Author response: Constitutive deficiency of the neurogenic hippocampal modulator AP2γ promotes anxiety-like behavior and cumulative memory deficits in mice from juvenile to adult periods
Year: 2021
Type: peer-review
Abstract: Article Figures and data Abstract Editor's evaluation Introduction Results Discussion Materials and methods Data availability References Decision letter Author response Article and author information Metrics Abstract The transcription factor activating protein two gamma (AP2γ) is an important regulator of neurogenesis both during embryonic development as well as in the postnatal brain, but its role for neurophysiology and behavior at distinct postnatal periods is still unclear. In this work, we explored the neurogenic, behavioral, and functional impact of a constitutive and heterozygous AP2γ deletion in mice from early postnatal development until adulthood. AP2γ deficiency promotes downregulation of hippocampal glutamatergic neurogenesis, altering the ontogeny of emotional and memory behaviors associated with hippocampus formation. The impairments induced by AP2γ constitutive deletion since early development leads to an anxious-like phenotype and memory impairments as early as the juvenile phase. These behavioral impairments either persist from the juvenile phase to adulthood or emerge in adult mice with deficits in behavioral flexibility and object location recognition. Collectively, we observed a progressive and cumulative impact of constitutive AP2γ deficiency on the hippocampal glutamatergic neurogenic process, as well as alterations on limbic-cortical connectivity, together with functional behavioral impairments. The results herein presented demonstrate the modulatory role exerted by the AP2γ transcription factor and the relevance of hippocampal neurogenesis in the development of emotional states and memory processes. Editor's evaluation The aim of this study was to examine the impact of AP2γ deficiency on the development of sensorimotor skills, cognitive, and emotional function. This paper will be of interest to scientists in the fields of developmental psychobiology and neurogenesis. https://doi.org/10.7554/eLife.70685.sa0 Decision letter eLife's review process Introduction New cells are continuously generated, differentiated into neurons, and integrated into the preexisting neural networks in restricted regions of the postnatal mouse brain (Dennis et al., 2016; Kempermann et al., 2018; Moreno-Jiménez et al., 2019; Tobin et al., 2019). One of these so-called neurogenic niches is the subgranular zone (SGZ) of the hippocampal dentate gyrus (DG). Here, neural stem cells (NSC) give rise to mature neural cells including glutamatergic granular neurons in a finely tuned process with many developmental steps sensitive to different regulatory influences (Kempermann et al., 2004; Mateus-Pinheiro et al., 2017; Tobin et al., 2019; Toda et al., 2019). The last years have seen an increase in the number of studies on the functional specificity of hippocampal neurogenesis during development (DHN) and adult hippocampal neurogenesis (AHN). The ontogenetic interpretation of hippocampal neurogenesis assigns different functional relevance to DHN as the neurogenic process that establishes the basic repertoire of adaptable behaviors and AHN as the neurogenic process that underpins the adult brain's ability to adapt functional behaviors (Abrous et al., 2021; Masachs et al., 2021; Tronel et al., 2015). This functional dissociation between these two stages of hippocampal neurogenesis allows us to understand how influences in the neurogenic process at different phases can lead to distinct impairments in emotional states and cognitive functions. Postnatal hippocampal glutamatergic neurogenesis exhibits a regulatory transcriptional sequence (Sox2→ Pax6→ Ngn2→ AP2γ→ Tbr2→ NeuroD→ Tbr1) that recapitulates the hallmarks of the embryonic glutamatergic neurogenic process in the cerebral cortex (Hochgerner et al., 2018; Mateus-Pinheiro et al., 2017; Nacher et al., 2005). Transcriptional factors as Pax6, Ngn2, Tbr2, NeuroD, and Tbr1 have several and distinct roles in proliferation, cell kinetics, fate specification, and axonal growth (Englund et al., 2005; Götz et al., 1998; Hevner, 2019; Hevner et al., 2006; Hochgerner et al., 2018). Despite several efforts to understand the complex transcriptional network orchestration involved in the regulation of neurogenesis, both in early developmental stages and during adulthood, these are still to be fully understood (Bertrand et al., 2002; Brill et al., 2009; Englund et al., 2005; Hack et al., 2005; Hsieh, 