Giant ankyrin-G stabilizes somatodendritic GABAergic synapses through opposing endocytosis of GABA
            <sub>A</sub>
            receptors

Tseng, Wei Chou; Jenkins, Paul M.; Tanaka, Masashi; Mooney, Richard; Bennett, Vann

doi:10.1073/pnas.1417989112

Cited by 78 publications

(106 citation statements)

References 40 publications

(54 reference statements)

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“…Previous studies also identified a mutation (R290H) in collybistin, a regulator of gephyrin localization, that causes epilepsy and intellectual disability (45,46). In addition, the 480-kDa ankyrin-G protein itself promotes stability of somatodendritic GABAergic synapses in vitro and in vivo through opposing endocytosis of GABA A via interaction with GABA RAP (24). These observations fit well with our data showing that loss of αII spectrin disrupts inhibitory innervation by perturbing gephyrin and ankyrin-G.…”

Section: Discussionsupporting

confidence: 91%

“…Together with our morphological studies, these data demonstrate defective GABAergic innervation of cortical pyramidal neurons lacking αII spectrin. Our findings are also supported by the observation that ankyrin-G promotes stability of somatodendritic GABAergic synapses in vitro and in vivo through opposing endocytosis of GABA A Rs via interaction with GABA A R-associated protein (GABARAP) (24).…”

Section: Discussionsupporting

confidence: 79%

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Critical roles of αII spectrin in brain development and epileptic encephalopathy

Wang¹,

Ji²,

Nelson³

et al. 2018

Journal of Clinical Investigation

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Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 79%

Critical roles of αII spectrin in brain development and epileptic encephalopathy

Wang¹,

Ji²,

Nelson³

et al. 2018

Journal of Clinical Investigation

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“…Some of these effects likely result from abnormal AP frequency as well as loss of GABA synapses at the AIS. The 480-kDa AnkG also has recently been discovered to form somatodendritic microdomains in cortical neurons that stabilize cell-surface expression of GABA-A receptors and promote GABAergic synaptogenesis (69). Thus, humans with a mutated or absent AnkG giant exon likely suffer from a major disruption of GABA inhibitory circuits (41).…”

Section: Discussionmentioning

confidence: 99%

Giant ankyrin-G: A critical innovation in vertebrate evolution of fast and integrated neuronal signaling

Jenkins

Kim²,

Jones

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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147

217

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Axon initial segments (AISs) and nodes of Ranvier are sites of clustering of voltage-gated sodium channels (VGSCs) in nervous systems of jawed vertebrates that facilitate fast long-distance electrical signaling. We demonstrate that proximal axonal polarity as well as assembly of the AIS and normal morphogenesis of nodes of Ranvier all require a heretofore uncharacterized alternatively spliced giant exon of ankyrin-G (AnkG). This exon has sequence similarity to I-connectin/Titin and was acquired after the first round of whole-genome duplication by the ancestral ANK2/ANK3 gene in early vertebrates before development of myelin. The giant exon resulted in a new nervous system-specific 480-kDa polypeptide combining previously known features of ANK repeats and β-spectrin-binding activity with a fibrous domain nearly 150 nm in length. We elucidate previously undescribed functions for giant AnkG, including recruitment of β4 spectrin to the AIS that likely is regulated by phosphorylation, and demonstrate that 480-kDa AnkG is a major component of the AIS membrane "undercoat' imaged by platinum replica electron microscopy. Surprisingly, giant AnkG-knockout neurons completely lacking known AIS components still retain distal axonal polarity and generate action potentials (APs), although with abnormal frequency. Giant AnkG-deficient mice live to weaning and provide a rationale for survival of humans with severe cognitive dysfunction bearing a truncating mutation in the giant exon. The giant exon of AnkG is required for assembly of the AIS and nodes of Ranvier and was a transformative innovation in evolution of the vertebrate nervous system that now is a potential target in neurodevelopmental disorders.neuropsychiatric disease | cognitive impairment disorder | axon initial segment | ankyrin-G | axonal polarity

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“…Recent findings implicate ankyrin-G in AMPA glutamate receptor-excitatory synapse structure and function, as well as in GABA synapses onto the cell body (12,52). Future research may be designed to determine the contribution of these different aspects.…”

Section: Discussionmentioning

confidence: 99%

Genetic disruption of ankyrin-G in adult mouse forebrain causes cortical synapse alteration and behavior reminiscent of bipolar disorder

Zhu

Cordner²,

Xiong

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Genome-wide association studies have implicated the ANK3 locus in bipolar disorder, a major human psychotic illness. ANK3 encodes ankyrin-G, which organizes the neuronal axon initial segment (AIS).We generated a mouse model with conditional disruption of ANK3 in pyramidal neurons of the adult forebrain (Ank-G cKO). This resulted in the expected loss of pyramidal neuron AIS voltage-gated sodium and potassium channels. There was also dramatic loss of markers of afferent GABAergic cartridge synapses, resembling the cortical microcircuitry changes in brains from psychotic patients, and suggesting disinhibition. Expression of c-fos was increased in cortical pyramidal neurons, consistent with increased neuronal activity due to disinhibition. The mice showed robust behavioral phenotypes reminiscent of aspects of human mania, ameliorated by antimania drugs lithium and valproate. Repeated social defeat stress resulted in repeated episodes of dramatic behavioral changes from hyperactivity to "depressionlike" behavior, suggestive of some aspects of human bipolar disorder. Overall, we suggest that this Ank-G cKO mouse model recapitulates some of the core features of human bipolar disorder and indicates that cortical microcircuitry alterations during adulthood may be involved in pathogenesis. The model may be useful for studying disease pathophysiology and for developing experimental therapeutics.B ipolar disorder and schizophrenia are major psychiatric disorders. Bipolar patients experience both mania, with elevated mood and activity, and depression (often triggered by stress), with low mood and activity. Bipolar disorder is often uniquely responsive to lithium (Li). Many loci have been identified by genome-wide association studies (GWASs) for schizophrenia (1). By contrast, fewer loci with genome-wide significance have been identified for bipolar disorder (2), with some overlap, suggesting some shared mechanisms.In a recent large GWAS of bipolar disorder (3), the most significant signal was detected at the ANK3 locus. This finding has been replicated in many (if not all) GWASs of bipolar disorder (3-5). The ANK3 locus is also found to be associated, to a lesser extent, with schizophrenia (6, 7).The ANK3 gene encodes ankyrin-G, a large scaffold protein highly expressed in neurons in the brain (8). Three main brainspecific splice variants encode 190, 270, and 480 kDa polypeptides. The 480-kDa peptide is the major isoform responsible for organization of the components of the axon initial segment (AIS), including the clustering of voltage-gated sodium and potassium channels important for generation of the action potential (9, 10). The 190-kDa isoform is present at dendritic spines (11,12). Many of the risk alleles for ANK3 are in the five-prime upstream region, suggestive of changes of expression (13, 14). Ankyrin-G protein expression was reduced in pyramidal AISs in superficial layers of schizophrenia cortex (15). These data suggest that ANK3 risk alleles can cause ankyrin-G loss of function.In cortex, the AISs of pyramidal n...

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Giant ankyrin-G stabilizes somatodendritic GABAergic synapses through opposing endocytosis of GABA _A receptors

Cited by 78 publications

References 40 publications

Critical roles of αII spectrin in brain development and epileptic encephalopathy

Critical roles of αII spectrin in brain development and epileptic encephalopathy

Giant ankyrin-G: A critical innovation in vertebrate evolution of fast and integrated neuronal signaling

Genetic disruption of ankyrin-G in adult mouse forebrain causes cortical synapse alteration and behavior reminiscent of bipolar disorder

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Giant ankyrin-G stabilizes somatodendritic GABAergic synapses through opposing endocytosis of GABA A receptors

Cited by 78 publications

References 40 publications

Critical roles of αII spectrin in brain development and epileptic encephalopathy

Critical roles of αII spectrin in brain development and epileptic encephalopathy

Giant ankyrin-G: A critical innovation in vertebrate evolution of fast and integrated neuronal signaling

Genetic disruption of ankyrin-G in adult mouse forebrain causes cortical synapse alteration and behavior reminiscent of bipolar disorder

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Giant ankyrin-G stabilizes somatodendritic GABAergic synapses through opposing endocytosis of GABA _A receptors