◽  
Data Prediction ◽  
Cortical Interneurons ◽  
Assignment Analysis

AbstractConsistent identification of neurons and neuronal cell types across different observation modalities is an important problem in neuroscience. Here, we present an optimization framework to learn coordinated representations of multimodal data, and apply it to a large Patch-seq dataset of mouse cortical interneurons. Our approach reveals strong alignment between transcriptomic and electrophysiological profiles of neurons, enables accurate cross-modal data prediction, and identifies cell types that are consistent across modalities.HighlightsCoupled autoencoders for multimodal assignment, Analysis of Patch-seq data consisting of more than 3000 cells

scholarly journals The Tuberous Sclerosis gene, Tsc1, represses parvalbumin+/fast-spiking properties in somatostatin-lineage cortical interneurons

2019 ◽  
Author(s):  
Ruchi Malik ◽  
Emily Ling-Lin Pai ◽  
Anna N Rubin ◽  
April M Stafford ◽  
Kartik Angara ◽  
...  
Keyword(s):  
Tuberous Sclerosis ◽  
Neuropsychiatric Symptoms ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Signaling ◽  
Medial Ganglionic Eminence ◽  
Ganglionic Eminence ◽  
Adult Mice ◽  
Physiological Properties ◽  
Cortical Interneurons ◽  
Fast Spiking

AbstractMedial ganglionic eminence (MGE)-derived somatostatin (SST)+ and parvalbumin (PV)+ cortical interneurons (CINs), have characteristic molecular, anatomical and physiological properties. However, mechanisms regulating their diversity remain poorly understood. Here, we show that conditional loss of the Tuberous Sclerosis (TS) gene, Tsc1, which inhibits mammalian target of rapamycin (MTOR), causes a subset of SST+ CINs, to express PV and adopt fast-spiking (FS) properties, characteristic of PV+ CINs. These changes also occur when only one allele of Tsc1 is deleted, making these findings relevant to individuals with TS. Notably, treatment with rapamycin, which inhibits MTOR, reverses these changes in adult mice. These data reveal novel functions of MTOR signaling in regulating PV expression and FS properties, which may contribute to some neuropsychiatric symptoms observed in TS. Moreover, they suggest that CINs can exhibit properties intermediate between those classically associated with PV+ or SST+ CINs, which may be dynamically regulated by the MTOR signaling.

scholarly journals Tsc1 represses parvalbumin expression and fast-spiking properties in somatostatin lineage cortical interneurons

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Ruchi Malik ◽  
Emily Ling-Lin Pai ◽  
Anna N Rubin ◽  
April M Stafford ◽  
Kartik Angara ◽  
...  
Keyword(s):  
Neuropsychiatric Symptoms ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Signaling ◽  
Medial Ganglionic Eminence ◽  
Ganglionic Eminence ◽  
Adult Mice ◽  
Intermediate Phenotypes ◽  
Physiological Properties ◽  
Cortical Interneurons ◽  
Fast Spiking

Abstract Medial ganglionic eminence (MGE)-derived somatostatin (SST)+ and parvalbumin (PV)+ cortical interneurons (CINs), have characteristic molecular, anatomical and physiological properties. However, mechanisms regulating their diversity remain poorly understood. Here, we show that conditional loss of the Tuberous Sclerosis Complex (TSC) gene, Tsc1, which inhibits the mammalian target of rapamycin (MTOR), causes a subset of SST+ CINs, to express PV and adopt fast-spiking (FS) properties, characteristic of PV+ CINs. Milder intermediate phenotypes also occur when only one allele of Tsc1 is deleted. Notably, treatment of adult mice with rapamycin, which inhibits MTOR, reverses the phenotypes. These data reveal novel functions of MTOR signaling in regulating PV expression and FS properties, which may contribute to TSC neuropsychiatric symptoms. Moreover, they suggest that CINs can exhibit properties intermediate between those classically associated with PV+ or SST+ CINs, which may be dynamically regulated by the MTOR signaling.

scholarly journals Nf1 deletion results in depletion of the Lhx6 transcription factor and a specific loss of parvalbumin+ cortical interneurons

2019 ◽  
Author(s):  
Kartik Angara ◽  
Emily Ling-Lin Pai ◽  
Stephanie M Bilinovich ◽  
April M Stafford ◽  
Julie T Nguyen ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Benign Tumors ◽  
Gabaergic Interneurons ◽  
Medial Ganglionic Eminence ◽  
Ganglionic Eminence ◽  
Monogenic Disorder ◽  
Cognitive Changes ◽  
Specific Loss ◽  
Ras Gtpase ◽  
Cortical Interneurons

SummaryNeurofibromatosis-1 (NF-1) is a monogenic disorder caused by mutations in the NF1 gene, which encodes the protein, Neurofibromin, an inhibitor of Ras GTPase activity. While NF-1 is often characterized by café-au-lait skin spots and benign tumors, the mechanisms underlying cognitive changes in NF-1 are poorly understood. Cortical GABAergic interneurons (CINs) are implicated in NF-1 pathology but cellular and molecular changes to CINs are poorly understood. We deleted Nf1 from the medial ganglionic eminence (MGE), which gives rise to both oligodendrocytes and CINs that express somatostatin and parvalbumin. Loss of Nf1 led to a persistence of immature oligodendrocytes that prevented later born oligodendrocytes from occupying the cortex. Moreover, PV+ CINs were uniquely lost, without changes in SST+ CINs. We discovered that loss of Nf1 results in a graded decrease in Lhx6 expression, the transcription factor necessary to establish SST+ and PV+ CINs, revealing a mechanism whereby Nf1 regulates a critical CIN developmental milestone.

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