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Phosphoproteomics of tau from tau knockout mice expressing tau or phospho-deficient tauT205A in active hippocampal cells upon fear conditioning

ABSTRACT: This dataset describes the mass spectrometric identification of tau phosphorylation sites in hippocampal neurons active during fear memory encoding. Tau knockout (tau‑/‑) mice were used as a background to selectively express human 2N4R tau variants in behaviourally activated neuronal populations. Tau‑/‑ mice received bilateral injections into the dorsal and ventral hippocampus with doxycycline‑regulated AAV vectors under control of the robust activity‑marking (RAM) promoter. Experimental groups expressed either wild‑type human 2N4R tau (tauWT; n = 4), a phosphorylation‑deficient tau mutant (tauT205A; n = 4), or eGFP as a negative control (n = 2). Following postoperative recovery, mice underwent fear conditioning. Hippocampal tissue was collected 120 minutes after conditioning, prior to induction of transgene expression. Temporal control of tau, tauT205A, or eGFP expression was achieved by doxycycline withdrawal, allowing expression during a defined 20‑hour window corresponding to neuronal activity associated with fear memory encoding. Tau protein was subsequently immunoprecipitated from hippocampal lysates and subjected to bottom‑up phosphoproteomic analysis. Immunoprecipitated tau was reduced, alkylated, and digested with trypsin, followed by enrichment of phosphopeptides using titanium dioxide (TiO₂) affinity chromatography. Enriched phosphopeptides were buffer‑exchanged, dried by vacuum centrifugation, resuspended, and analysed by liquid chromatography–tandem mass spectrometry (LC‑MS/MS). This dataset enables comparative analysis of tau phosphorylation patterns associated with neuronal activation during fear learning and provides insight into the role of the T205 phosphorylation site in activity‑dependent tau regulation.

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ORGANISM(S): Homo Sapiens (human) Mus Musculus (mouse)

TISSUE(S): Brain

SUBMITTER: Arne Ittner

LAB HEAD: Arne Ittner

PROVIDER: PXD076837 | Pride | 2026-04-10

REPOSITORIES: Pride

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Project description:Extinction learning refers to the phenomenon that a previously learned response to an environmental stimulus, for example the expression of an aversive behavior upon exposure to a specific context, is reduced when the stimulus is repeatedly presented in the absence of a previously paired aversive event. Extinction of fear memories has been implicated with the treatment of anxiety disease but the molecular processes that underlie fear extinctionare only beginning to emerge. Here we show that fear extinction initiates up-regulation of hippocampal insulin-growth factor 2 (Igf2) and down-regulation of insulin-growth factor binding protein 7 (Igfbp7). In line with this observation we demonstrate that IGF2 facilitates fear extinction, while IGFBP7 impairs fear extinction in an IGF2-dependent manner. Furthermore, we identify one cellular substrate of altered IGF2-signaling during fear extinction. To this end we show that fear extinction-induced IGF2/IGFBP7-signaling promotes the survival of 17-19 day-old newborn hippocampal neurons. In conclusion, our data suggests that therapeutic strategies that enhance IGF2-signaling and adult neurogenesis might be suitable to treat disease linked to excessive fear memory. We employed mice to investigate fear extinction in the hippocampus-dependent contextual fear conditioning paradigm. To this end, male C57BL/6J mice were exposed to the fear conditioning box (context) followed by an electric foot-shock which elicits the acquisition of conditioned contextual fear. For extinction training animals were repeatedly reexposed to the conditioned context on consecutive days (24h interval) without receiving the footshockagain (extinction trial, E). This procedure eventually results in the decline of the aversive freezing behavior. Mice that were exposed to the conditioning context without receiving fear conditioning training served as control groups. To gain a better understanding of the molecular processes underlying fear extinction we performed a genome-wide analysis of the hippocampal transcriptome during fear extinction. In the employed paradigm fear extinction is a gradual process. To capture the longitudinal course of fear extinction we decided to perform hippocampal microarray analysis at two time points: (1) After the first extinction trial (E1) when animals display high levels of aversive freezing behavior and (2) at the extinction trial on which the freezing behavior was significantly reduced when compared to E1. This extinction trial, in the case of this experiment E5, we termed “extinction trial low freezing” (ELF). Mice that were exposed to the conditioning context without receiving fear conditioning training served as control groups (3). For all three groups we hybridized 5 samples (biological replicates).

Project description:The mechanisms underlying age-associated memory impairment are not well understood. We have shown that the onset of memory disturbances in the aging brain is associated with altered hippocampal chromatin plasticity. During learning, aged mice display a specific deregulation of histone H4 lysine 12 (H4K12) acetylation. To analyze if deregulated H4K12 acetylation impacts on learning-induced gene-expression required for memory consolidation we performed a high-density oligonucleotide microarray to compare the entire hippocampal gene-expression profile of 3 and 16-month-old mice during memory consolidation. In order to identify genes differentially regulated between 3- and 16-month old mice upon fear conditioning we subjected 3- and 16-month old mice to fear conditioning (4 mice each group, total 8 mice) . Mice of the same age that were handled but not subjected to any of the employed behavior paradigms served as control (4 mice 3-month old and 4 mice 16-month old, total 8 mice). During fear conditioning mice are subjected to a novel context followed by a mild electric foot-shock (context-shock exposure). In order to identify genes that are differentially regulated upon fear conditioning and are specific to associative learning we also tested the hippocampal gene-expression profile of 3-month old mice subjected to the same context-exposure that is not followed by a foot-shock (Context-exposure) (4 mice) or receive an immediate foot shock once they are placed in the context and only afterwards are allowed to explore the context (shock-context exposure) (4 mice). In order to identify genes that are regulated upon fear conditioning and are specific to associative learning we compared the hippocampal gene-expression profile of mice subjected to fear conditioning (context-shock), context or shock-context exposure regarding to their age-matched control mice (3 month old) mentioned above (control). Hippocampi from each mice were tested resulting to 24 samples which were separately hybridized (OneColor Array Design).

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Phosphoproteomics of tau from tau knockout mice expressing tau or phospho-deficient tauT205A in active hippocampal cells upon fear conditioning

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