Neto Auxiliary Subunits Regulate Interneuron Somatodendritic and Presynaptic Kainate Receptors to Control Network Inhibition

Wyeth, Megan S.; Pelkey, Kenneth A.; Yuan, Xitong; Vargish, Geoffrey A.; Johnston, April D.; Hunt, Steven; Fang, Calvin; Abebe, Daniel; Mahadevan, Vivek; Fisahn, André; Salter, Michael W.; McInnes, Roderick R.; Chittajallu, Ramesh; McBain, Chris J.

doi:10.1016/j.celrep.2017.08.017

Cited by 42 publications

(50 citation statements)

References 63 publications

(135 reference statements)

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“…To better understand the mechanisms related to the behavioral phenotype of the Neto2 -/mice, we investigated Neto2 expression pattern that remains poorly characterized. Previous studies have shown that it is highly expressed in the cerebellum [3,5], and that in the Hpc it co-localizes with major KAR subunits in interneurons [8]. To determine the expression pattern of Neto2 in fear-related brain regions [i.e.…”

Section: Neto2 Is Expressed In Both Excitatory and Inhibitory Cells Imentioning

confidence: 99%

“…NETO2 expression is highest in the cerebellum where it plays a crucial role in determining KAR subunit composition at the postsynaptic density [5]. The expression of NETO1 is highest in the hippocampus (Hpc) [3], where it regulates KAR-mediated excitatory post-synaptic currents [4,8] and axonal targeting of KARs [9]. Recently Wyeth et al [8] showed that both NETO1 and NETO2 tonically inhibit cholecystokinin (CCK)-expressing interneurons and that NETO1 regulates KAR-mediated excitation of interneurons in the developing Hpc.…”

Section: Introductionmentioning

confidence: 99%

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Kainate receptor auxiliary subunit NETO2 is required for normal fear expression and extinction

Mennesson

Rydgren

Lipina

et al. 2019

Neuropsychopharmacol.

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NETO1 and NETO2 are auxiliary subunits of kainate receptors (KARs). They interact with native KAR subunits to modulate multiple aspects of receptor function. Variation in KAR genes has been associated with psychiatric disorders in humans, and in mice, knockouts of the Grik1 gene have increased, while Grik2 and Grik4 knockouts have reduced anxiety-like behavior. To determine whether the NETO proteins regulate anxiety and fear through modulation of KARs, we undertook a comprehensive behavioral analysis of adult Neto1-/and Neto2-/mice. We observed no differences in anxiety-like behavior. However, in cued fear conditioning, Neto2-/-, but not Neto1-/mice, showed higher fear expression and delayed extinction compared to wild type mice. We established, by in situ hybridization, that Neto2 was expressed in both excitatory and inhibitory neurons throughout the fear circuit including the medial prefrontal cortex, amygdala, and hippocampus. Finally, we demonstrated that the relative amount of synaptosomal KAR GLUK2/3 subunit was 20.8% lower in the ventral hippocampus and 36.5% lower in the medial prefrontal cortex in Neto2-/compared to the Neto2 +/+ mice. The GLUK5 subunit abundance was reduced 23.8% in the ventral hippocampus and 16.9% in the amygdala. We conclude that Neto2 regulates fear expression and extinction in mice, and that its absence increases conditionability, a phenotype related to posttraumatic stress disorder and propose that this phenotype is mediated by reduced KAR subunit abundance at synapses of fear-associated brain regions.

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Section: Neto2 Is Expressed In Both Excitatory and Inhibitory Cells Imentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Kainate receptor auxiliary subunit NETO2 is required for normal fear expression and extinction

Mennesson

Rydgren

Lipina

et al. 2019

Neuropsychopharmacol.