2012; Mateus-Pinheiro et al., 2017; Waclaw et al., 2006). Recently, the transcription factor activating protein two gamma (AP2γ, also known as Tcfap2c or Tfap2c) was described to be an important regulator of glutamatergic neurogenesis in the adult hippocampus, being involved in the regulation of transient amplifying progenitors (TAPs) cells (Hochgerner et al., 2018; Mateus-Pinheiro et al., 2018; Mateus-Pinheiro et al., 2017). AP2γ belongs to the AP2 family of transcription factors that is highly involved in several systems and biological processes, such as cell proliferation, adhesion, developmental morphogenesis, tumor progression, and cell fate determination (Eckert et al., 2005; Hilger-Eversheim et al., 2000; Thewes et al., 2010). In addition, AP2γ is functionally relevant during embryonic neocortical development, playing detrimental roles in early mammalian extraembryonic development and organogenesis, being one of the molecular components regulating the number of upper layer neurons during ontogeny and phylogeny in the developing cortex (Pinto et al., 2009). AP2γ is critical for the specification of glutamatergic neocortical neurons and their progenitors, acting as a downstream target of Pax6 and being involved in the regulation of Tbr2 and NeuroD basal progenitors' determinants (Mateus-Pinheiro et al., 2017; Pinto et al., 2009). Strikingly, in humans, defects in the AP2γ gene were reported in patients with severe pre- and post-natal growth retardation (Geneviève et al., 2005), and to be involved in the mammary, ovarian and testicular carcinogenesis (Hoei-Hansen et al., 2004; Li et al., 2002; Odegaard et al., 2006). AP2γ deletion during embryonic development results in a specific reduction of upper layer neurons in the occipital cerebral cortex, while its overexpression increases region- and time-specific generation of neurons from cortical layers II/III (Pinto et al., 2009). AP2γ expression persists in the adult hippocampus, particularly in a sub-population of TAPs acting as a positive regulator of the cell fate modulators, Tbr2 and NeuroD, and therefore as a promoter of proliferation and neuronal differentiation (Mateus-Pinheiro et al., 2017). Conditional and specific downregulation of AP2γ in the adult brain NSCs decreases the generation of new neurons in the hippocampal DG and disrupts the electrophysiological synchronization between the hippocampus and the medial prefrontal cortex (mPFC). Furthermore, mice with conditional deletion of AP2γ exhibit behavioral impairments, particularly a deficient performance in cognitive-related tasks (Mateus-Pinheiro et al., 2018; Mateus-Pinheiro et al., 2017). These studies reveal the crucial modulatory role of AP2γ during embryonic cerebral cortex development as well as its influence on glutamatergic neurogenesis and hippocampal-dependent behaviors during adulthood. Still, it is relevant to assess the importance of AP2γ for postnatal neurophysiology and behavior since development, comprehending how defects in the neurogenic process since early development can impact on behavior at specific developmental stages. Herein, we explored the neurogenic, behavioral, and functional effects of AP2γ constitutive and heterozygous deletion in mice from early postnatal development to adulthood. We revealed that AP2γ deficiency promotes downregulation of the hippocampal glutamatergic neurogenic process, compromises functional limbic-cortical connectivity, and leads to significant behavioral impairments on emotional and memory functional modalities. We showed that these impairments induced by AP2γ deficiency do not occur only during adulthood and that compromised hippocampal neurogenesis leads to emotional and memory deficits as early as the juvenile phase. These functional behavioral impairments are either maintained from the juvenile phase to adulthood or emerge as behavioral flexibility and object location recognition deficits in adult mice with AP2γ constitutive deletion. Results Constitutive AP2γ deficiency decreases proliferation and neurogenesis in the postnatal DG, reduces dendritic length and complexity of short-DCX+ cells, without affecting neuronal morphology of mature granular neurons We sought to dissect the impact of constitutive and heterozygous deficiency of AP2γ in the modulation of postnatal neuronal plasticity in the hippocampus, including its effect in the hippocampal neurogenic niche on proliferation and morphology of doublecortin+ (DCX) cells and pre-existing DG granule neurons (Figure 1A). In juvenile (P31) and adult mice (P70 – P84), we assessed the expression of markers for different