Retrolinkin cooperates with endophilin A1 to mediate BDNF–TrkB early endocytic trafficking and signaling from early endosomes

Neurotransmission in dentate gyrus (DG) is critical for spatial coding, learning memory, and emotion processing. Although DG dysfunction is implicated in psychiatric disorders, including schizophrenia, underlying pathological mechanisms remain unclear. Here we report that transmembrane protein 108 (Tmem108), a novel schizophrenia susceptibility gene, is highly enriched in DG granule neurons and its expression increased at the postnatal period critical for DG development. Tmem108 is specifically expressed in the nervous system and enriched in the postsynaptic density fraction. Tmem108-deficient neurons form fewer and smaller spines, suggesting that Tmem108 is required for spine formation and maturation. In agreement, excitatory postsynaptic currents of DG granule neurons were decreased in Tmem108 mutant mice, indicating a hypofunction of glutamatergic activity. Further cell biological studies indicate that Tmem108 is necessary for surface expression of AMPA receptors. Tmem108-deficient mice display compromised sensorimotor gating and cognitive function. Together, these observations indicate that Tmem108 plays a critical role in regulating spine development and excitatory transmission in DG granule neurons. When Tmem108 is mutated, mice displayed excitatory/inhibitory imbalance and behavioral deficits relevant to schizophrenia, revealing potential pathophysiological mechanisms of schizophrenia. dentate gyrus | spine | glutamatergic transmission | AMPA receptors | schizophrenia S chizophrenia is a disabling psychiatric disorder that affects 1% of the general population. It is thought to be a neurodevelopment disorder, as many symptoms appear or worsen during adolescence, a time of great transition and refinements in brain structure and function (1, 2). Consequently, patients display characteristic positive symptoms including delusions and hallucinations, negative symptoms including abnormal emotional reactivity and anhedonia and cognitive deficits. Underlying pathophysiological mechanisms have been explored extensively. The medial temporal lobe, including hippocampal dentate gyrus (DG), is thought to be involved in mediating aspects of psychosis and memory deficits in schizophrenia (3, 4). Impaired glutamatergic transmission in DG causes deficits in spatial coding, learning, and memory and emotion processing (5-7). However, detailed molecular mechanisms of DG dysfunction in schizophrenia remain unclear.Identification of risk genes in recent genetic studies has contributed to a better understanding of pathophysiological mechanisms of schizophrenia. Transmembrane protein 108 (TMEM108) has recently been linked with schizophrenia and alcoholism in genome-wide association studies (8, 9). In human, TMEM108 is located on chromosome 3q21-q22, a risk locus for bipolar disorder, schizophrenia and other psychosis (10, 11). In particular, an intronic single nucleotide polymorphism (SNP) (rs7624858) is associated with schizophrenia (8). These findings raise an important question regarding the physiological function of TMEM108 a...

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“…S3 B and C). Previous studies suggest that Tmem108 regulates dendritic outgrowth of hippocampal neurons (13,14). As shown in Fig.…”

Section: Resultsmentioning

confidence: 69%

“…Tmem108 is also present in dendrites of hippocampal neurons and has been implicated in BDNF-induced TrkB endocytosis and dendrite outgrowth in cultured neurons (13,14). However, genetic evidence is lacking regarding the in vivo function of Tmem108 and whether its mutation impairs neural development and causes schizophrenia-relevant behavioral deficits.…”

mentioning

confidence: 99%

Transmembrane protein 108 is required for glutamatergic transmission in dentate gyrus

Jiao

Sun

Bates

et al. 2017

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

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“…However, our previous study has demonstrated that endophilin A1 interacts with retrolinkin in dendrites of mammalian central nervous system neurons and mediates the endocytic trafficking and signaling of the BDNF-TrkB ligand-receptor complex during dendrite outgrowth [22]. To further explore its function(s) in dendrites, we first examined its expression levels in mouse brain at different developmental stages.…”

Section: Endophilin A1 Localizes In Dendritic Spinesmentioning

confidence: 99%

“…Previously we have found that endophilin A1 interacts with retrolinkin and mediates BDNF-TrkB endocytic trafficking and signaling during dendrite outgrowth [22]. In this study, we used genetic manipulations in combination with biochemical and cell biological approaches to investigate the role of endophilin A1 in dendritic spines.…”

Section: Introductionmentioning

confidence: 99%

Endophilin A1 regulates dendritic spine morphogenesis and stability through interaction with p140Cap

et al. 2015

Self Cite

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Dendritic spines are actin-rich membrane protrusions that are the major sites of excitatory synaptic input in the mammalian brain, and their morphological plasticity provides structural basis for learning and memory. Here we report that endophilin A1, with a well-established role in clathrin-mediated synaptic vesicle endocytosis at the presynaptic terminal, also localizes to dendritic spines and is required for spine morphogenesis, synapse formation and synaptic function. We identify p140Cap, a regulator of cytoskeleton reorganization, as a downstream effector of endophilin A1 and demonstrate that disruption of their interaction impairs spine formation and maturation. Moreover, we demonstrate that knockdown of endophilin A1 or p140Cap impairs spine stabilization and synaptic function. We further show that endophilin A1 regulates the distribution of p140Cap and its downstream effector, the F-actin-binding protein cortactin as well as F-actin enrichment in dendritic spines. Together, these results reveal a novel function of postsynaptic endophilin A1 in spine morphogenesis, stabilization and synaptic function through the regulation of p140Cap.

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“…This implies that an elevated level of endophilin-1 at the synapse can interfere with normal neurotransmitter signaling. Indeed, it is possible to speculate that an increase in endophilin-1 may have different effects in different locations, as endophilin-1 has been found both in the pre-synaptic neuron [75][76][77] but also the post-synaptic density [78], where it has recently been given a role in dendritic development [79]. In either case, the relative presence or absence of other signaling molecules will determine which pathways endophilin-1 can influence inside the cell.…”

Section: Consequences Of Abad and Aβ Bindingmentioning

confidence: 99%

Is Amyloid Binding Alcohol Dehydrogenase a Drug Target for Treating Alzheimer’s Disease?

Borger¹,

Aitken²,

Du³

et al. 2013

CAR

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Current strategies for the treatment of Alzheimer's disease (AD) involve tackling the formation or clearance of the amyloid-beta peptide (Aβ) and/or hyper-phosphorylated tau, or the support and stabilization of the remaining neuronal networks. However, as we gain a clearer idea of the large number of molecular mechanisms at work in this disease, it is becoming clearer that the treatment of AD should take a combined approach of dealing with several aspects of the pathology. The concept that we also need to protect specific sensitive targets within the cell should also be considered. In particular the role of protecting the function of a specific mitochondrial protein, amyloid binding alcohol dehydrogenase (ABAD), will be the focus of this review. Mitochondrial dysfunction is a well-recognized fact in the progression of AD, though until recently the mechanisms involved could only be loosely labeled as changes in `metabolism'. The discovery that Aβ can be present within the mitochondria and specifically bind to ABAD, has opened up a new area of AD research. Here we review the evidence that the prevention of Aβ binding to ABAD is a drug target for the treatment of AD.

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Retrolinkin cooperates with endophilin A1 to mediate BDNF–TrkB early endocytic trafficking and signaling from early endosomes

Cited by 45 publications

References 51 publications

Transmembrane protein 108 is required for glutamatergic transmission in dentate gyrus

Transmembrane protein 108 is required for glutamatergic transmission in dentate gyrus

Endophilin A1 regulates dendritic spine morphogenesis and stability through interaction with p140Cap

Is Amyloid Binding Alcohol Dehydrogenase a Drug Target for Treating Alzheimer’s Disease?

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