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“…We have generated several isoform specific antibodies but they could only detect Neto-α when overexpressed (not shown). Similar challenges have been encountered in the vertebrate Neto field (Wyeth et al, 2017).…”

Section: Discussionmentioning

confidence: 63%

Neto-α controls synapse organization and homeostasis at the Drosophila neuromuscular junction

Han

Vicidomini

Ramos

et al. 2019

Preprint

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Glutamate receptor auxiliary proteins control receptor distribution and function, ultimately controlling synapse assembly, maturation and plasticity. At the Drosophila neuromuscular junction (NMJ), a synapse with both pre-and post-synaptic kainate-type glutamate receptors (KARs), we show that the auxiliary protein Neto evolved functionally distinct isoforms to modulate synapse development and homeostasis. Using genetics, cell biology and electrophysiology we demonstrate that Neto-α functions on both sides of the NMJ. In muscle, Neto-α limits the size of the postsynaptic receptors field. In motor neurons, Neto-α controls neurotransmitter release in a KAR-dependent manner. Furthermore, Neto-α is both required and sufficient for the presynaptic increase in neurotransmitter release in response to reduced postsynaptic sensitivity. This KARindependent function of Neto-α is involved in activity-induced cytomatrix remodeling. We propose that Drosophila ensured NMJ functionality by acquiring two Neto isoforms with differential expression patterns and activities.

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“…Other CUB/Sushi-containing proteins have been described in previous reports as auxiliary subunits of synaptic ionotropic glutamate receptors that regulate receptor subunit composition, localization, clustering, and transport throughout the dendritic arbor and finally to the synapse (Gendrel et al, 2009;Ng et al, 2009;Cousins et al, 2013;Fisher and Mott, 2013;Lomash et al, 2017;Wyeth et al, 2017). Additionally, Reelin has been reported to induce signal transduction through phosphoinositide-3 kinase (PI3K) to enhance surface insertion of AMPA receptors (AMPARs), contributing to an enhanced NMDAR response (Qiu et al, 2006).…”

Section: Discussionmentioning

confidence: 98%

Csmd2 interacts with Dab1 and is Required in Reelin-Mediated Neuronal Maturation

Gutierrez

Dwyer

Franco

2020

Preprint

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Reelin is a glycoprotein secreted by Cajal-Retzius cells to regulate development of the cerebral cortex. Reelin binding to its receptors on immature neurons initiates a signaling cascade through the downstream adaptor protein, Dab1. Defects in this signaling mechanism result in perturbed neuronal migration, reductions in dendrite complexity, and deficits in synapse development and function. How Reelin controls neuronal migration and brain lamination have been extensively investigated over the years, but the pathways that regulate dendrite and spine development downstream of Reelin and Dab1 have yet to be fully elucidated. Here, we have identified a novel interaction between Dab1 and Csmd2, a synaptic transmembrane protein required for dendrite and dendritic spine development in forebrain excitatory neurons. We demonstrate that Csmd2 contains an NPxY motif on its intracellular region, through which Dab1 interacts with Csmd2. Interestingly, we find that this NPxY consensus motif is not required for Csmd2 to localize at the postsynaptic densities of spiny neurons. Rather, the introduction of an NPxY mutant form of Csmd2 results in a significant overproduction of immature, filopodia-like dendritic spines in maturing neurons. Moreover, we show that knockdown of Csmd2 mRNA expression in immature developing neurons abolishes the ability of Reelin to promote dendrite elaboration and dendritic spine maturation. This suggests that the Csmd2-Dab1 interaction may be a requirement of Reelin/Dab1 signaling to mediate the structural maturation of neurons. Together, these results point toward a role of Csmd2 in the Reelin/Dab1 signaling axis that promotes the development of dendrites and dendritic spines in maturing neurons.Summary StatementHow Reelin controls neuronal maturation remains to be understood. We demonstrate that the synaptic protein Csmd2 interacts with the Reelin-associated adaptor protein Dab1. We also determine that Reelin requires Csmd2 to regulate structural development and maturation of forebrain neurons.

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Neto Auxiliary Subunits Regulate Interneuron Somatodendritic and Presynaptic Kainate Receptors to Control Network Inhibition

Cited by 42 publications

References 63 publications

Kainate receptor auxiliary subunit NETO2 is required for normal fear expression and extinction

Kainate receptor auxiliary subunit NETO2 is required for normal fear expression and extinction

Neto-α controls synapse organization and homeostasis at the Drosophila neuromuscular junction

Csmd2 interacts with Dab1 and is Required in Reelin-Mediated Neuronal Maturation

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