Postsynaptic receptors regulate presynaptic transmitter stability through transsynaptic bridges.

Stable matching of neurotransmitters with their receptors is fundamental to synapse function and reliable communication in neural circuits. Presynaptic neurotransmitters regulate the stabilization of postsynaptic transmitter receptors. Whether postsynaptic receptors regulate stabilization of presynaptic transmitters has received less attention. Here, we show that blockade of endogenous postsynaptic acetylcholine receptors (AChR) at the neuromuscular junction destabilizes the cholinergic phenotype in motor neurons and stabilizes an earlier, developmentally transient glutamatergic phenotype. Further, expression of exogenous postsynaptic gamma-aminobutyric acid type A receptors (GABAA receptors) in muscle cells stabilizes an earlier, developmentally transient GABAergic motor neuron phenotype. Both AChR and GABAA receptors are linked to presynaptic neurons through transsynaptic bridges. Knockdown of specific components of these transsynaptic bridges prevents stabilization of the cholinergic or GABAergic phenotypes. Bidirectional communication can enforce a match between transmitter and receptor and ensure the fidelity of synaptic transmission. Our findings suggest a potential role of dysfunctional transmitter receptors in neurological disorders that involve the loss of the presynaptic transmitter.

All SNAP25 molecules in the vesicle-plasma membrane contact zone change conformation during vesicle priming.

In neuronal cell types, vesicular exocytosis is governed by the SNARE (soluble NSF attachment receptor) complex consisting of synaptobrevin2, SNAP25, and syntaxin1. These proteins are required for vesicle priming and fusion. We generated an improved SNAP25-based SNARE COmplex Reporter (SCORE2) incorporating mCeruelan3 and Venus and overexpressed it in SNAP25 knockout embryonic mouse chromaffin cells. This construct rescues vesicle fusion with properties indistinguishable from fusion in wild-type cells. Combining electrochemical imaging of individual release events using electrochemical detector arrays with total internal reflection fluorescence resonance energy transfer (TIR-FRET) imaging reveals a rapid FRET increase preceding individual fusion events by 65 ms. The experiments are performed under conditions of a steady-state cycle of docking, priming, and fusion, and the delay suggests that the FRET change reflects tight docking and priming of the vesicle, followed by fusion after ~65 ms. Given the absence of wt SNAP25, SCORE2 allows determination of the number of molecules at fusion sites and the number that changes conformation. The number of SNAP25 molecules changing conformation in the priming step increases with vesicle size and SNAP25 density in the plasma membrane and equals the number of copies present in the vesicle-plasma membrane contact zone. We estimate that in wt cells, 6 to 7 copies of SNAP25 change conformation during the priming step.

Neurotransmitter Switching in the Developing and Adult Brain.

Neurotransmitter switching is the gain of one neurotransmitter and the loss of another in the same neuron in response to chronic stimulation. Neurotransmitter receptors on postsynaptic cells change to match the identity of the newly expressed neurotransmitter. Neurotransmitter switching often appears to change the sign of the synapse from excitatory to inhibitory or from inhibitory to excitatory. In these cases, neurotransmitter switching and receptor matching thus change the polarity of the circuit in which they take place. Neurotransmitter switching produces up or down reversals of behavior. It is also observed in response to disease. These findings raise the possibility that neurotransmitter switching contributes to depression, schizophrenia, and other illnesses. Many early discoveries of the single gain or loss of a neurotransmitter may have been harbingers of neurotransmitter switching.

Graded control of Purkinje cell outputs by cAMP through opposing actions on axonal action potential and transmitter release.

