Biology subjects

Akbergenova, Y.

Publications and source records attributed to Akbergenova, Y..

7 recordsLinked to original sources

bioRxiv2025

Active zone maturation state controls synaptic output and release mode and is differentially regulated by neuronal activity

Synapse formation requires the gradual accumulation of cytomatrix proteins and voltage-gated Ca2+ channels (VDCCs) at presynaptic active zones (AZs) to support neurotransmitter release. To correlate AZ maturation with synaptic output, quantal imaging was performed at serially imaged time-stamped Drosophila synapses. Evoked release strength correlated strongly with AZ age and accumulation of late AZ scaffolds, while immature sites lacking VDCC accumulation supported spontaneous release. To examine how neuronal activity regulates AZ maturation and protein accumulation, the effects of disruptions to SV fusion or action potential generation were analyzed. Decreasing neuronal activity reduced AZ seeding and caused hyperaccumulation of presynaptic material at existing AZs. Although enlarged AZs are also observed in rab3 mutants, activity reduction acted through an independent mechanism that required postsynaptic glutamate receptor-dependent signaling. Together, these data indicate AZ maturation state sets distinct presynaptic release modes and output strength, with neuronal activity shaping both AZ number and size across development.

neuroscience↗

bioRxiv2023

Loss of the extracellular matrix protein Perlecan disrupts axonal and synaptic stability during Drosophila development

Heparan sulfate proteoglycans (HSPGs) form essential components of the extracellular matrix (ECM) and basement membrane (BM) and have both structural and signaling roles. Perlecan is a secreted ECM-localized HSPG that contributes to tissue integrity and cell-cell communication. Although a core component of the ECM, the role of Perlecan in neuronal structure and function is less understood. Here we identify a role for Drosophila Perlecan in the maintenance of larval motoneuron axonal and synaptic stability. Loss of Perlecan causes alterations in the axonal cytoskeleton, followed by axonal breakage and synaptic retraction of neuromuscular junctions. These phenotypes are not prevented by blocking Wallerian degeneration and are independent of Perlecans role in Wingless signaling. Expression of Perlecan solely in motoneurons cannot rescue synaptic retraction phenotypes. Similarly, removing Perlecan specifically from neurons, glia or muscle does not cause synaptic retraction, indicating the protein is secreted from multiple cell types and functions non-cell autonomously. Within the peripheral nervous system, Perlecan predominantly localizes to the neural lamella, a specialized ECM surrounding nerve bundles. Indeed, the neural lamella is disrupted in the absence of Perlecan, with axons occasionally exiting their usual boundary in the nerve bundle. In addition, entire nerve bundles degenerate in a temporally coordinated manner across individual hemi-segments throughout larval development. These observations indicate disruption of neural lamella ECM function triggers axonal destabilization and synaptic retraction of motoneurons, revealing a role for Perlecan in axonal and synaptic integrity during nervous system development.

neuroscience↗

bioRxiv2023

Molecular Logic of Synaptic Diversity Between Drosophila Tonic and Phasic Motoneurons

Although neuronal subtypes display unique synaptic organization and function, the underlying transcriptional differences that establish these features is poorly understood. To identify molecular pathways that contribute to synaptic diversity, single neuron PatchSeq RNA profiling was performed on Drosophila tonic and phasic glutamatergic motoneurons. Tonic motoneurons form weaker facilitating synapses onto single muscles, while phasic motoneurons form stronger depressing synapses onto multiple muscles. Super-resolution microscopy and in vivo imaging demonstrated synaptic active zones in phasic motoneurons are more compact and display enhanced Ca2+ influx compared to their tonic counterparts. Genetic analysis identified unique synaptic properties that mapped onto gene expression differences for several cellular pathways, including distinct signaling ligands, post-translational modifications and intracellular Ca2+ buffers. These findings provide insights into how unique transcriptomes drive functional and morphological differences between neuronal subtypes.

neuroscience↗

bioRxiv2021

The decoy SNARE Tomosyn sets tonic versus phasic release properties and is required for homeostatic synaptic plasticity

Synaptic vesicle release probability (Pr) is a key presynaptic determinant of synaptic strength established by cell intrinsic properties and further refined by plasticity. To characterize mechanisms that generate Pr heterogeneity between distinct neuronal populations, we examined glutamatergic tonic (Ib) and phasic (Is) motoneurons in Drosophila with stereotyped differences in Pr and synaptic plasticity. We found the decoy SNARE Tomosyn is differentially expressed between these motoneuron subclasses and contributes to intrinsic differences in their synaptic output. Tomosyn expression enables tonic release in Ib motoneurons by reducing SNARE complex formation and suppressing Pr to generate decreased levels of synaptic vesicle fusion and enhanced resistance to synaptic fatigue. In contrast, phasic release dominates when Tomosyn expression is low, enabling high intrinsic Pr at Is terminals at the expense of sustained release and robust presynaptic potentiation. In addition, loss of Tomosyn disrupts the ability of tonic synapses to undergo presynaptic homeostatic potentiation (PHP).

