Channel Clustering Research Articles

Angular Clustering of Millimeter-Wave Propagation Channels With Watershed Transformation

An angular clustering method based on image processing is proposed in this paper. It is used to identify clusters in 2D representations of propagation channels. The approach uses operations such as watershed segmentation and is particularly well suited for clustering directional channels obtained by beam-steering at millimeter-wave. This situation occurs for instance with electronic beam-steering using analog antenna arrays during beam training process or during channel modeling measurements using either electronic or mechanical beam-steering. In particular, the proposed technique is used here to cluster two-dimensional power angular spectrum maps. The proposed clustering is unsupervised and is well suited to preserve the shape of clusters by considering the angular connection between neighbor samples, which is useful to obtain more accurate descriptions of channel angular properties. The approach is found to outperform approaches based on K-Power-Means in terms of accuracy as well as computational resources. The technique is assessed in simulation using IEEE 802.11ad channel model and in measurement using experiments conducted at 60 GHz in an indoor environment.

Nanoscale Organization, Regulation, and Dynamic Reorganization of Cardiac Calcium Channels.

The architectural specializations and targeted delivery pathways of cardiomyocytes ensure that L-type Ca2+ channels (CaV1.2) are concentrated on the t-tubule sarcolemma within nanometers of their intracellular partners the type 2 ryanodine receptors (RyR2) which cluster on the junctional sarcoplasmic reticulum (jSR). The organization and distribution of these two groups of cardiac calcium channel clusters critically underlies the uniform contraction of the myocardium. Ca2+ signaling between these two sets of adjacent clusters produces Ca2+ sparks that in health, cannot escalate into Ca2+ waves because there is sufficient separation of adjacent clusters so that the release of Ca2+ from one RyR2 cluster or supercluster, cannot activate and sustain the release of Ca2+ from neighboring clusters. Instead, thousands of these Ca2+ release units (CRUs) generate near simultaneous Ca2+ sparks across every cardiomyocyte during the action potential when calcium induced calcium release from RyR2 is stimulated by depolarization induced Ca2+ influx through voltage dependent CaV1.2 channel clusters. These sparks summate to generate a global Ca2+ transient that activates the myofilaments and thus the electrical signal of the action potential is transduced into a functional output, myocardial contraction. To generate more, or less contractile force to match the hemodynamic and metabolic demands of the body, the heart responds to β-adrenergic signaling by altering activity of calcium channels to tune excitation-contraction coupling accordingly. Recent accumulating evidence suggests that this tuning process also involves altered expression, and dynamic reorganization of CaV1.2 and RyR2 channels on their respective membranes to control the amplitude of Ca2+ entry, SR Ca2+ release and myocardial function. In heart failure and aging, altered distribution and reorganization of these key Ca2+ signaling proteins occurs alongside architectural remodeling and is thought to contribute to impaired contractile function. In the present review we discuss these latest developments, their implications, and future questions to be addressed.

Deep Constraints Space via Channel Alignment for Visible-Infrared Person Re-identification

Reducing the inter-modality gap has been the core of visible-infrared person re-identification (VI-ReID). Most of the existing methods directly constrain the features to reduce the gap between the different modalities. However, the consistency of channel semantic information across different modalities is ignored. In this letter, channel alignment along with severe semantic constraints is proposed to alleviate the significant distribution differences between modalities. To obtain the optimum channel matching mode, a novel channel alignment mechanism termed Channel Instance Level Alignment (CILA) is proposed at the shallow layer, and matched channel features are constrained by the proposed Channel Instance Alignment (CIA) Loss. In the middle layer, we divide the features into multiple hierarchically-aware channel clusters and align the channel clusters by Channel Cluster Alignment (CCA) Loss. The proposed method is validated on SYSU-MM01 and RegDB, and extensive experiments show that the proposed method achieves competitive performance compared with the state of the arts.

