Complete Disruption of the Kainate Receptor Gene Family Results in Corticostriatal Dysfunction in Mice

Xu, Jian; Marshall, John; Fernandes, Herman B.; Nomura, Toshihiro; Copits, Bryan A.; Procissi, Daniele; Mori, Susumu; Wang, Lei; Zhu, Yongling; Swanson, Geoffrey T.; Contractor, Anis

doi:10.1016/j.celrep.2017.01.073

Cited by 31 publications

(22 citation statements)

References 43 publications

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“…Wild-type animals are C57Bl/6 from Charles River (Wilmington, MA, USA). Five-KAR subunit knockout mice were provided Dr Anis Contractor (Xu et al 2017). HNK-1ST knockout mice (B6;129-Chst10 tm1Mifu /Mmjax) were obtained from Jackson Laboratories (Bar Harbor, ME, USA) (RRID:MMRRC 037129-JAX).…”

Section: Ethical Approvalmentioning

confidence: 99%

N‐glycan content modulates kainate receptor functional properties

Vernon

Copits

Stolz

et al. 2017

The Journal of Physiology

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Ionotropic glutamate receptors (iGluRs) are tetrameric proteins with between four and 12 consensus sites for N-glycosylation on each subunit, which potentially allows for a high degree of structural diversity conferred by this post-translational modification. N-glycosylation is required for proper folding of iGluRs in mammalian cells, although the impact of oligosaccharides on the function of successfully folded receptors is less clear. Glycan moieties are large, polar, occasionally charged and mediate many protein-protein interactions throughout the nervous system. Additionally, they are attached at sites along iGluR subunits that position them for involvement in the structural changes underlying gating. In the present study, we show that altering glycan content on kainate receptors (KARs) changes the functional properties of the receptors in a manner dependent on the identity of both the modified sugars and the subunit composition of the receptor to which they are attached. We also report that native KARs carry the complex capping oligosaccharide human natural killer-1. Glycosylation patterns probably differ between cell types, across development or with pathologies, and thus our findings reveal a potential mechanism for context-specific fine-tuning of KAR function through diversity in glycan structure.

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Section: Ethical Approvalmentioning

confidence: 99%

N‐glycan content modulates kainate receptor functional properties

Vernon

Copits

Stolz

et al. 2017

The Journal of Physiology

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“…KCC2 interacts with the GluK2 subunit of kainate type of glutamate receptors (KARs), which play important roles in both pre and postsynaptic modulation and influence the functional development of limbic networks (Pinheiro and Mulle, 2008 ; Contractor et al, 2011 ; Lerma and Marques, 2013 ; Xu et al, 2017 ). The interaction with GluK2 regulates trafficking and surface expression of KCC2 in hippocampal neurons (Mahadevan et al, 2014 ; Pressey et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

The Kainate Receptor Subunit GluK2 Interacts With KCC2 to Promote Maturation of Dendritic Spines

Kesaf

Khirug

Dinh

et al. 2020

Front. Cell. Neurosci.

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Kainate receptors (KAR) play a crucial role in the plasticity and functional maturation of glutamatergic synapses. However, how they regulate structural plasticity of dendritic spines is not known. The GluK2 subunit was recently shown to coexist in a functional complex with the neuronal K-Cl cotransporter KCC2. Apart from having a crucial role in the maturation of GABAergic transmission, KCC2 has a morphogenic role in the maturation of dendritic spines. Here, we show that in vivo local inactivation of GluK2 expression in CA3 hippocampal neurons induces altered morphology of dendritic spines and reduction in mEPSC frequency. GluK2 deficiency also resulted in a strong change in the subcellular distribution of KCC2 as well as a smaller somatodendritic gradient in the reversal potential of GABA A. Strikingly, the aberrant morphology of dendritic spines in GluK2-deficient CA3 pyramidal neurons was restored by overexpression of KCC2. GluK2 silencing in hippocampal neurons significantly reduced the expression of 4.1N and functional form of the actin filament severing protein cofilin. Consistently, assessment of actin dynamics using fluorescence recovery after photobleaching (FRAP) of β-actin showed a significant increase in the stability of F-actin filaments in dendritic spines. In conclusion, our results demonstrate that GluK2-KCC2 interaction plays an important role in the structural maturation of dendritic spines. This also provides novel insights into the connection between KAR dysfunction, structural plasticity, and developmental disorders.

