Neurexins play a crucial role in cerebellar granule cell survival by organizing autocrine machinery for neurotrophins

Uemura, Takeshi; Suzuki-Kouyama, Emi; Kawase, Shiori; Kurihara, Taiga; Yasumura, Motoï; Yoshida, Tomoyuki; Fukai, Shuya; Yamazaki, Maya; Peng, Fei; Abe, Manabu; Watanabe, Masahiko; Sakimura, Kenji; Mishina, Masayoshi; Tabuchi, Katsuhiko

doi:10.1016/j.celrep.2022.110624

Cited by 11 publications

(20 citation statements)

References 78 publications

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“…To test the roles of Nrxns in 5-HT neurons, we generated 5-HT neuron-specific Nrxn TKO mice by crossing Fev Cre , an ETS family transcription factor promoting 5-HT neuron-specific Cre expression, tdTomato (RFP) reporter, and triple Nrxn1/2/3 floxed lines (Fev/RFP/NrxnTKO) ( Scott et al, 2005 ; Uemura et al, 2022 ). Cre-negative littermates and Fev/RFP mice were used as control (Cntl) cohorts.…”

Section: Resultsmentioning

confidence: 99%

“…It has been reported that Nrxn TKO in cerebellar granule cells cause cell death ( Uemura et al, 2022 ), which raises the possibility that the reduced 5-HT fiber density is due to 5-HT neuron cell death. To address this possibility, we compared the population of RFP-expressing 5-HT-positive 5-HT neurons in the DRN and MRN between Fev/RFP (Cntl) and Fev/RFP/NrxnTKO mice at different ages ( Figure 3L, M ).…”

Section: Resultsmentioning

confidence: 99%

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Neurexins in serotonergic neurons regulate neuronal survival, serotonin transmission, and complex mouse behaviors

Cheung

Konno

Imamura

et al. 2023

eLife

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Extensive serotonin (5-hydroxytryptamine, 5-HT) innervation throughout the brain corroborates 5-HT’s modulatory role in numerous cognitive activities. Volume transmission is the major mode for 5-HT transmission but mechanisms underlying 5-HT signaling are still largely unknown. Abnormal brain 5-HT levels and function have been implicated in autism spectrum disorder (ASD). Neurexin (Nrxn) genes encode presynaptic cell adhesion molecules important for the regulation of synaptic neurotransmitter release, notably glutamatergic and GABAergic transmission. Mutations in Nrxn genes are associated with neurodevelopmental disorders including ASD. However, the role of Nrxn genes in the 5-HT system is poorly understood. Here, we generated a mouse model with all three Nrxn genes disrupted specifically in 5-HT neurons to study how Nrxns affect 5-HT transmission. Loss of Nrxns in 5-HT neurons reduced the number of serotonin neurons in the early postnatal stage, impaired 5-HT release, and decreased 5-HT release sites and serotonin transporter expression. Furthermore, 5-HT neuron-specific Nrxn knockout reduced sociability and increased depressive-like behavior. Our results highlight functional roles for Nrxns in 5-HT neurotransmission, 5-HT neuron survival, and the execution of complex behaviors.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Neurexins in serotonergic neurons regulate neuronal survival, serotonin transmission, and complex mouse behaviors

Cheung

Konno

Imamura

et al. 2023

eLife

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“…To test the roles of Nrxns in 5-HT neurons, we generated 5-HT neuron-specific Nrxn triple knockout (TKO) mice by crossing Fev-Cre, an ETS family transcription factor promoting 5-HT neuron-specific Cre expression, tdTomato (RFP) reporter, and triple Nrxn1/2/3 floxed lines (Fev/RFP/NrxnTKO) (Scott et al, 2005; Uemura et al, 2022). Cre-negative littermates and Fev/RFP mice were used as control (Cntl) cohorts.…”