Clustered Double-Scattering Channel Modeling for XL-MIMO With Uniform Arrays

Extra-large multiple-input multiple-output (XL-MIMO) systems reveal themselves as a potential candidate for the sixth generation (6G) of wireless communication systems due to their features. As XL-MIMO has a large antenna array, and, typically, the urban environment is plenty of obstacles and reflectors, the spatial non-stationarities are introduced in the signal received at the base station (BS), which means that only a portion of the antenna array is visible to users; hence, accurately modeling XL-MIMO channels is paramount. Previous works on XL-MIMO channel modeling have adopted the non-stationarities only in a spatial sense, and do not consider spatial-time evolution scenarios. Moreover, simplified models with only one set of clusters between the BS and the user equipment (UE) are usually adopted; hence, there is a lack of understanding regarding such channels modeling in the literature. This work proposes and extensively analyzes a double-scattering XL-MIMO channel model, by admitting two types of scattering clusters, one placed at the BS side, and another one located near the UEs. In addition, two distinct antenna array configurations are included in the analysis, the uniform linear and planar arrays (ULA and UPA). We propose a new double-scattering channel model under UPA arrangements, suitable for modeling spatial non-stationarities scenarios in XL-MIMO dynamic environment subject to BS-cluster and UE-cluster correlation, and birth-death channel clusters and scatterers. Numerical results for signal-to-interference-plus-noise ratio (SINR), condition number (CN), and spectral efficiency (SE) performance metrics considering different XL-MIMO channels and system configurations are analyzed via Monte-Carlo simulations, under linear combiners MRC, ZF, and MMSE. Also, we characterize the impact of the number of visible clusters per user, the birth-death rate growth effect on the channel clusters and scatterers, and the favorable propagation effect according to the size of visibility region (VR) overlap. It can be observed that the birth and death processes have a significant impact on the system performance. Under the proposed clustered double-scattering channel modeling, the analyzed XL-MIMO linear receivers presented an SINR degradation around 3 to 4 dB for the MMSE when the number of UEs substantially increased, while the ZF and MRC receivers present a decrease of 1 to 2 dB, approximately, in SINR for the considered dynamic configuration compared with static scenarios.

Virus spreading and heat spreading

Here we propose a heat transfer framework for how human-to-human interaction spreads everything on the landscape: disease, goods, knowledge, news, technology, science, language and culture. We show that the phenomenon of “human spreading” shares key features with phenomena that are fundamental in physics (heat, electricity, species, Darcy fluid flow), which spread through continua. As example for discussion and illustration, we construct this theoretical framework by using the early phase of the coronavirus outbreak, from before May 2020. The human spreading phenomenon (S curve) is unveiled systematically by using a minimum of measurable parameters: the number of persons with whom one person comes in contact, the radial size of each step in the growth of the swept territory, the radial scale of the inhabited territory, and the directions in which infrastructure (e.g., air routes) are available for long and fast spreading. The resulting configuration of spreading is a multiscale assembly of clusters of fast channels embedded in interstices with slow diffusion. The configuration is dendritic, where each direction of long and fast spreading is covered by a finger of clusters, and each finger generates its own ramifications. The similarities between this configuration and the dendritic architectures for heat and fluid flow through heterogeneous media are discussed.

Length impairments of the axon initial segment in rodent models of attention-deficit hyperactivity disorder and autism spectrum disorder

The axon initial segment (AIS) is a structural neuronal compartment of the proximal axon that plays key roles in sodium channel clustering, action potential initiation, and signal propagation of neuronal outputs. Mutations in constitutive genes of the AIS, such as ANK3, have been identified in patients with neurodevelopmental disorders. Nevertheless, morphological changes in the AIS in neurodevelopmental disorders have not been characterized. In this study, we investigated the length of the AIS in rodent models of attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). We observed abnormalities in AIS length in both animal models. In ADHD model rodents, we observed shorter AIS length in layer 2/3 (L2/3) neurons of the medial prefrontal cortex (mPFC) and primary somatosensory barrel field (S1BF). Further, we observed shorter AIS length in S1BF L5 neurons. In ASD model mice, we observed shorter AIS length in L2/3 and L5 neurons of the S1BF. These results suggest that impairments in AIS length are common phenomena in neurodevelopmental disorders such as ADHD and ASD and may be conserved across species. Our findings provide novel insight into the potential contribution of the AIS to the pathophysiology and pathogenesis of neurodevelopmental disorders.

Width and Clustering of Ion-Conducting Channels in Fuel Cell Membranes Are Insensitive to the Length of Ion Tethers

Width and Clustering of Ion-Conducting Channels in Fuel Cell Membranes Are Insensitive to the Length of Ion Tethers

Cx43 carboxyl terminal domain determines AQP4 and Cx30 endfoot organization and blood brain barrier permeability