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“…While it is important to recognise that no animal model can recapitulate all aspects of OCD, these experimental systems serve as valuable tools for examining component processes and pathophysiologic/therapeutic mechanisms with a level of precision that cannot be achieved in clinical research. These preclinical models, which aim to mimic disturbances hypothesised to contribute to the aetiology of OCD, have been generated through a variety of methods, including genetic manipulations (Greer and Capecchi, 2002; Shmelkov et al, 2010; Ullrich et al, 2018; Welch et al, 2007; Xu et al, 2017), pharmacological manipulations (Shanahan et al, 2009, 2011) and, more recently, neural circuit perturbations (Ahmari et al, 2013; Burguiere et al, 2013; Rapanelli et al, 2017a). A number of different behaviours relevant to OCD have been measured in these models, including compulsive self-grooming (Kalueff et al, 2016), other repetitive actions (Pogorelov et al, 2015; Xu et al, 2015; Zike et al, 2017b), prepulse inhibition (PPI; Baldan Ramsey et al, 2011; Shanahan et al, 2009) and anxiety-like behaviour (Ade et al, 2016; Shmelkov et al, 2010; Welch et al, 2007).…”

Section: Preclinical Ocd Researchmentioning

confidence: 99%

“…Genome-wide association studies (GWAS) conducted to date have been underpowered, with a recent meta-analysis of the two largest studies including less than 3000 patients (International Obsessive Compulsive Disorder Foundation Genetics Collaborative (IOCDF-GC) and OCD Collaborative Genetics Association Studies (OCGAS), 2018). Nevertheless, there has been strong convergent evidence that genes expressed at the glutamatergic synapse are involved in OCD risk (Wu et al, 2012), and a number of transgenic models have attempted to test this hypothesis (Aida et al, 2015; Shmelkov et al, 2010; Welch et al, 2007; Xu et al, 2017; Zike et al, 2017b).…”

Section: Advanced Neuroscience Approaches For Gaining Mechanistic Insmentioning

confidence: 99%

How can preclinical mouse models be used to gain insight into prefrontal cortex dysfunction in obsessive-compulsive disorder?

Manning

Ahmari

2018

Brain and Neuroscience Advances

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Obsessive-compulsive disorder is a debilitating psychiatric disorder that is characterised by perseverative thoughts and behaviours. Cognitive and affective disturbances play a central role in this illness, and it is therefore not surprising that clinical neuroimaging studies have demonstrated widespread alterations in prefrontal cortex functioning in patients. Preclinical mouse experimental systems provide the opportunity to gain mechanistic insight into the neurobiological changes underlying prefrontal cortex dysfunction through new technologies that allow measurement and manipulation of activity in discrete neural populations in awake, behaving mice. However, recent preclinical research has focused on striatal dysfunction, and has therefore provided relatively little insight regarding the role of the prefrontal cortex in obsessive-compulsive disorder-relevant behaviours. Here, we will discuss a number of translational prefrontal cortex-dependent paradigms, including obsessive-compulsive disorder-relevant tasks that produce compulsive responding, and how they can be leveraged in this context. Drawing on recent examples that have led to mechanistic insight about specific genes, cell types and circuits that mediate prefrontal cortex contributions to distinct aspects of cognition, we will provide a framework for applying similar strategies to identify neural mechanisms underlying obsessive-compulsive disorder-relevant behavioural domains. We propose that research using clinically relevant paradigms will accelerate translation of findings from preclinical mouse models, thus supporting the development of novel therapeutics targeted to specific pathophysiological mechanisms.

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Complete Disruption of the Kainate Receptor Gene Family Results in Corticostriatal Dysfunction in Mice

Cited by 31 publications

References 43 publications

N‐glycan content modulates kainate receptor functional properties

N‐glycan content modulates kainate receptor functional properties

The Kainate Receptor Subunit GluK2 Interacts With KCC2 to Promote Maturation of Dendritic Spines

How can preclinical mouse models be used to gain insight into prefrontal cortex dysfunction in obsessive-compulsive disorder?

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