Biology subjects

Taschenberger, H.

Publications and source records attributed to Taschenberger, H..

4 recordsLinked to original sources

bioRxiv2023

Fully-primed slowly-recovering vesicles mediate presynaptic LTP at neocortical neurons

Pre- and postsynaptic forms of long-term potentiation (LTP) are candidate synaptic mechanisms underlying learning and memory. At layer 5 pyramidal neurons LTP increases the initial synaptic strength but also short-term depression during high-frequency transmission. This classical form of presynaptic LTP has been referred to as redistribution of synaptic efficacy. However, the underlying mechanisms remain unclear. We therefore performed whole-cell recordings from layer 5 pyramidal neurons in acute cortical slices of rats and analyzed presynaptic function before and after LTP induction by paired pre- and postsynaptic neuronal activity. LTP was successfully induced in about half of the synaptic connections tested and resulted in increased synaptic depression during high-frequency transmission and a decelerated recovery from depression due to an increased occurrence of a slow recovery component. Analysis with a recently established sequential two-step vesicle priming model indicates an increase in the abundance of fully-primed and slowly-recovering vesicles. A systematic analysis of short-term plasticity and synapse-to-synapse variability of synaptic strength at various types of synapses revealed that stronger synapses generally recover more slowly from synaptic depression. Finally, pharmacological stimulation of the cyclic adenosine monophosphate (cAMP) and diacylglycerol (DAG) signaling pathways, which are both known to promote synaptic vesicle priming mimicked electrically-induced LTP and slowed the recovery from depression. Our data thus demonstrate that LTP at layer 5 pyramidal neurons increases synaptic strength primarily by enlarging a subpool of fully-primed slowly-recovering vesicles.

neuroscience↗

bioRxiv2023

Transcriptional networks predating cognition-associated pyramidal lineages are restructured by erythropoietin

Recombinant human erythropoietin (rhEPO) has potent procognitive effects, hematopoiesis-independent, but underlying mechanisms and physiological role of brain-expressed EPO have remained obscure. Here, we provide encyclopedic transcriptional hippocampal profiling of mice treated with rhEPO. Based on [~]108,000 single nuclei, we unmask multiple pyramidal lineages with their comprehensive molecular signatures. By temporal profiling and gene regulatory analysis, we build a developmental trajectory of CA1 pyramidal neurons derived from multiple predecessor lineages and elucidate gene regulatory networks underlying their fate determination. With EPO as tool, we discover novel populations of newly differentiating pyramidal neurons, overpopulating to [~]200% upon rhEPO with upregulation of genes crucial for neurodifferentiation, dendrite growth, synaptogenesis, memory formation, and cognition. Using a Cre-based approach to visually distinguish pre-existing from newly formed pyramidal neurons for patch-clamp recordings, we learn that rhEPO treatment differentially affects excitatory and inhibitory inputs. Our findings provide mechanistic insight into how EPO modulates neuronal functions and networks.

neuroscience↗

bioRxiv2022

Functional Neuroligin-2-MDGA1 interactions differentially regulate synaptic GABAARs and cytosolic gephyrin aggregation

AO_SCPLOWBSTRACTC_SCPLOWThe function of GABAergic synapses is critically shaped by cell adhesion proteins that recruit GABAARs to synapses and mediate transsynaptic signalling, but the synapse-type-specific function of such synaptic adhesion proteins and their mutual interaction remain incompletely understood. A ubiquitous cell adhesion protein at GABAergic synapses is Neuroligin-2 (Nlgn2), which recruits synaptic GABAARs by promoting the assembly of the postsynaptic gephyrin scaffold. While Nlgn2 is present at virtually all GABAergic synapses throughout the forebrain, its loss affects different GABAergic synapse subtypes with different severity, indicating that synapse-specific interactors and synapse-organizer-redundancies define the function of Nlgn2 for a given synapse type. Here we investigated how Nlgn2 function at GABAergic synapses in mouse hippocampal area CA1 is modulated by two recently identified interaction partners, MDGA1 and MDGA2. We show that Nlgn2 and MDGA1 colocalize most prominently in the stratum radiatum (S.R.) of area CA1, and that combined Nlgn2 and MDGA1 deletion causes a layer-specific exacerbation of the loss of gephyrin puncta in layer S.R. seen following Nlgn2 deletion. Intriguingly, combined Nlgn2 and MDGA1 deletion concurrently ameliorates the abnormal cytosolic gephyrin aggregation, the reduction in inhibitory synaptic transmission and the exacerbated anxiety-related behavior seen in Nlgn2 knockout (KO) mice. In contrast, heterozygous deletion of MDGA2 in Nlgn2 KO mice has only minor effects on gephyrin and GABAAR puncta and does not normalize cytosolic gephyrin aggregates, inhibitory synaptic transmission or anxiety-related behavior. Our data indicate that MDGA1, but not MDGA2, modulates Nlgn2 function, primarily by regulating the formation of cytosolic gephyrin aggregates. Given that both Nlgn2 and the MDGA family of proteins have been linked to psychiatric disorders, such as autism and schizophrenia, our data lead to the notion that abnormal gephyrin aggregation may contribute to the pathophysiology of these disorders, and that intervention with gephyrin aggregation could present a novel therapeutic strategy.

neuroscience↗

bioRxiv2022

A sequential two-step priming scheme reproduces diversity in synaptic strength and short-term plasticity

Glutamatergic synapses display variable strength and diverse short-term plasticity (STP), even for a given type of connection. Using non-negative tensor factorization (NTF) and conventional state modelling, we demonstrate that a kinetic scheme consisting of two sequential and reversible steps of release-machinery assembly and a final step of synaptic vesicle (SV) fusion reproduces STP and its diversity among synapses. Analyzing transmission at calyx of Held synapses reveals that differences in synaptic strength and STP are not primarily caused by variable fusion probability (pfusion) but determined by the fraction of docked synaptic vesicles equipped with a mature release machinery. Our simulations show, that traditional quantal analysis methods do not necessarily report pfusion of SVs with a mature release machinery but reflect both pfusion and the distribution between mature and immature priming states at rest. Thus, the approach holds promise for a better mechanistic dissection of the roles of presynaptic proteins in the sequence of SV docking, two-step priming and fusion and suggests a mechanism for activity-induced redistribution of synaptic efficacy.

neuroscience↗