The neurovascular unit (NVU) consists of cells intrinsic to the vessel wall, the endothelial cells and pericytes, and astrocyte endfeet that surround the vessel but are separated from it by basement membrane. Endothelial cells are primarily responsible for creating and maintaining blood–brain-barrier (BBB) tightness, but astrocytes contribute to the barrier through paracrine signaling to the endothelial cells and by forming the glia limitans. Gap junctions (GJs) between astrocyte endfeet are composed of connexin 43 (Cx43) and Cx30, which form plaques between cells. GJ plaques formed of Cx43 do not diffuse laterally in the plasma membrane and thus potentially provide stable organizational features to the endfoot domain, whereas GJ plaques formed of other connexins and of Cx43 lacking a large portion of its cytoplasmic carboxyl terminus are quite mobile. In order to examine the organizational features that immobile GJs impose on the endfoot, we have used super-resolution confocal microscopy to map number and sizes of GJ plaques and aquaporin (AQP)-4 channel clusters in the perivascular endfeet of mice in which astrocyte GJs (Cx30, Cx43) were deleted or the carboxyl terminus of Cx43 was truncated. To determine if BBB integrity was compromised in these transgenic mice, we conducted perfusion studies under elevated hydrostatic pressure using horseradish peroxide as a molecular probe enabling detection of micro-hemorrhages in brain sections. These studies revealed that microhemorrhages were more numerous in mice lacking Cx43 or its carboxyl terminus. In perivascular domains of cerebral vessels, we found that density of Cx43 GJs was higher in the truncation mutant, while GJ size was smaller. Density of perivascular particles formed by AQP4 and its extended isoform AQP4ex was inversely related to the presence of full length Cx43, whereas the ratio of sizes of the particles of the AQP4ex isoform to total AQP4 was directly related to the presence of full length Cx43. Confocal analysis showed that Cx43 and Cx30 were substantially colocalized in astrocyte domains near vasculature of truncation mutant mice. These results showing altered distribution of some astrocyte nexus components (AQP4 and Cx30) in Cx43 null mice and in a truncation mutant, together with leakier cerebral vasculature, support the hypothesis that localization and mobility of gap junction proteins and their binding partners influences organization of astrocyte endfeet which in turn impacts BBB integrity of the NVU.

Dynamic Clustering of Multipath Components for Time-Varying Propagation Channels

Dynamic channel clustering and modeling have recently attracted much interest. Extensive channel measurements have shown that multipath components (MPCs) generally exist as clusters. Therefore, an accurate clustering algorithm is required to model the time-varying channels. However, the dynamic behaviors of MPCs have not been well considered in the existing algorithms. In this paper, we present a new metric for MPCs’ clustering in time-variant channels, which considers MPC’s evolution in time domain and clusters MPCs based on the fluctuation and multi-dimension distance of MPC’s trajectories. The performance of the new metric is verified by comparing measurements and simulations. It is found that the proposed algorithm using the new metric can well recognize the dynamic behaviors of MPCs and identify time-varying clusters accurately.

Sparsity-Exploiting Blind Receiver Algorithms for Unsourced Multiple Access in MIMO and Massive MIMO Channels

We propose new transmission schemes and receiver algorithms for unsourced multiple access (UMA) in MIMO and massive MIMO channels. Each active transmitter’s information bits are first channel encoded. The coded bits are divided into sub-blocks and each sub-block is modulated and transmitted. For both MIMO and massive MIMO channels, the conventional nonlinear modulation can be employed where each sub-block of coded bits is mapped to a transmitted signal vector. For the massive MIMO channel, we propose a new hybrid modulation scheme to reduce the receiver complexity, where the first sub-block is nonlinearly modulated, and the subsequent sub-blocks are linearly modulated and spread by the first sub-block signal. We also propose sparsity-exploiting blind receiver algorithms. Specifically, for the MIMO case, we exploit the codeword sparsity inherent in the UMA system, and a channel clustering technique, to estimate the channel and the transmitted signal of each transmitter. For the massive MIMO, in addition to the codeword sparsity, we further exploit the channel sparsity and user sparsity in estimating the channel and transmitted signal of each transmitter. The proposed receiver algorithms for both MIMO and massive MIMO channels output either hard or soft estimates of the coded bits, and therefore single-user channel decoding of the information bits can be performed for each transmitter. Extensive simulation results are provided to demonstrate the performances of the proposed algorithms.

EP News: Basic and Translational

Pérez-Hernández et al (Circ Res 2021;128:419, PMID 33342222) investigated the subcellular domain formed by cardiac Na+ channel (Nav1.5) clusters in the crest region of the adult ventricular myocytes by using super-resolution microscopy and electron microscopy. The investigators identified an Nav1.5 subpopulation in close proximity to subjacent subsarcolemmal mitochondria that preferentially host the mitochondrial Na+/Ca2+ exchanger (NCLX). Upon tetrodotoxin exposure, mitochondria near Nav1.5 channels accumulated more Ca2+ and showed increased reactive oxygen species production.