neuroscience↗

bioRxiv2020

Synaptic plasticity induced by differential manipulation of tonic and phasic motoneurons in Drosophila

Structural and functional plasticity induced by neuronal competition is a common feature of developing nervous systems. However, the rules governing how postsynaptic cells differentiate between presynaptic inputs are unclear. In this study we characterized synaptic interactions following manipulations of Ib tonic or Is phasic glutamatergic motoneurons that co-innervate postsynaptic muscles at Drosophila neuromuscular junctions (NMJs). After identifying drivers for each neuronal subtype, we performed ablation or genetic manipulations to alter neuronal activity and examined the effects on synaptic innervation and function. Ablation of either Ib or Is resulted in decreased muscle response, with some functional compensation occurring in the tonic Ib input when Is was missing. In contrast, the phasic Is terminal failed to show functional or structural changes following loss of the co-innervating Ib input. Decreasing the activity of the Ib or Is neuron with tetanus toxin light chain resulted in structural changes in muscle innervation. Decreased Ib activity resulted in reduced active zone (AZ) number and decreased postsynaptic subsynaptic reticulum (SSR) volume, with the emergence of filopodial-like protrusions from synaptic boutons of the Ib input. Decreased Is activity did not induce structural changes at its own synapses, but the co-innervating Ib motoneuron increased the number of synaptic boutons and AZs it formed. These findings indicate tonic and phasic neurons respond independently to changes in activity, with either functional or structural alterations in the tonic motoneuron occurring following ablation or reduced activity of the co-innervating phasic input, respectively. Significance StatementBoth invertebrate and vertebrate nervous systems display synaptic plasticity in response to behavioral experiences, indicating underlying mechanisms emerged early in evolution. How specific neuronal classes innervating the same postsynaptic target display distinct types of plasticity is unclear. Here, we examined if Drosophila tonic Ib and phasic Is motoneurons display competitive or cooperative interactions during innervation of the same muscle, or compensatory changes when the output of one motoneuron is altered. We established a system to differentially manipulate the motoneurons and examined the effects of cell-type specific changes to one of the inputs. Our findings indicate Ib and Is motoneurons respond differently to activity mismatch or loss of the co-innervating input, with the tonic subclass responding robustly compared to phasic motoneurons.

neuroscience↗

bioRxiv2020

Drosophila Synaptotagmin 7 negatively regulates synaptic vesicle fusion and replenishment in a dosage-dependent manner

Synchronous neurotransmitter release is triggered by Ca2+ binding to the synaptic vesicle protein Synaptotagmin 1, while asynchronous fusion and short-term facilitation is hypothesized to be mediated by plasma membrane-localized Synaptotagmin 7 (SYT7). We generated mutations in Drosophila Syt7 to determine if it plays a conserved role as the Ca2+ sensor for these processes. Electrophysiology and quantal imaging revealed evoked release was elevated 2-fold. Syt7 mutants also had a larger pool of readily-releasable vesicles, faster recovery following stimulation, and robust facilitation. Syt1/Syt7 double mutants displayed more release than Syt1 mutants alone, indicating SYT7 does not mediate the residual asynchronous release remaining in the absence of SYT1. SYT7 localizes to an internal membrane tubular network within the peri-active zone, but does not enrich at release sites. These findings indicate the two Ca2+ sensor model of SYT1 and SYT7 mediating all phases of neurotransmitter release and facilitation is not applicable at Drosophila synapses.

neuroscience↗

bioRxiv2017

Examining molecular determinants underlying heterogeneity of synaptic release probability using optical quantal imaging

Neurons communicate through neurotransmitter release at specialized synaptic regions known as active zones (AZs). Using transgenic biosensors to image postsynaptic glutamate receptor activation following single vesicle fusion events at Drosophila neuromuscular junctions, we analyzed release probability (Pr) maps for a defined connection with ~300 AZs between synaptic partners. Although Pr was very heterogeneous, it represented a stable and unique feature of each AZ. Pr heterogeneity was not abolished in mutants lacking Synaptotagmin 1, suggesting the AZ itself is likely to harbor a key determinant(s). Indeed, AZ Pr was strongly correlated with presynaptic Ca2+ channel density and Ca2+ influx at single release sites. In addition, Pr variability was reflected in the postsynaptic compartment, as high Pr AZs displayed a distinct pattern of glutamate receptor clustering. Developmental analysis suggests that high Pr sites emerge from earlier formed AZs, with a temporal maturation in transmission strength occurring over several days.

neuroscience↗