Biology subjects

Nowacka, A.

Publications and source records attributed to Nowacka, A..

5 recordsLinked to original sources

bioRxiv2024

Synapse specific and plasticity-regulated AMPAR mobility tunes synaptic integration

Synaptic responses adapt to fast repetitive inputs during bursts of neuronal network activity over timescales of milliseconds to seconds, either transiently facilitating or depressing. This high-frequency stimulus-dependent short-term synaptic plasticity (HF-STP) relies on a number of molecular processes that collectively endow synapses with filtering properties for information processing, optimized for the transmission of certain input frequencies and patterns in distinct circuits 1-3. Changes in HF-STP are traditionally thought to stem from changes in pre-synaptic transmitter release 1,2, but post-synaptic modifications in receptor biophysical properties or surface diffusion also regulate HF-STP 4-11. A major challenge in understanding synapse function is to decipher how pre- and post-synaptic mechanisms synergistically tune synaptic transmission efficacy during HF-STP, and to determine how neuronal activity modifies post-synaptic signal computation and integration to diversify neuronal circuit function. Here, taking advantage of new molecular tools to directly visualize glutamate release 12 and specifically manipulate the surface diffusion of endogenous AMPAR in intact circuits 13, we define the respective contributions of pre-synaptic glutamate release, AMPAR desensitization and surface mobility to frequency-dependent synaptic adaptation. We demonstrate that post-synaptic gain control and signal integration capacity in synaptic networks is influenced by synapse-specific differences in AMPAR desensitization and diffusion-trapping characteristics that are shaped by molecular signaling events recruited during LTP.

neuroscience↗

bioRxiv2023

Phosphorylation of PSD-95 at Serine 73 in dCA1 is required for extinction of contextual fear

The updating of contextual memories is essential for survival in a changing environment. Accumulating data indicate that the dorsal CA1 area (dCA1) contributes to this process. However, the cellular and molecular mechanisms of contextual fear memory updating remain poorly understood. Postsynaptic density protein 95 (PSD-95) regulates the structure and function of glutamatergic synapses. Here, using dCA1-targeted genetic manipulations in vivo, combined with ex vivo 3D electron microscopy and electrophysiology, we identify a novel, synaptic mechanism that is induced during attenuation of contextual fear memories and involves phosphorylation of PSD-95 at Serine 73 in dCA1. Our data provide the proof that PSD-95-dependent synaptic plasticity in dCA1 is required for updating of contextual fear memory.

neuroscience↗

bioRxiv2021

High-resolution imaging and manipulation of endogenous AMPA receptor surface mobility during synaptic plasticity and learning

Regulation of synaptic neurotransmitter receptor content is a fundamental mechanism for tuning synaptic efficacy during experience-dependent plasticity and behavioral adaptation. However, experimental approaches to track and modify receptor movements in integrated experimental systems are limited. Exploiting AMPA-type glutamate receptors (AMPAR) as a model, we generated a knock-in mouse expressing the biotin acceptor peptide (AP) tag on the GluA2 extracellular N-terminus. Cell-specific introduction of biotin ligase allows the use of monovalent or tetravalent avidin variants to respectively monitor or manipulate the surface mobility of endogenous AMPAR containing biotinylated AP-GluA2 in neuronal subsets. AMPAR immobilization precluded the expression of long-term potentiation and formation of contextual fear memory, allowing for target-specific control of the expression of synaptic plasticity and animal behavior. The AP tag knock-in model offers unprecedented access to resolve and control the spatiotemporal dynamics of endogenous receptors, and opens new avenues to study the molecular mechanisms of synaptic plasticity and learning.

neuroscience↗

bioRxiv2020

PSD-95 in dorsal CA1 contributes to the persistence of fear memory

The ability to extinguish fearful memories is essential for survival. Accumulating data indicate that the dorsal CA1 area (dCA1) contributes to this process. However, the cellular and molecular basis of fear memory extinction remains poorly understood. Postsynaptic density protein 95 (PSD-95) regulates the structure and function of glutamatergic synapses. Here, using dCA1-targeted genetic and chemogenetic manipulations in vivo combined with PSD-95 immunostaining and 3D electron microscopy ex vivo, we demonstrate that phosphorylation of PSD-95 at serine 73 PSD-95(S73) is necessary for contextual fear extinction-induced expression of PSD-95 and synaptic plasticity. Moreover, PSD-95(S73) phosphorylation is not necessary for fear memory formation and recall but is required for extinction of contextual fear. Overall, our data shows how PSD-95-dependent synaptic plasticity in the hippocampus contributes to the persistence of fear memories.

neuroscience↗

bioRxiv2019

Contribution of PSD-95 protein to reward location memory

The molecular mechanisms involved in formation of memory are still poorly understood. We focus here on the function of post-synaptic density protein 95 (PSD-95) and its phosphorylation by CaMKII in spontaneous learning about reward location in female mice. We show that formation of reward location memory leads to downregulation of PSD-95 protein in dendritic spines of the stratum radiatum, area CA1, and selective shrinkage of dendritic spines that contain PSD-95. ShRNA-driven, long-term downregulation of PSD-95 in the area CA1 decreases precision of memory. Autophosphorylation deficient CaMKII mutant mice (CaMKII:T286A) need more time than wild-type animals to learn the location of reward. The same impairment is observed after CA1-targeted overexpression of CaMKII phosphorylation-deficient form of PSD-95 (PSD-95:S73A). In contrast to young adult mice, in aged animals reward location learning affects only spines that lack PSD-95. The frequency and size of the spines without PSD-95 are increased, while shRNA targeted to PSD-95 affects neither speed of learning nor precision of memory indicating alternative mechanisms to support successful memory formation in old mice. Altogether, our data suggest that dynamic regulation of PSD-95 expression is a mechanism that accelerates learning and improves precision of reward location memory in young mice. The function of PSD-95 in memory processes changes in aged animals.

neuroscience↗