The great reset: Transcranial pulse stimulation reduces global EEG-entropy in Alzheimer's Disease

Abstract Background: Transcranial Pulse Stimulation (TPS) is a new therapy that uses shockwaves for the treatment of Alzheimer's Disease (AD). In humans, there is first evidence for beneficial clinical effects after a series of six TPS sessions. Magnetic resonance imaging studies suggest up-regulation of memory networks as well as increased cortical thickness after stimulation. Effects on oscillatory electrical brain activity measured with resting state electroencephalography (EEG) have not been reported so far. Methods: A consecutive number of four pilot TPS-treated AD-patients was examined. TPS-naïve resting EEGs were recorded before treatment and compared with EEG-recordings directly after first stimulation. All patients received 4Hz TPS of about 6000 pulses of 0.2 mJ/mm2 (navigated bifrontally, biparietally, bitemporally and praecuneus) using the Neurolith System (Storz Medical). Frontal, parietal, central and temporal channel clusters were analyzed with regard to their alpha, theta delta and gamma power and for a measure of Tsallis entropy. Results: The immediate effect after first TPS on grand-average EEG resting state showed an increase of power in all frequency bands and for total power, although a significant difference between pre- and post-stimulation was not revealed due to power variability. However, the grand-average across patients and channels of Tsallis entropy showed a significant reduction after a single stimulation session. Discussion / Conclusion: Limited due to a high variability (and possibly due to underpower) we found power increase across frequency bands and channels which failed signifance. On the other hand Tsallis entropy was a more sensitive measure for change on EEG activity after stimulation. This might reflect a global reset of uncoordinated and thus pathological neural activity after TPS stimulation. More measurements should be added including longitudinal serial recordings over the treatment course of six sessions with correlations of clinical treatment effects. Keywords: transcranial pulse stimulation, shock wave , Alzheimer, EEG

Topographical distance between presynaptic Ca2+ channels and exocytotic Ca2+ sensors contributes to differential facilitatory actions of roscovitine on neurotransmitter release at cerebellar glutamatergic and GABAergic synapses.

Calcium influx into presynaptic terminals through voltage-gated Ca2+ channels triggers univesicular or multivesicular release of neurotransmitters depending on the characteristics of the release machinery. However, the mechanisms underlying multivesicular release (MVR) and its regulation remain unclear. Previous studies showed that in rat cerebellum, the cyclin-dependent kinase inhibitor roscovitine profoundly increases excitatory postsynaptic current (EPSC) amplitudes at granule cell (GC)-Purkinje cell (PC) synapses by enhancing the MVR of glutamate. This compound can also moderately augment the amplitude and prolong the decay time of inhibitory postsynaptic currents (IPSCs) at molecular layer interneuron (MLI)-PC synapses via MVR enhancement and GABA spillover, thus allowing for persistent activation of perisynaptic GABA receptors. The enhanced MVR may depend on the driving force for Cav 2.1 channel-mediated Ca2+ influx. To determine whether the distinct spatiotemporal dynamics of presynaptic Ca2+ influence MVR, we compared the effects of slow and fast Ca2+ chelators, that is, EGTA and BAPTA, respectively, on roscovitine-induced actions at GC-PC and MLI-PC synapses. Membrane-permeable EGTA-AM decreased GC-PC EPSC and MLI-PC IPSC amplitudes to a similar extent but suppressed the roscovitine-induced enhancement of EPSCs. In contrast, BAPTA-AM attenuated the effects of roscovitine on IPSCs. These results suggest that roscovitine augmented glutamate release by activating the release machinery located distally from the Cav 2.1 channel clusters, while it enhanced GABA release in a manner less dependent on those at distal sites. Therefore, the spatial relationships among Ca2+ channels, buffers, and sensors are critical determinants of the differential facilitatory actions of roscovitine on glutamatergic and GABAergic synapses in the cerebellar cortex.

Sodium channels and the intercalated disk - it is all about location, location, location.

Sodium channels and the intercalated disk - it is all about location, location, location.

