Neuronal cell type specific roles for Nprl2 in neurodevelopmental disorder-relevant behaviors
Loss of function in the subunits of the GTPase-activating protein (GAP) activity toward Rags-1 (GATOR1) complex, an amino-acid sensitive negative regulator of the mechanistic target of rapamycin complex 1 (mTORC1), is implicated in both genetic familial epilepsies and Neurodevelopmental Disorders (N...
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Elsevier
2025-02-01
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| Series: | Neurobiology of Disease |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996125000063 |
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| author | Brianne Dentel Lidiette Angeles-Perez Abigail Y. Flores Katherine Lei Chongyu Ren Andrea Pineda Sanchez Peter T. Tsai |
| author_facet | Brianne Dentel Lidiette Angeles-Perez Abigail Y. Flores Katherine Lei Chongyu Ren Andrea Pineda Sanchez Peter T. Tsai |
| author_sort | Brianne Dentel |
| collection | DOAJ |
| description | Loss of function in the subunits of the GTPase-activating protein (GAP) activity toward Rags-1 (GATOR1) complex, an amino-acid sensitive negative regulator of the mechanistic target of rapamycin complex 1 (mTORC1), is implicated in both genetic familial epilepsies and Neurodevelopmental Disorders (NDDs) (Baldassari et al., 2018). Previous studies have found seizure phenotypes and increased activity resulting from conditional deletion of GATOR1 function from forebrain excitatory neurons (Yuskaitis et al., 2018; Dentel et al., 2022); however, studies focused on understanding mechanisms contributing to NDD-relevant behaviors are lacking, especially studies understanding the contributions of GATOR1's critical GAP catalytic subunit, nitrogen permease regulator like-2 (Nprl2). Given the clinical phenotypes observed in patients with Nprl2 mutations, in this study, we sought to investigate the neuronal cell type contributions of Nprl2 to NDD behaviors. We conditionally deleted Nprl2 broadly in most neurons (Synapsin1cre), in inhibitory neurons only (Vgatcre), and in Purkinje cells within the cerebellum (L7cre). Broad neuronal deletion of Nprl2 resulted in seizures, social and learning deficits, and hyperactivity. In contrast, deleting Nprl2 from inhibitory neurons led to increased motor learning, hyperactive behavior, in addition to social and learning deficits. Lastly, Purkinje cell (PC) loss of Nprl2 also led to learning and social deficits but did not affect locomotor activity. These phenotypes enhance understanding of the spectrum of disease found in human populations with GATOR1 loss of function and highlight the significance of distinct cellular populations to NDD-related behaviors. Significance statement: We aim to elucidate the neuronal-specific contributions of nitrogen permease regulator like-2 (Nprl2) to its neurodevelopmental disorder (NDD)-relevant phenotypes. We conditionally deleted Nprl2 broadly in neurons (Syn1cre), in inhibitory neurons (Vgatcre), and in cerebellar Purkinje cells (L7cre). We identify seizures only in the Syn1cre conditional mutant (cKO); hyperactivity, learning difficulties, social deficits, and impulsivity in the Syn1cre and Vgatcre cKOs; and social deficits, and fear learning deficits in L7cre cKOs. To our knowledge, we are the first to describe the behavioral contributions of Nprl2's function across multiple cell types. Our findings highlight both critical roles for Nprl2 in learning and behavior and also distinct contributions of select neuronal populations to these NDD-relevant behaviors. |
| format | Article |
| id | doaj-art-88d07dee70334b3780012aa251c98402 |
| institution | Kabale University |
| issn | 1095-953X |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj-art-88d07dee70334b3780012aa251c984022025-01-24T04:44:41ZengElsevierNeurobiology of Disease1095-953X2025-02-01205106790Neuronal cell type specific roles for Nprl2 in neurodevelopmental disorder-relevant behaviorsBrianne Dentel0Lidiette Angeles-Perez1Abigail Y. Flores2Katherine Lei3Chongyu Ren4Andrea Pineda Sanchez5Peter T. Tsai6The University of Texas Southwestern Medical Center, Department of Neurology, Dallas, TX, United States of AmericaThe University of Texas Southwestern Medical Center, Department of Neurology, Dallas, TX, United States of AmericaThe University of Texas Southwestern Medical Center, Department of Neurology, Dallas, TX, United States of AmericaThe University of Texas Southwestern Medical Center, Department of Neurology, Dallas, TX, United States of AmericaThe University of