All-or-none signalling by action potentials (APs) in neuronal axons is pivotal for the precisely timed and identical size of outputs to multiple distant targets. However, technical limitations with respect to measuring the signalling in small intact axons have hindered the evaluation of high-fidelity signal propagation. Here, using direct recordings from axonal trunks and/or terminals of cerebellar Purkinje cells in slice and culture, we demonstrate that the timing and amplitude of axonal outputs are gradually modulated by cAMP depending on the length of axon. During the propagation in long axon, APs were attenuated and slowed in conduction by cAMP via specifically decreasing axonal Na+ currents. Consequently, the Ca2+ influx and transmitter release at distal boutons are reduced by cAMP, counteracting its direct facilitating effect on release machinery as observed at various CNS synapses. Together, our tour de force functional dissection has unveiled the axonal distance-dependent graded control of output timing and strength by intracellular signalling. KEY POINTS: The information processing in the nervous system has been classically thought to rely on the axonal faithful and high-speed conduction of action potentials (APs). We demonstrate that the strength and timing of axonal outputs are weakened and delayed, respectively, by cytoplasmic cAMP depending on the axonal length in cerebellar Purkinje cells (PCs). Direct axonal patch clamp recordings uncovered axon-specific attenuation of APs by cAMP through reduction of axonal Na+ currents. cAMP directly augments transmitter release at PC terminals without changing presynaptic Ca2+ influx or readily releasable pool of vesicles, although the extent is weaker compared to other CNS synapses. Two opposite actions of cAMP on PC axons, AP attenuation and release augmentation, together give rise to graded control of synaptic outputs in a manner dependent on the axonal length.

Interactions of catecholamines and GABA+ in cognitive control: Insights from EEG and 1H-MRS.

Catecholamines and amino acid transmitter systems are known to interact, the exact links and their impact on cognitive control functions have however remained unclear. Using a multi-modal imaging approach combining EEG and proton-magnetic resonance spectroscopy (1H-MRS), we investigated the effect of different degrees of pharmacological catecholaminergic enhancement onto theta band activity (TBA) as a measure of interference control during response inhibition and execution. It was central to our study to evaluate the predictive impact of in-vivo baseline GABA+ concentrations in the striatum, the anterior cingulate cortex (ACC) and the supplemental motor area (SMA) of healthy adults under varying degrees of methylphenidate (MPH) stimulation. We provide evidence for a predictive interrelation of baseline GABA+ concentrations in cognitive control relevant brain areas onto task-induced TBA during response control stimulated with MPH. Baseline GABA+ concentrations in the ACC, the striatum, and the SMA had a differential impact on predicting interference control-related TBA in response execution trials. GABA+ concentrations in the ACC appeared to be specifically important for TBA modulations when the cognitive effort needed for interference control was high - that is when no prior task experience exists, or in the absence of catecholaminergic enhancement with MPH. The study highlights the predictive role of baseline GABA+ concentrations in key brain areas influencing cognitive control and responsiveness to catecholaminergic enhancement, particularly in high-effort scenarios.

Presynaptic cGMP sets synaptic strength in the striatum and is important for motor learning.

The striatum is a subcortical brain region responsible for the initiation and termination of voluntary movements. Striatal spiny projection neurons receive major excitatory synaptic input from neocortex and thalamus, and cyclic nucleotides have long been known to play important roles in striatal function. Yet, the precise mechanism of action is unclear. Here, we combine optogenetic stimulation, 2-photon imaging, and genetically encoded scavengers to dissect the regulation of striatal synapses in mice. Our data show that excitatory striatal inputs are tonically depressed by phosphodiesterases (PDEs), in particular PDE1. Blocking PDE activity boosts presynaptic calcium entry and glutamate release, leading to strongly increased synaptic transmission. Although PDE1 degrades both cAMP and cGMP, we uncover that the concentration of cGMP, not cAMP, controls the gain of striatal inputs. Disturbing this gain control mechanism in vivo impairs motor skill learning in mice. The tight dependence of striatal excitatory synapses on PDE1 and cGMP offers a new perspective on the molecular mechanisms regulating striatal activity.

Presynaptic Adrenoceptors.