Localization of Na+ channel clusters in narrowed perinexi of gap junctions enhances cardiac impulse transmission via ephaptic coupling: a model study

It has been proposed that when gap junctional coupling is reduced in cardiac tissue, action potential propagation can be supported via ephaptic coupling, a mechanism mediated by negative electric potentials occurring in narrow intercellular clefts of intercalated discs (IDs). Recent studies showed that sodium (Na+) channels form clusters near gap junction plaques in nanodomains called perinexi, where the ID cleft is even narrower. To examine the electrophysiological relevance of Na+ channel clusters being located in perinexi, we developed a 3D finite element model of two longitudinally abutting cardiomyocytes, with a central Na+ channel cluster on the ID membranes. When this cluster was located in the perinexus of a closely positioned gap junction plaque, varying perinexal width greatly modulated impulse transmission from one cell to the other, with narrow perinexi potentiating ephaptic coupling. This modulation occurred via the interplay of Na+ currents, extracellular potentials in the cleft and patterns of current flow within the cleft. In contrast, when the Na+ channel cluster was located remotely from the gap junction plaque, this modulation by perinexus width largely disappeared. Interestingly, the Na+ current in the ID membrane of the pre‐junctional cell switched from inward to outward during excitation, thus contributing ions to the activating channels on the post‐junctional ID membrane. In conclusion, these results indicate that the localization of Na+ channel clusters in the perinexi of gap junction plaques is crucial for ephaptic coupling, which is furthermore greatly modulated by perinexal width. These findings are relevant for a comprehensive understanding of cardiac excitation.Key points Ephaptic coupling is a cardiac conduction mechanism involving nanoscale‐level interactions between the sodium (Na+) current and the extracellular potential in narrow intercalated disc clefts.When gap junctional coupling is reduced, ephaptic coupling acts in conjunction with the classical cardiac conduction mechanism based on gap junctional current flow.In intercalated discs, Na+ channels form clusters that are preferentially located in the periphery of gap junction plaques, in nanodomains known as perinexi, but the electrophysiological role of these perinexi has never been examined.In our new 3D finite element model of two cardiac cells abutting each other with their intercalated discs, a Na+ channel cluster located inside a narrowed perinexus facilitated impulse transmission via ephaptic coupling.Our simulations demonstrate the role of narrowed perinexi as privileged sites for ephaptic coupling in pathological situations when gap junctional coupling is decreased.

Pathogenesis of acute and chronic inflammatory neuropathies

Guillain-Barre syndrome (GBS) is classified into axonal and demyelinating categories. Acute motor axonal neuropathy (AMAN), an axonal subtype, was widely recognized in the 1990's. Whereas in Europe and North America, classical demyelinating GBS is the major subtype, AMAN is found for 30–80% of GBS cases in Asia. Over the past 25 years, major advances have been made in understanding the immunopathogenesis of AMAN; animal model studies have shown that there is good evidence to support an anti-GM1 antibody-mediated immune process, triggered by molecular mimicry between gangliosides of motor axons and the microorganism. Complement-mediated attack leads to disruption of nodal sodium channel clusters, and paranodal myelin detachment that is responsible for axonal dysfunction/degeneration in AMAN. CIDP is currently classified into “typical CIDP” and other variants such as “multifocal CIDP (mononeuropathy multiplex type)” and distal CIDP. Typical CIDP is a classic form, characterized by symmetric proximal and distal muscle weakness and motor-dominant manifestation. In typical CIDP, demyelination predominantly affects the distal nerve terminals and nerve roots, presumably because of the lack of the blood-nerve barrier in these regions, and this could be responsible for the “non-nerve length-dependent” distribution of muscle weakness. These findings suggest an importance of humoral immunity in typical CIDP. In contrast, multifocal CIDP is characterized by multifocal demyelination in the intermediate nerve trunks, suggesting that cellular immunity may be predominantly involved in breakdown of the blood-nerve barrier at the site of conduction block. The understanding of the pathophysiology of each CIDP subtype is important for appropriate immune-treatments.

Ankyrin-dependent Na+ channel clustering prevents neuromuscular synapse fatigue

Skeletal muscle contraction depends on activation of clustered acetylcholine receptors (AchRs) and muscle-specific Na+ channels (Nav1.4). Some Nav1.4 channels are highly enriched at the neuromuscular junction (NMJ), and their clustering is thought to be essential for effective muscle excitation. However, this has not been experimentally tested, and how NMJ Na+ channels are clustered is unknown. Here, using muscle-specific ankyrinR, ankyrinB, and ankyrinG single, double, and triple-conditional knockout mice, we show that Nav1.4 channels fail to cluster only after deletion of all three ankyrins. Remarkably, ankyrin-deficient muscles have normal NMJ morphology, AchR clustering, sarcolemmal levels of Nav1.4, and muscle force, and they show no indication of degeneration. However, mice lacking clustered NMJ Na+ channels have significantly reduced levels of motor activity and their NMJs rapidly fatigue after repeated nerve-dependent stimulation. Thus, the triple redundancy of ankyrins facilitates NMJ Na+ channel clustering to prevent neuromuscular synapse fatigue.