Section: Resultsmentioning

confidence: 99%

Section: Reduced 5-ht Release In Fev/rfp/nrxntko Micementioning

confidence: 99%

“…Both Fev-Cre and RFP lines were backcrossed with C57BL/6J line for at least 10 generations. Fev/RFP mice were crossed with Nrxn1 f/f /2 f/f /3 f/f mouse line (Uchigashima, Konno, et al, 2020;Uemura et al, 2022) to generate 5-HT neuron-specific triple Nrxn knockout mouse line (Fev Cre / lox-STOP-lox/lox-STOP-lox tdTomato/Nrxn1 f/f /2 f/f /3 f/f : Fev/RFP/NrxnTKO). The Fev/RFP/NrxnTKO line was maintained by breeding Fev/RFP/NrxnTKO mice with littermate Crenegative ( lox-STOP-lox tdTomato/Nrxn1 f/f /2 f/f /3 f/f : Cntl) mice.…”

Section: Animalsmentioning

confidence: 99%

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Neurexins in serotonergic neurons regulate serotonin transmission and complex mouse behaviors

Cheung

Matsui

Abe

et al. 2021

Preprint

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Extensive serotonin (5-HT) innervation throughout the brain corroborates 5-HT’s modulatory role in numerous cognitive activities. Volume transmission is the major mode for 5-HT transmission but mechanisms underlying 5-HT signaling are still largely unknown. Abnormal brain 5-HT levels and function have been implicated in autism spectrum disorder (ASD). Neurexin (Nrxn) genes encode presynaptic cell adhesion molecules important for the regulation of synaptic neurotransmitter release, notably glutamatergic and GABAergic transmission. Mutations in Nrxn genes are associated with neurodevelopmental disorders including ASD. However, the role of Nrxn genes in the 5-HT system is poorly understood. Here, we generated a mouse model with all three Nrxn genes disrupted specifically in 5-HT neurons to study how Nrxns affect 5-HT transmission. Loss of Nrxns in 5-HT neurons impaired 5-HT release in the dorsal raphe nucleus and dorsal hippocampus and decreased serotonin transporter distribution in specific brain areas. Furthermore, 5-HT neuron-specific Nrxn knockout reduced sociability and increased depressive-like behavior. Our results highlight functional roles for Nrxns in 5-HT neurotransmission and the execution of complex behaviors.

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Concerted roles of LRRTM1 and SynCAM 1 in organizing prefrontal cortex synapses and cognitive functions

et al. 2023

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Multiple trans-synaptic complexes organize synapse development, yet their roles in the mature brain and cooperation remain unclear. We analyzed the postsynaptic adhesion protein LRRTM1 in the prefrontal cortex (PFC), a region relevant to cognition and disorders. LRRTM1 knockout (KO) mice had fewer synapses, and we asked whether other synapse organizers counteract further loss. This determined that the immunoglobulin family member SynCAM 1 controls synapse number in PFC and was upregulated upon LRRTM1 loss. Combined LRRTM1 and SynCAM 1 deletion substantially lowered dendritic spine number in PFC, but not hippocampus, more than the sum of single KO impairments. Their cooperation extended presynaptically, and puncta of Neurexins, LRRTM1 partners, were less abundant in double KO (DKO) PFC. Electrophysiology and fMRI demonstrated aberrant neuronal activity in DKO mice. Further, DKO mice were impaired in social interactions and cognitive tasks. Our results reveal concerted roles of LRRTM1 and SynCAM 1 across synaptic, network, and behavioral domains.

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Neurexins play a crucial role in cerebellar granule cell survival by organizing autocrine machinery for neurotrophins

Cited by 11 publications

References 78 publications

Neurexins in serotonergic neurons regulate neuronal survival, serotonin transmission, and complex mouse behaviors

Neurexins in serotonergic neurons regulate neuronal survival, serotonin transmission, and complex mouse behaviors

Neurexins in serotonergic neurons regulate serotonin transmission and complex mouse behaviors

Concerted roles of LRRTM1 and SynCAM 1 in organizing prefrontal cortex synapses and cognitive functions

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