Presynaptic α2-adrenoceptors are localized on axon terminals of many noradrenergic and non-noradrenergic neurons in the peripheral and central nervous systems. Their activation by exogenous agonists leads to inhibition of the exocytotic release of noradrenaline and other transmitters from the neurons. Most often, the α2A-receptor subtype is involved in this inhibition. The chain of molecular events between receptor occupation and inhibition of the exocytotic release of transmitters has been determined. Physiologically released endogenous noradrenaline elicits retrograde autoinhibition of its own release. Some clonidine-like α2-receptor agonists have been used to treat hypertension. Dexmedetomidine is used for prolonged sedation in the intensive care; It also has a strong analgesic effect. The α2-receptor antagonist mirtazapine increases the noradrenaline concentration in the synaptic cleft by interrupting physiological autoinhibion of release. It belongs to the most effective antidepressive drugs. ß2-Adrenoceptors are also localized on axon terminals in the peripheral and central nervous systems. Their activation leads to enhanced transmitter release, however, they are not activated by endogenous adrenaline.

Involvement of Scratch2 in GalR1-mediated depression-like behaviors in the rat ventral periaqueductal gray.

Galanin receptor1 (GalR1) transcript levels are elevated in the rat ventral periaqueductal gray (vPAG) after chronic mild stress (CMS) and are related to depression-like behavior. To explore the mechanisms underlying the elevated GalR1 expression, we carried out molecular biological experiments in vitro and in animal behavioral experiments in vivo. It was found that a restricted upstream region of the GalR1 gene, from -250 to -220, harbors an E-box and plays a negative role in the GalR1 promoter activity. The transcription factor Scratch2 bound to the E-box to down-regulate GalR1 promoter activity and lower expression levels of the GalR1 gene. The expression of Scratch2 was significantly decreased in the vPAG of CMS rats. Importantly, local knockdown of Scratch2 in the vPAG caused elevated expression of GalR1 in the same region, as well as depression-like behaviors. RNAscope analysis revealed that GalR1 mRNA is expressed together with Scratch2 in both GABA and glutamate neurons. Taking these data together, our study further supports the involvement of GalR1 in mood control and suggests a role for Scratch2 as a regulator of depression-like behavior by repressing the GalR1 gene in the vPAG.

Deep Learning-Based Transmitter Localization in Sparse Wireless Sensor Networks.

In the field of wireless communication, transmitter localization technology is crucial for achieving accurate source tracking. However, the extant methodologies for localization face numerous challenges in wireless sensor networks (WSNs), particularly due to the constraints posed by the sparse distribution of sensors across large areas. We present DSLoc, a deep learning-based approach for transmitter localization in sparse WSNs. Our method is based on an improved high-resolution network model in neural networks. To address localization in sparse wireless sensor networks, we design efficient feature enhancement modules, and propose to locate transmitter locations in the heatmap using an image centroid-based method. Experiments conducted on WSNs with a 0.01% deployment density demonstrate that, compared to existing deep learning models, our method significantly reduces the transmitter miss rate and improves the localization accuracy by more than double. The results indicate that the proposed method offers more accurate and robust performance in sparse WSN environments.

A 2.4 GHz Wide-Range CMOS Current-Mode Class-D PA with HD2 Suppression for Internet of Things Applications.

Short-range Internet of Things (IoT) sensor nodes operating at 2.4 GHz must provide ubiquitous wireless sensor networks (WSNs) with energy-efficient, wide-range output power (POUT). They must also be fully integrated on a single chip for wireless body area networks (WBANs) and wireless personal area networks (WPANs) using low-power Bluetooth (BLE) and Zigbee standards. The proposed fully integrated transmitter (TX) utilizes a digitally controllable current-mode class-D (CMCD) power amplifier (PA) with a second harmonic distortion (HD2) suppression to reduce VCO pulling in an integrated system while meeting harmonic limit regulations. The CMCD PA is divided into 7-bit slices that can be reconfigured between differential and single-ended topologies. Duty cycle distortion compensation is performed for HD2 suppression, and an HD2 rejection filter and a modified C-L-C low-pass filter (LPF) reduce HD2 further. Implemented in a 28 nm CMOS process, the TX achieves a wide POUT range of from 12.1 to -31 dBm and provides a maximum efficiency of 39.8% while consuming 41.1 mW at 12.1 dBm POUT. The calibrated HD2 level is -82.2 dBc at 9.93 dBm POUT, resulting in a transmitter figure of merit (TX_FoM) of -97.52 dB. Higher-order harmonic levels remain below -41.2 dBm even at 12.1 dBm POUT, meeting regulatory requirements.