Texas Southwestern Medical Center, Department of Neurology, Dallas, TX, United States of AmericaThe University of Texas Southwestern Medical Center, Department of Neurology, Dallas, TX, United States of AmericaThe University of Texas Southwestern Medical Center, Department of Neurology, Dallas, TX, United States of America; The University of Texas Southwestern Medical Center, Department of Psychiatry, Dallas, TX, United States of America; The University of Texas Southwestern Medical Center, Department of Pediatrics, Dallas, TX, United States of America; The University of Texas Southwestern Medical Center, Department of Neuroscience; O'Donnell Brain Institute, Dallas, TX, United States of America; Corresponding author at: 6000 Harry Hines BLVD NL09138B, Dallas, TX 75390, United States of America.Loss of function in the subunits of the GTPase-activating protein (GAP) activity toward Rags-1 (GATOR1) complex, an amino-acid sensitive negative regulator of the mechanistic target of rapamycin complex 1 (mTORC1), is implicated in both genetic familial epilepsies and Neurodevelopmental Disorders (NDDs) (Baldassari et al., 2018). Previous studies have found seizure phenotypes and increased activity resulting from conditional deletion of GATOR1 function from forebrain excitatory neurons (Yuskaitis et al., 2018; Dentel et al., 2022); however, studies focused on understanding mechanisms contributing to NDD-relevant behaviors are lacking, especially studies understanding the contributions of GATOR1's critical GAP catalytic subunit, nitrogen permease regulator like-2 (Nprl2). Given the clinical phenotypes observed in patients with Nprl2 mutations, in this study, we sought to investigate the neuronal cell type contributions of Nprl2 to NDD behaviors. We conditionally deleted Nprl2 broadly in most neurons (Synapsin1cre), in inhibitory neurons only (Vgatcre), and in Purkinje cells within the cerebellum (L7cre). Broad neuronal deletion of Nprl2 resulted in seizures, social and learning deficits, and hyperactivity. In contrast, deleting Nprl2 from inhibitory neurons led to increased motor learning, hyperactive behavior, in addition to social and learning deficits. Lastly, Purkinje cell (PC) loss of Nprl2 also led to learning and social deficits but did not affect locomotor activity. These phenotypes enhance understanding of the spectrum of disease found in human populations with GATOR1 loss of function and highlight the significance of distinct cellular populations to NDD-related behaviors. Significance statement: We aim to elucidate the neuronal-specific contributions of nitrogen permease regulator like-2 (Nprl2) to its neurodevelopmental disorder (NDD)-relevant phenotypes. We conditionally deleted Nprl2 broadly in neurons (Syn1cre), in inhibitory neurons (Vgatcre), and in cerebellar Purkinje cells (L7cre). We identify seizures only in the Syn1cre conditional mutant (cKO); hyperactivity, learning difficulties, social deficits, and impulsivity in the Syn1cre and Vgatcre cKOs; and social deficits, and fear learning deficits in L7cre cKOs. To our knowledge, we are the first to describe the behavioral contributions of Nprl2's function across multiple cell types. Our findings highlight both critical roles for Nprl2 in learning and behavior and also distinct contributions of select neuronal populations to these NDD-relevant behaviors.http://www.sciencedirect.com/science/article/pii/S0969996125000063BehaviorNprl2mTORC1 |
| spellingShingle | Brianne Dentel Lidiette Angeles-Perez Abigail Y. Flores Katherine Lei Chongyu Ren Andrea Pineda Sanchez Peter T. Tsai Neuronal cell type specific roles for Nprl2 in neurodevelopmental disorder-relevant behaviors Neurobiology of Disease Behavior Nprl2 mTORC1 |
| title | Neuronal cell type specific roles for Nprl2 in neurodevelopmental disorder-relevant behaviors |
| title_full | Neuronal cell type specific roles for Nprl2 in neurodevelopmental disorder-relevant behaviors |
| title_fullStr | Neuronal cell type specific roles for Nprl2 in neurodevelopmental disorder-relevant behaviors |
| title_full_unstemmed | Neuronal cell type specific roles for Nprl2 in neurodevelopmental disorder-relevant behaviors |
| title_short | Neuronal cell type specific roles for Nprl2 in neurodevelopmental disorder-relevant behaviors |
| title_sort | neuronal cell type specific roles for nprl2 in neurodevelopmental disorder relevant behaviors |
| topic | Behavior Nprl2 mTORC1 |
| url | http://www.sciencedirect.com/science/article/pii/S0969996125000063 |
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