Recent evidence implicates glutamatergic synapses as key pathogenic sites in psychiatric disorders. Common and rare variants in the ANK3 gene, encoding ankyrin-G, have been associated with bipolar ...disorder, schizophrenia, and autism. Here we demonstrate that ankyrin-G is integral to AMPAR-mediated synaptic transmission and maintenance of spine morphology. Using superresolution microscopy we find that ankyrin-G forms distinct nanodomain structures within the spine head and neck. At these sites, it modulates mushroom spine structure and function, probably as a perisynaptic scaffold and barrier within the spine neck. Neuronal activity promotes ankyrin-G accumulation in distinct spine subdomains, where it differentially regulates NMDA receptor-dependent plasticity. These data implicate subsynaptic nanodomains containing a major psychiatric risk molecule, ankyrin-G, as having location-specific functions and open directions for basic and translational investigation of psychiatric risk molecules.
•Superresolution imaging reveals functional roles of disease risk factors•Leading psychiatric risk factor, ankyrin-G, regulates synaptic structure and function•Ankyrin-G localizes to and functions in novel types of nanodomains•Ankyrin-G may act as a perisynaptic anchor and a spine neck barrier
Smith et al. show that psychiatric risk factor ankyrin-G regulates synaptic structure and function by localizing to distinct nanodomain structures within the spine head and neck, where it probably functions as a perisynaptic scaffold and spine neck barrier.
Ankyrins are broadly expressed adaptors that organize diverse membrane proteins into specialized domains and link them to the sub-membranous cytoskeleton. In neurons, ankyrins are known to have ...essential roles in organizing the axon initial segment and nodes of Ranvier. However, recent studies have revealed novel functions for ankyrins at synapses, where they organize and stabilize neurotransmitter receptors, modulate dendritic spine morphology and control adhesion to the presynaptic site. Ankyrin genes have also been highly associated with a range of neurodevelopmental and psychiatric diseases, including bipolar disorder, schizophrenia and autism, which all demonstrate overlap in their genetics, mechanisms and phenotypes. This review discusses the novel synaptic functions of ankyrin proteins in neurons, and places these exciting findings in the context of ANK genes as key neuropsychiatric disorder risk-factors.
•Ankyrin proteins link membrane proteins to the submembranous actin cytoskeleton.•Ankyrins organize synapses, in addition to their canonical roles in the axon.•Dendritic spines rely on ankyrin-G for proper stability and synaptic plasticity.•Synaptic functions of ankyrins may contribute to neuropsychiatric diseases.
Mitochondria are critical metabolic and signaling hubs, and dysregulated mitochondrial homeostasis is implicated in many diseases. Degradation of damaged mitochondria by selective ...GABARAP/LC3-dependent macro-autophagy (mitophagy) is critical for maintaining mitochondrial homeostasis. To identify alternate forms of mitochondrial quality control that functionally compensate if mitophagy is inactive, we selected for autophagy-dependent cancer cells that survived loss of LC3-dependent autophagosome formation caused by inactivation of ATG7 or RB1CC1/FIP200. We discovered rare surviving autophagy-deficient clones that adapted to maintain mitochondrial homeostasis after gene inactivation and identified two enhanced mechanisms affecting mitochondria including mitochondrial dynamics and mitochondrial-derived vesicles (MDVs). To further understand these mechanisms, we quantified MDVs via flow cytometry and confirmed an SNX9-mediated mechanism necessary for flux of MDVs to lysosomes. We show that the autophagy-dependent cells acquire unique dependencies on these processes, indicating that these alternate forms of mitochondrial homeostasis compensate for loss of autophagy to maintain mitochondrial health.
Display omitted
•Autophagy-dependent cells maintain functional mitochondria when mitophagy is blocked•Cancer cells can adapt to loss of canonical autophagy/mitophagy•Cancer cells upregulate mitochondrial dynamics to maintain mitochondrial homeostasis•ATG7 KO cells are dependent on mitochondrial-derived vesicles to degrade mitochondria
Towers et al. show that autophagy-dependent cancer cells can survive loss of canonical mitochondrial recycling pathways, known as mitophagy. Rare surviving autophagy-deficient clones have upregulated mitochondrial dynamics to maintain mitochondrial homeostasis and become more dependent on mitochondrial-derived vesicles to degrade damaged mitochondria independent of LC3-conjugation.
•We summarize recent advances in our understanding of activity-dependent and synapse-specific mechanisms of GABAergic synapse development.•We provide a detailed overview of key molecular mechanisms ...underlying GABAergic synapse development.•We focus our discussion on glutamatergic synapses that have been recently shown to play a critical role in GABAergic synapse development.
In the brain, dendrites of pyramidal neurons contain intermingled excitatory and inhibitory synapses. Synaptic connections dynamically change during development and throughout our lifetime, yet the brain can properly maintain an optimal ratio of synaptic excitation to inhibition. Despite recent advances in our understanding of the formation and refinement of excitatory glutamatergic synapses, little is known about signals that regulate inhibitory GABAergic synapse development. In this review, we discuss previous and recent insights in the cellular and molecular mechanisms that underlie GABAergic synapse formation and plasticity, with a specific focus on the key roles of synaptic activity and postsynaptic membrane molecules.
Inhibitory synapses mediate the majority of synaptic inhibition in the brain, thereby controlling neuronal excitability, firing, and plasticity. Although essential for neuronal function, the central ...question of how these synapses are organized at the subsynaptic level remains unanswered. Here, we use three-dimensional (3D) super-resolution microscopy to image key components of the inhibitory postsynaptic domain and presynaptic terminal, revealing that inhibitory synapses are organized into nanoscale subsynaptic domains (SSDs) of the gephyrin scaffold, GABAARs and the active-zone protein Rab3-interacting molecule (RIM). Gephyrin SSDs cluster GABAAR SSDs, demonstrating nanoscale architectural interdependence between scaffold and receptor. GABAAR SSDs strongly associate with active-zone RIM SSDs, indicating an important role for GABAAR nanoscale organization near sites of GABA release. Finally, we find that in response to elevated activity, synapse growth is mediated by an increase in the number of postsynaptic SSDs, suggesting a modular mechanism for increasing inhibitory synaptic strength.
Display omitted
•Inhibitory synapses are composed of nanoscale subsynaptic domains (SSDs)•Gephyrin and GABAAR SSDs closely associate and are dependent on each other•GABAAR SSDs are closely associated with presynaptic active-zone SSDs•Inhibitory synapses recruit additional SSDs during activity-dependent growth
Crosby et al. reveal that inhibitory synapses are composed of nanoscale subsynaptic domains of GABAA receptors, the inhibitory scaffold gephyrin and the active-zone protein RIM. During plasticity, additional subsynaptic domains are recruited to the synapse, suggesting a mechanism for activity-dependent synaptic growth.
Brain ischemia causes oxygen and glucose deprivation (OGD) in neurons, triggering a cascade of events leading to synaptic accumulation of glutamate. Excessive activation of glutamate receptors causes ...excitotoxicity and delayed cell death in vulnerable neurons. Following global cerebral ischemia, hippocampal CA1 pyramidal neurons are more vulnerable to injury than their cortical counterparts, but the mechanisms that underlie this difference are unclear. Signaling via Rho-family small GTPases, their upstream guanine nucleotide exchange factors, and GTPase-activating proteins (GAPs) is differentially dysregulated in response to OGD/ischemia in hippocampal and cortical neurons. Increased Rac1 activity caused by OGD/ischemia contributes to neuronal death in hippocampal neurons via diverse effects on NADPH oxidase activity and dendritic spine morphology. The Rac1 guanine nucleotide exchange factor Tiam1 mediates an OGD-induced increase in Rac1 activity in hippocampal neurons; however, the identity of an antagonistic GAP remains elusive. Here we show that the Rac1 GAP breakpoint cluster region (BCR) associates with NMDA receptors (NMDARs) along with Tiam1 and that this protein complex is more abundant in hippocampal compared with cortical neurons. Although total BCR is similar in the two neuronal types, BCR is more active in hippocampal compared with cortical neurons. OGD causes an NMDAR- and Ca2+-permeable AMPAR-dependent deactivation of BCR in hippocampal but not cortical neurons. BCR knockdown occludes OGD-induced Rac1 activation in hippocampal neurons. Furthermore, disrupting the Tiam1–NMDAR interaction with a fragment of Tiam1 blocks OGD-induced Tiam1 activation but has no effect on the deactivation of BCR. This work identifies BCR as a critical player in Rac1 regulation during OGD in hippocampal neurons.