Endocytosis of Synaptic Vesicle in Motor Nerve Endings of FUS Transgenic Mice with a Model of Amyotrophic Lateral Sclerosis.

In experiments on the motor nerve endings of the diaphragm of transgenic FUS mice with a model of amyotrophic lateral sclerosis at the pre-symptomatic stage of the disease, the processes of transmitter release and endocytosis of synaptic vesicles were studied. In FUS mice, the intensity of transmitter release during high-frequency stimulation of the motor nerve (50 imp/sec) was lowered. At the same duration of stimulation, the loading of fluorescent dye FM1-43 was lower in FUS mice. However, at the time of stimulation, during which an equal number of quanta are released in wild-type and FUS mice, no differences in the intensity of dye loading were found. Thus, endocytosis is not the key factor in the mechanism of synaptic dysfunction in FUS mice at the pre-symptomatic stage.

A phospho-deficient α3 glycine receptor mutation alters synaptic glycine and GABA release in mouse spinal dorsal horn neurons.

Glycine receptors (GlyRs), together with GABAA receptors, mediate postsynaptic inhibition in most spinal cord and hindbrain neurons. In several CNS regions, GlyRs are also expressed in presynaptic terminals. Here, we analysed the effects of a phospho-deficient mutation (S346A) in GlyR α3 subunits on inhibitory synaptic transmission in superficial spinal dorsal horn neurons, where this subunit is abundantly expressed. Unexpectedly, we found that not only were the amplitudes of evoked glycinergic inhibitory postsynaptic currents (IPSCs) significantly larger in GlyRα3(S346A) mice than in mice expressing wild-type α3GlyRs (GlyRα3(WT) mice), but so were those of GABAergic IPSCs. Decreased frequencies of spontaneously occurring glycinergic and GABAergic miniature IPSCs (mIPSCs) with no accompanying change in mIPSC amplitudes suggested a change in presynaptic transmitter release. Paired-pulse experiments on glycinergic IPSCs revealed an increased paired-pulse ratio and a smaller coefficient of variation in GlyRα3(S346A) mice, which together indicate a reduction in transmitter release probability and an increase in the number of releasable vesicles. Paired-pulse ratios of GABAergic IPSCs recorded in the presence of strychnine were not different between genotypes, while the coefficient of variation was smaller in GlyRα3(S346A) mice, demonstrating that the decrease in release probability was readily reversible by GlyR blockade, while the difference in the size of the pool of releasable vesicles remained. Taken together, our results suggest that presynaptic α3 GlyRs regulate synaptic glycine and GABA release in superficial dorsal horn neurons, and that this effect is potentially regulated by their phosphorylation status. KEY POINTS: A serine-to-alanine point mutation was introduced into the glycine receptor α3 subunit of mice. This point mutation renders α3 glycine receptors resistant to protein kinase A mediated phosphorylation but has otherwise only small effects on receptor function. Patch-clamp recordings from neurons in mouse spinal cord slices revealed an unexpected increase in the amplitudes of both glycinergic and GABAergic evoked inhibitory postsynaptic currents (IPSCs). Miniature IPSCs, paired-pulse ratios and synaptic variation analyses indicate a change in synaptic glycine and GABA release. The results strongly suggest that α3 subunit-containing glycine receptors are expressed on presynaptic terminals of inhibitory dorsal horn neurons where they regulate transmitter release.

Neurochemical Anatomy of the Mammalian Carotid Body.

Carotid body (CB) glomus cells in most mammals, including humans, contain a broad diversity of classical neurotransmitters, neuropeptides and gaseous signaling molecules as well as their cognate receptors. Among them, acetylcholine, adenosine triphosphate and dopamine have been proposed to be the main excitatory transmitters in the mammalian CB, although subsequently dopamine has been considered an inhibitory neuromodulator in almost all mammalian species except the rabbit. In addition, co-existence of biogenic amines and neuropeptides has been reported in the glomus cells, thus suggesting that they store and release more than one transmitter in response to natural stimuli. Furthermore, certain metabolic and transmitter-degrading enzymes are involved in the chemotransduction and chemotransmission in various mammals. However, the presence of the corresponding biosynthetic enzyme for some transmitter candidates has not been confirmed, and neuroactive substances like serotonin, gamma-aminobutyric acid and adenosine, neuropeptides including opioids, substance P and endothelin, and gaseous molecules such as nitric oxide have been shown to modulate the chemosensory process through direct actions on glomus cells and/or by producing tonic effects on CB blood vessels. It is likely that the fine balance between excitatory and inhibitory transmitters and their complex interactions might play a more important than suggested role in CB plasticity.