SY7.2. Electrophysiological features in GBS and CIDP

GBS is currently classified into axonal and demyelinating categories. Acute motor axonal neuropathy (AMAN), an axonal subtype of GBS, was widely recognized in the 1990s. Whereas in Europe and North America, acute inflammatory demyelinating polyneuropathy (AIDP) is considered the major subtype of GBS, in East Asia, and Central and South America, AMAN is found for 30–80% of GBS cases. Over the past 20 years, major advances have been made in understanding the immunopathogenesis and pathophysiology of AMAN. Clinically, AMAN is characterized by pure motor involvement, frequent antecedent Campylobacter jejuni enteritis, and serum anti-ganglioside antibodies. Electrophysiological studies frequently reveal, as well as axonal degeneration, rapidly reversible nerve conduction block/slowing (resolved within days to a few weeks); the time-course suggests functional or microstructural changes at the nodes of Ranvier. It is now established that disrupted nodal sodium channel clusters, and paranodal myelin detachment is responsible for conduction block in AMAN. CIDP is currently classified into “typical CIDP” and other variants such as “multifocal acquired demyelinating sensory and motor neuropathy (MADSAM)”. Typical CIDP is a classic form, clinically characterized by symmetric proximal and distal muscle weakness and motor- dominant manifestation. In typical CIDP, demyelination predominantly affects the distal nerve terminals and nerve roots, presumably because of the lack of the blood-nerve barrier in these regions, and this could be responsible for the “non-nerve length-dependent” distribution of muscle weakness. These findings suggest an importance of humoral immunity in typical CIDP. In contrast, MADSAM is characterized by multifocal demyelination in the intermediate nerve trunks. In MADSAM neuropathy, cellular immunity may be predominantly involved in breakdown of the blood-nerve barrier at the site of conduction block. Among the CIDP spectrum, typical CIDP and MADSAM are the major subtypes, and their pathophysiology appears to be distinct. The understanding of the pathophysiology of each CIDP subtype is important for appropriate immune treatments.

Characterizing the voltage fluctuations driven by a cluster of ligand-gated channels.

In this paper we present the properties of the voltage fluctuations driven by a cluster of ligand-gated channels. First, the second-order moment of the voltage is expressed in form of the integrated resistance and the random force. Then the power spectrum of the voltage noise is obtained analytically, and it is proved to have the 1/ω^{4}-form. Its mechanism lies in that the randomness of the voltage fluctuation is weaker than channel (conductance) noise, which can be approximately described by the Ornstein-Ulenbeck process.

Presynaptic α2δ subunits are key organizers of glutamatergic synapses

In nerve cells the genes encoding for α2δ subunits of voltage-gated calcium channels have been linked to synaptic functions and neurological disease. Here we show that α2δ subunits are essential for the formation and organization of glutamatergic synapses. Using a cellular α2δ subunit triple-knockout/knockdown model, we demonstrate a failure in presynaptic differentiation evidenced by defective presynaptic calcium channel clustering and calcium influx, smaller presynaptic active zones, and a strongly reduced accumulation of presynaptic vesicle-associated proteins (synapsin and vGLUT). The presynaptic defect is associated with the downscaling of postsynaptic AMPA receptors and the postsynaptic density. The role of α2δ isoforms as synaptic organizers is highly redundant, as each individual α2δ isoform can rescue presynaptic calcium channel trafficking and expression of synaptic proteins. Moreover, α2δ-2 and α2δ-3 with mutated metal ion-dependent adhesion sites can fully rescue presynaptic synapsin expression but only partially calcium channel trafficking, suggesting that the regulatory role of α2δ subunits is independent from its role as a calcium channel subunit. Our findings influence the current view on excitatory synapse formation. First, our study suggests that postsynaptic differentiation is secondary to presynaptic differentiation. Second, the dependence of presynaptic differentiation on α2δ implicates α2δ subunits as potential nucleation points for the organization of synapses. Finally, our results suggest that α2δ subunits act as transsynaptic organizers of glutamatergic synapses, thereby aligning the synaptic active zone with the postsynaptic density.