Shank3, which encodes a scaffolding protein at glutamatergic synapses, is a genetic risk factor for autism. In this study, we examined the impact of Shank3 deficiency on the NMDA-type glutamate ...receptor, a key player in cognition and mental illnesses. We found that knockdown of Shank3 with a small interfering RNA (siRNA) caused a significant reduction of NMDAR-mediated ionic or synaptic current, as well as the surface expression of NR1 subunits, in rat cortical cultures. The effect of Shank3 siRNA on NMDAR currents was blocked by an actin stabilizer, and was occluded by an actin destabilizer, suggesting the involvement of actin cytoskeleton. Since actin dynamics is regulated by the GTPase Rac1 and downstream effector p21-activated kinase (PAK), we further examined Shank3 regulation of NMDARs when Rac1 or PAK was manipulated. We found that the reducing effect of Shank3 siRNA on NMDAR currents was mimicked and occluded by specific inhibitors for Rac1 or PAK, and was blocked by constitutively active Rac1 or PAK. Immunocytochemical data showed a strong reduction of F-actin clusters after Shank3 knockdown, which was occluded by a PAK inhibitor. Inhibiting cofilin, the primary downstream target of PAK and a major actin depolymerizing factor, prevented Shank3 siRNA from reducing NMDAR currents and F-actin clusters. Together, these results suggest that Shank3 deficiency induces NMDAR hypofunction by interfering with the Rac1/PAK/cofilin/actin signaling, leading to the loss of NMDAR membrane delivery or stability. It provides a potential mechanism for the role of Shank3 in cognitive deficit in autism.
Postsynaptic trafficking plays a key role in regulating synapse structure and function. While spiny excitatory synapses can be stable throughout adult life, their morphology and function is impaired ...in Alzheimer's disease (AD). However, little is known about how AD risk genes impact synaptic function. Here we used structured superresolution illumination microscopy (SIM) to study the late-onset Alzheimer's disease (LOAD) risk factor BIN1, and show that this protein is abundant in postsynaptic compartments, including spines. While postsynaptic Bin1 shows colocalization with clathrin, a major endocytic protein, it also colocalizes with the small GTPases Rab11 and Arf6, components of the exocytic pathway. Bin1 participates in protein complexes with Arf6 and GluA1, and manipulations of Bin1 lead to changes in spine morphology, AMPA receptor surface expression and trafficking, and AMPA receptor-mediated synaptic transmission. Our data provide new insights into the mesoscale architecture of postsynaptic trafficking compartments and their regulation by a major LOAD risk factor.
Malbrancheamide is a dichlorinated fungal indole alkaloid isolated from both Malbranchea aurantiaca and Malbranchea graminicola that belongs to a family of natural products containing a ...characteristic bicyclo2.2.2diazaoctane core. The introduction of chlorine atoms on the indole ring of malbrancheamide differentiates it from other members of this family and contributes significantly to its biological activity. In this study, we characterized the two flavin-dependent halogenases involved in the late-stage halogenation of malbrancheamide in two different fungal strains. MalA and MalA′ catalyze the iterative dichlorination and monobromination of the free substrate premalbrancheamide as the final steps in the malbrancheamide biosynthetic pathway. Two unnatural bromo-chloro-malbrancheamide analogues were generated through MalA-mediated chemoenzymatic synthesis. Structural analysis and computational studies of MalA′ in complex with three substrates revealed that the enzyme represents a new class of zinc-binding flavin-dependent halogenases and provides new insights into a potentially unique reaction mechanism.
A meta‐analysis was conducted to assess the efficacy of neurofeedback (NFB) in the treatment of individuals with substance use disorder (SUD) in between‐group studies. This study reports findings ...from the first exhaustive search of the literature on the topic and included articles selected from a total of 58 databases/repositories. Studies were evaluated using Hedge's g as the effect size measure and were assessed for risk of bias using funnel plot, Fail‐Safe N, and Trim and Fill analysis. Ten studies, containing 30 effect sizes were evaluated to determine the overall efficacy of NFB for decreasing symptoms of SUD (N = 397), yielding a mean effect size of g = –1.49 (CI 95 = –1.95, –1.03; PI 95 = –4.37 to 1.39). This meta‐analysis provides strong evidence for the efficacy of NFB in treating SUD while also highlighting the value of wholistic client care in SUD treatment.
PDF