Neuropeptides and small-molecule amine transmitters: cooperative signaling in the nervous system.

Neuropeptides are expressed in cell-specific patterns throughout mammalian brain. Neuropeptide gene expression has been useful for clustering neurons by phenotype, based on single-cell transcriptomics, and for defining specific functional circuits throughout the brain. How neuropeptides function as first messengers in inter-neuronal communication, in cooperation with classical small-molecule amine transmitters (SMATs) is a current topic of systems neurobiology. Questions include how neuropeptides and SMATs cooperate in neurotransmission at the molecular, cellular and circuit levels; whether neuropeptides and SMATs always co-exist in neurons; where neuropeptides and SMATs are stored in the neuron, released from the neuron and acting, and at which receptors, after release; and how neuropeptides affect 'classical' transmitter function, both directly upon co-release, and indirectly, via long-term regulation of gene transcription and neuronal plasticity. Here, we review an extensive body of data about the distribution of neuropeptides and their receptors, their actions after neuronal release, and their function based on pharmacological and genetic loss- and gain-of-function experiments, that addresses these questions, fundamental to understanding brain function, and development of neuropeptide-based, and potentially combinatorial peptide/SMAT-based, neurotherapeutics.

Improvement in Intraoperative Image Quality in Transcranial Magnetic Resonance-Guided Focused Ultrasound Surgery Using Transmitter Gain Adjustment.

INTRODUCTION: Transcranial magnetic resonance-guided focused ultrasound surgery (TcMRgFUS) has the advantage of allowing immediate evaluation of therapeutic effects after each sonication and intraoperative magnetic resonance imaging (MRI) to visualize the lesion. When the image shows that the lesion has missed the planned target and the therapeutic effects are insufficient, the target of the subsequent ablation can be finely adjusted based on the image. The precision of this adjustment is determined by the image quality. However, the current intraoperative image quality with a 3.0T MRI system is insufficient for precisely detecting the lesion. Thus, we developed and validated a method for improving intraoperative image quality. METHODS: Because intraoperative image quality is affected by transmitter gain (TG), we acquired T2-weighted images (T2WIs) with two types of TG: the automatically adjusted TG (auto TG) and the manually adjusted TG (manual TG). To evaluate the character of images with 2 TGs, the actual flip angle (FA), the image uniformity, and the signal-to-noise ratio (SNR) were measured using a phantom. Then, to assess the quality of intraoperative images, T2WIs with both TGs were acquired during TcMRgFUS for 5 patients. The contrast-to-noise ratio (CNR) of the lesion was retrospectively estimated. RESULTS: The images of the phantom with the auto TG showed substantial variations between the preset and actual FAs (p < 0.01), whereas on the images with the manual TG, there were no variations between the two FAs (p > 0.05). The total image uniformity was considerably lower with the manual TG than with the auto TG (p < 0.01), indicating that the image's signal values with the manual TG were more uniform. The manual TG produced significantly higher SNRs than the auto TG (p < 0.01). In the clinical study, the lesions were clearly detected in intraoperative images with the manual TG, but they were difficult to identify in images with the auto TG. The CNR of lesions in images with manual TG was considerably higher than in images with auto TG (p < 0.01). CONCLUSION: Regarding intraoperative T2WIs using a 3.0T MRI system during TcMRgFUS, the manual TG method improved image quality and delineated the ablative lesion more clearly than the current method with auto TG.

Optimal distribution of VLBI transmitters in the Galileo space segment for frame ties.

Equipping Galileo satellites with a VLBI transmitter (VT) will allow to observe satellites next to quasars with Very Long Baseline Interferometry (VLBI) radio telescopes. This concept will facilitate the direct estimation of the satellite orbits in the celestial reference frame. Moreover, these observations along with usual Galileo observations can be used to transfer the space tie between the VT and the antenna on the Galileo satellite to the Earth surface realizing the frame tie at the geodetic site with VLBI radio telescope and Galileo antenna. In this study, we assess the accuracy of that frame tie by simulating the estimation of station coordinates from VLBI observations to Galileo satellites next to quasars. We find that at least two or three satellites need to be equipped with a VT with the best results if all satellites with a VT are placed in the same plane. Concerning the ratio between satellite and quasar observations within a schedule, the results suggest that the optimal ratio is around 30% to 40% satellite observations out of the total number of observations in order to have enough observations for the estimation of the station coordinates but still enough quasar observations to ensure a sufficient sky-coverage for the estimation of troposphere parameters. The best scenario with two satellites yields repeatabilities for the east and north components between 7.5 and 10 mm, and for the up component between 9.5 and 12 mm. In case there is a third satellite with a VLBI transmitter in the same plane, the repeatabilities are reduced by up to 2 mm for the horizontal components and up to 3 to 4 mm for the up component. Rotating the schedules over the constellation repeat cycle of Galileo of 10 days reveals that there are differences between the individual days, but there are no days with a significantly worse precision of the estimated station coordinates.

Energy-Efficient Unmanned Aerial Vehicle-Aided Visible Light Communication with an Angle Diversity Transmitter for Joint Emergency Illumination and Communication.

Unmanned aerial vehicle-aided visible light communication (UAV-VLC) can be used to realize joint emergency illumination and communication, but the endurance of UAV is a key limiting factor. In order to overcome this limitation, this paper proposes the use of an angle diversity transmitter (ADT) to enhance the energy efficiency of the UAV-VLC system. The ADT is designed with one bottom LED and several evenly distributed inclined side LEDs. By jointly optimizing the inclination angle of the side LEDs in the ADT and the height of the hovering UAV, the study aims to minimize the power consumption of the UAV-VLC system while satisfying the requirements of both illumination and communication. Simulation results show that the energy efficiency of the UAV-VLC system can be greatly enhanced by applying the optimized ADT. Moreover, the energy efficiency enhancement is much more significant when the LEDs in the ADT have a smaller divergence angle, or more side LEDs are configured in the ADT. More specifically, a 50.9% energy efficiency improvement can be achieved by using the optimized ADT in comparison to the conventional non-angle diversity transmitter (NADT).

Front-End Development for Radar Applications: A Focus on 24 GHz Transmitter Design.

The proliferation of radar technology has given rise to a growing demand for advanced, high-performance transmitter front-ends operating in the 24 GHz frequency band. This paper presents a design analysis of a radio frequency (RF) transmitter (TX) front-end operated at a 24 GHz frequency and designed using 65 nm complementary metal-oxide-semiconductor (CMOS) technology for radar applications. The proposed TX front-end design includes the integration of an up-conversion mixer and power amplifier (PA). The up-conversion mixer is a Gilbert cell-based design that translates the 2.4 GHz intermediate frequency (IF) signal and 21.6 GHz local oscillator (LO) signal to the 24 GHz RF output signal. The mixer is designed with a novel technique that includes a duplex transconductance path (DTP) for enhancing the mixer's linearity. The DTP of the mixer includes a primary transconductance path (PTP) and a secondary transconductance path (STP). The PTP incorporates a common source (CS) amplifier, while the STP incorporates an improved cross-quad transconductor (ICQT). The integrated PA in the TX front-end is a class AB tunable two-stage PA that can be tuned with the help of varactors as a synchronous mode to increase the PA bandwidth or stagger mode to obtain a high gain. The PA is tuned to 24 GHz as a synchronous mode PA for the TX front-end operation. The proposed TX front-end showed an excellent output power of 11.7 dBm and dissipated 7.5 mW from a 1.2 V supply. In addition, the TX front-end achieved a power-added efficiency (PAE) of 47% and 1 dB compression point (OP1dB) of 10.5 dBm. In this case, the output power is 10.5 dBm higher than the linear portion of the response. The methodologies presented herein have the potential to advance the state of the art in 24 GHz radar technology, fostering innovations in fields such as autonomous vehicles, industrial automation, and remote sensing.

TDOA-Based Target Tracking Filter While Reducing NLOS Errors in Cluttered Environments.

We consider tracking a moving target in a wireless communication system that is based on the radio signal. Considering a bounded workspace with many unknown obstacles, we handle tracking a non-cooperative transmitter using multiple signal receivers. Here, a non-cooperative transmitter is a transmitter whose signal emission time is not known in advance. We consider a time difference of arrival (TDOA) location problem, which locates the transmitter by processing the signal measurement time at multiple receivers. In tracking a non-cooperative transmitter, non-line-of-sight (NLOS) errors occur if obstacles block the LOS line connecting the receiver and the moving transmitter. Our article addresses how to track a moving transmitter while decreasing the NLOS error in TDOA-only measurements. We propose an algorithm to localize a transmitter while decreasing the NLOS error in TDOA measurements. For tracking a moving transmitter in real time, we integrate the proposed localization algorithm and the interacting multiple model Kalman filter (IMM KF). As far as we know, our article is novel in tracking a moving transmitter based on TDOA-only measurements in an unknown mixed LOS/NLOS workspace. We show that the proposed filter considerably decreases the NLOS errors in TDOA-only measurements while running fast. Therefore, the proposed tracking scheme is suitable for tracking a moving transmitter in real time. Through MATLAB simulations, we show that the proposed filter outperforms other state-of-the-art TDOA filters, considering both time efficiency and tracking accuracy.

RIM-Binding Protein 2 Organizes Ca2+ Channel Topography and Regulates Release Probability and Vesicle Replenishment at a Fast Central Synapse.

Rab-interacting molecule (RIM)-binding protein 2 (BP2) is a multidomain protein of the presynaptic active zone (AZ). By binding to RIM, bassoon (Bsn), and voltage-gated Ca2+ channels (CaV), it is considered to be a central organizer of the topography of CaV and release sites of synaptic vesicles (SVs) at the AZ. Here, we used RIM-BP2 knock-out (KO) mice and their wild-type (WT) littermates of either sex to investigate the role of RIM-BP2 at the endbulb of Held synapse of auditory nerve fibers (ANFs) with bushy cells (BCs) of the cochlear nucleus, a fast relay of the auditory pathway with high release probability. Disruption of RIM-BP2 lowered release probability altering short-term plasticity and reduced evoked EPSCs. Analysis of SV pool dynamics during high-frequency train stimulation indicated a reduction of SVs with high release probability but an overall normal size of the readily releasable SV pool (RRP). The Ca2+-dependent fast component of SV replenishment after RRP depletion was slowed. Ultrastructural analysis by superresolution light and electron microscopy revealed an impaired topography of presynaptic CaV and a reduction of docked and membrane-proximal SVs at the AZ. We conclude that RIM-BP2 organizes the topography of CaV, and promotes SV tethering and docking. This way RIM-BP2 is critical for establishing a high initial release probability as required to reliably signal sound onset information that we found to be degraded in BCs of RIM-BP2-deficient mice in vivoSIGNIFICANCE STATEMENT Rab-interacting molecule (RIM)-binding proteins (BPs) are key organizers of the active zone (AZ). Using a multidisciplinary approach to the calyceal endbulb of Held synapse that transmits auditory information at rates of up to hundreds of Hertz with submillisecond precision we demonstrate a requirement for RIM-BP2 for normal auditory signaling. Endbulb synapses lacking RIM-BP2 show a reduced release probability despite normal whole-terminal Ca2+ influx and abundance of the key priming protein Munc13-1, a reduced rate of SV replenishment, as well as an altered topography of voltage-gated (CaV)2.1 Ca2+ channels, and fewer docked and membrane proximal synaptic vesicles (SVs). This hampers transmission of sound onset information likely affecting downstream neural computations such as of sound localization.