cell populations (Figure 1B) along the neurogenic process through western blot and immunofluorescence. We observed a significant decrease in the expression levels of AP2γ protein in the hippocampal DG of juvenile (Figure 1C) and adult (Figure 1D) AP2γ heterozygous knockout mice (Tfap2c+/-, henceforth referred as AP2γ KO), with concomitant reduction of Pax6 and Tbr2 protein levels, but not Sox2, an upstream regulator of AP2γ (Mateus-Pinheiro et al., 2017). Figure 1 Download asset Open asset AP2γ constitutive and heterozygous deficiency reduces postnatal hippocampal neurogenesis both at juvenile and adult periods. (A) Experimental timeline. (B) Transcriptional network of hippocampal neurogenesis under modulatory role of AP2γ. Western-blot analysis of AP2γ, Sox2, Pax6, and Tbr2 in juvenile (C) and adult (D) dentate gyrus (DG). (E) Hippocampal DG coronal sections stained for bromodeoxyuridine (BrdU) (green), doublecortin (DCX) (red), and DAPI (blue). BrdU+/DCX+ cells are indicated by white arrows and solely BrdU+ cell is identified with yellow arrows. (F–I) Cell counts of BrdU+ and BrdU+/DCX+ cells in the hippocampal DG of juvenile and adult mice. Data presented as mean ± SEM. Sample size: Western-blot analysis: nWT juvenile = 4; nAP2γ KO juvenile = 4; nWT adult = 4; nAP2γ KOadult = 4; Immunostainings: nWT juvenile = 6; nAP2γ KO juvenile = 6; nWT adult = 5; nAP2γ KOadult = 5 [Student's t-test; ** p < 0.01; * p < 0.05; Statistical summary in Supplementary file 1]. Scale bars represent 50 μm. Abbreviations: WT, wild-type; AP2γ KO, AP2γ heterozygous knockout mice; O.D., optical density. Figure 1—source data 1 Western-blot analysis at the juvenile and adult timepoints. Western-blot analysis of AP2γ, Sox2, Pax6, and Tbr2 in juvenile (A) and adult (B) dentate gyrus (DG) protein extracts. (C and D) Representative Ponceau staining of membranes corresponding to the juvenile and adult timepoints. Surrounded by orange squares are demonstrated the quantified bands and denoted with a small orange star are identified the bands presented in the main Figure 1. Sample size: Western-blot analysis: nWT juvenile = 4; nAP2γ; KO juvenile = 4; nWT adult = 4; nAP2γ; KO adult = 4; Abbreviations: WT, wild-type; AP2γ KO, AP2γ heterozygous knockout mice. https://cdn.elifesciences.org/articles/70685/elife-70685-fig1-data1-v2.pdf Download elife-70685-fig1-data1-v2.pdf Analysis of cell populations in the hippocampal neurogenic niche using BrdU and DCX labeling (Figure 1E) revealed that the number of BrdU+ and BrdU+/DCX+ cells is reduced in both juvenile and adult AP2γ KO mice, suggesting a decrease in the number of fast proliferating cells (TAPs) and neuroblasts, respectively (Figure 1F–I). Of note, we observed a decrease in these cell populations with age in both WT and AP2γ KO mice in agreement with previous reports (Kase et al., 2020; Katsimpardi and Lledo, 2018; Supplementary file 1). To clarify the impact of AP2γ on the dendritic development and structural neuronal formation in the dorsal DG, we analyzed the dendritic structure and complexity of immature neurons based on DCX staining (Figure 2). DCX is a cytoskeletal protein expressed both in neuronal progenitors and immature neurons (Dioli et al., 2019; Francis et al., 1999; Horesh et al., 1999). We assessed the morphology of DCX+ cells only in adult animals as during juvenile period, the large amount of DCX+ cells does not allow a proper segmentation of dendrites through this methodology (Figure 2A). We divided the analysis of DCX+ immature neurons into those that exhibit dendrites that branch into the inner molecular layer (IML) – short-DCX+ cells – and DCX+ cells with dendritic trees that reach the medial/outer molecular layer (M/OML) – long-DCX+ cells, as previously described (Dioli et al., 2019; Figure 2B). Adult AP2γ KO mice presented decreased density of both short- and long-DCX+ cells in comparison to WT animals (Figure 2C and G). Moreover, deficiency of AP2γ led to a reduced dendritic length (Figure 2D and E) and neuronal arborization (Figure 2F) of short-DCX+ cells. Although the density of long-DCX+ cells is reduced in AP2γ KO mice, dendritic length and arborization complexity of the existing long cells are similar to the WT animals (Figure 2H-J). Interestingly, when we analyzed pre-existing granular hippocampal neurons, constitutive deficiency of AP2γ did not alter their dendritic length and the neuronal arborization complexity either during juvenile period (Figure 2—figure supplement 1A and C;) or at adulthood (Figure 2—figure supplement 1B and C), when compared to WT mice. These observations suggest that AP2γ deficiency in adult mice delays the maturation of granular neurons but has no impact on their definitive morphology. Figure 2 with 1 supplement see all Download asset Open asset AP2γ constitutive and heterozygous deficiency reduces DCX+ cell population, and the dendritic length of short-DCX+ cells and its arborization complexity in adult mice. (A and B) Dorsal hippocampal DG coronal sections stained for doublecortin (DCX) (red) and DAPI (blue) with the corresponding color conversion images. These representative images include the DG subregions, the granular cell layer (GCL), the inner and medial/outer molecular layers (IML and M/OML, respectively). Short DCX+ cells are indicated by orange arrows and long DCX+ cells by yellow arrows. (B) Dendritic tree of short (left) and long (right) DCX+ cells are traced in green. Cell counts of short (C) and long (G) DCX+ cells. Dendritic length of reconstructed short (D and E) and long DCX+ (H and I) cells, and respective sholl analysis (F and J). Data presented as mean ± SEM. Sample size: nWT adult = 4; nAP2γ KOadult = 4. [Student's t-test and Repeated measures ANOVA; ***p < 0.001, ** p < 0.01, * p < 0.05; Statistical summary in Supplementary file 1]. Scale bars represent 50 μm. Abbreviations: WT, wild-type; AP2γ KO, AP2γ heterozygous knockout mice; P, Postnatal day. Taken together, the results herein revealed that AP2γ modulatory actions in the hippocampal neurogenic niche are similar and maintained in juvenile and adult mice. AP2γ transcription factor regulates NSCs proliferation and neuronal differentiation in the postnatal hippocampus by interacting with the different modulators involved in the transcriptional regulation of postnatal hippocampal neurogenesis. Furthermore, it suggests an important role of AP2γ transcription factor for a timely maturation of dendritic branching in newly born granular neurons in adulthood. AP2γ KO mice display normal early postnatal development but anxiety-like behavior and memory impairments at juvenile period In light of the negative impact of AP2γ heterozygous deficiency in the postnatal neurogenic process in the hippocampus, known as an important modulator of emotional and memory functions (Christian et al., 2014; Toda et al., 2019), we assessed early postnatal development and the behavioral performance of WT and AP2γ KO at juvenile and adult periods. Evaluation of early postnatal development was performed through the assessment of somatic and neurobiological parameters during the first 21 postnatal days (Table 1; Figure 3—figure supplement 1). Despite a variation in the eye-opening day, responsiveness in sensory-motor functions, vestibular area-dependent tasks, and strength, as well as somatic parameters were similar in WT and AP2γ KO mice. Furthermore, all analyzed parameters were within the previously described range (Guerra-Gomes et al., 2021; Heyser, 2004). These observations suggest that constitutive heterozygous deletion of AP2γ has no impact on early postnatal development. Table 1 Results from the milestones protocol tests included in the assessment of early postnatal neurodevelopment. Sample size: nWT = 9; n AP2γ KO = 9. Abbreviations: WT, wild-type; AP2γ KO, AP2γ heterozygous mice; P, Postnatal day. Milestone testWTDay (median)AP2γ KODay (median)Statistical test, significanceMann-Whitney testTypical rangeRooting77U = 31.50, p = 0.43P1 – P15Ear twitch89U = 24.50, p = 0.16P6 – P14Auditory startle87U = 37.50, p = 0.85P7 – P16Open field88U = 39.50, p > 0.99P6 – P15Walking109U = 38.00, p = 0.78P7 – P14Surface righting77U = 38.50, p = 0.88P1 – P10Negative geotaxis89U = 25.00, p = 0.17P3 – P15Cliff aversion76U = 26.00; p = 0.22P1 – P14Postural reflex98U = 26.00, p = 0.21P5 – P21Air righting1211U = 29.00, p = 0.32P7 – P16Wire suspension1311U = 21.50, p = 0.10P5 – P21Grasping1616U = 30.00, p = 0.37P13 - P17Eye-opening1211U = 9.00, p < 0.01P7 - P17WTMean ±SEMAP2γ KOMean ± SEMStatistical test, significanceRepeated measures ANOVAHomingTrial 16.89 s ± 0.446.89 s ± 1.32F (1,48) = 0.06, p = 0.80Trial 26.33 s ± 1.126.89 s ± 1.12Trial 35.22 s ± 1.575.78 s ± 1.57Weight gain pattern8.99 g ± 0.539.22 g ± 0.16F (1,16) = 0.32, p = 0.58 We then performed an assessment of different behavioral domains in juvenile mice (P25 - P33; Figure 3A). The open-field (OF) and the novelty suppressed-feeding (NSF) tests were used to assess anxiety-like behavior. In the OF, juvenile AP2γ KO mice exhibited decreased distance traveled in the anxiogenic center of the arena, in comparison to WT animals, (Figure 3B) suggesting an anxiety-like phenotype promoted by AP2γ deficiency. Concomitantly, AP2γ KO mice exhibited an increased latency to reach and feed on the food pellet in the NSF test (Figure 3C and D). Of note, WT and AP2γ KO have similar locomotor activity (Figure 3—figure supplement 2A) and appetite drive (Figure 3—figure supplement 2B). Figure 3 with 2 supplements see all Download asset Open asset AP2γ constitutive and heterozygous deficiency increases anxiety-like behavior and promotes cognitive deficits in juvenile mice. (A) Timeline of behavioral assessment. Anxiety-like behavior was assessed through the open-field (OF) (B) and the novelty suppressed feeding (NSF) (C and D) tests. Coping and anhedonic-like behavior by the tail-suspension (TST) (C) and the sucrose splash (SST) (D) tests. (E) To evaluate cognitive behavior, juvenile mice were subjected to the Morris water maze (MWM) (G), the object recognition (ORT) (H–J), the object-in-context recognition (OIC) (K and L) and the contextual fear conditioning (CFC) (M–Q). Data presented as mean ± SEM. Sample size: OF: nWT = 13; nAP2γ KO = 11; NSF: nWT = 13; nAP2γ KO = 15; TST: nWT = 16; nAP2γ KO = 13; SST: nWT = 15; nAP2γ KO = 10; MWM: nWT = 10; nAP2γ KO = 9; ORT: nWT = 11; nAP2γ KO = 8; OIC: nWT = 16; nAP2γ KO = 17; CFC: nWT = 16; nAP2γ KO = 17. [Student's t-test, Repeated measures ANOVA and Two-way ANOVA; *** p < 0.001; ** p < 0.01; * p < 0.05; Statistical summary in Supplementary file 1]. Abbreviations: WT, wild-type; AP2γ KO, AP2γ heterozygous knockout mice. The assessment of adaptive behavior to cope with an inescapable stressor and self-care were then evaluated throughout the tail suspension test (TST) and the sucrose splash test (SST), respectively. We observed no impact of AP2γ constitutive and heterozygous deletion in these emotional domains, as no alterations were detected in the immobility time in the TST (Figure 3E) and grooming time in the SST (Figure 3F). Furthermore, we assessed memory in juvenile mice through the Morris water maze (MWM), the object recognition test (ORT), the object-in-context recognition test (OIC), and the contextual fear conditioning (CFC) test. In the MWM, WT and AP2γ KO juvenile mice present a high and steady escape latency to find the hidden platform throughout training, implying that, at this age, mice are unable to learn this spatial navigation task at this early age (Figure 3G). This phenotype is consistent with the postnatal maturation state of the DG (Hochgerner et al., 2018; Kozareva et al., 2019). In the ORT (Figure 3H), despite no differences in the object location (Figure AP2γ KO mice significant deficits in the object as denoted by a decreased to the object (Figure In the behavioral (Figure WT mice a of time the of the object in the AP2γ KO mice showed no of object (Figure AP2γ KO mice were not to between the two distinct an cortex network and In the a behavior test described to be sensitive to in hippocampal neurogenesis et al., juvenile mice were subjected to two distinct to test hippocampal-dependent and a to assess the of memory (Figure et al., 2012; Mateus-Pinheiro et al., 2017). to behavior was and WT and AP2γ KO mice explored the (Figure In juvenile AP2γ KO mice exhibited reduced behavior when to a (Figure alterations in behavior were observed in (Figure in the (Figure These along with the reveal that AP2γ KO juvenile mice exhibit deficits in contextual Despite no impact on early postnatal development, AP2γ constitutive heterozygous deficiency impairments in hippocampal neurogenesis since development leads to a as revealed by the of an anxious-like phenotype and memory impairments. These results the of the AP2γ transcription factor in the proper of important behavioral functions. Adult AP2γ KO mice emotional and memory while behavioral flexibility and object location recognition impairments emerge during adulthood Adult WT and AP2γ KO mice were also for emotional and memory to behavioral by the effects of AP2γ constitutive deletion on postnatal hippocampal neurogenesis were still present in adulthood (Figure Figure with 1 supplement see all Download asset Open asset assessment of adult mice. (A) Experimental timeline. Anxiety-like behavior was assessed through open-field (OF) (C) and novelty suppressed feeding (NSF) (D and E) while behavior was evaluated through test (G) and the tail-suspension test (TST) recognition test (ORT) (H and object-in-context recognition (OIC) and the contextual fear conditioning (CFC) were performed to assess cognitive behavior. Data presented as mean ± SEM. Sample size: OF, and nWT = nAP2γ KO = NSF: nWT = 10; nAP2γ KO = nWT = 6; nAP2γ KO = 6; ORT: nWT = nAP2γ KO = 9; OIC: nWT = nAP2γ KO = 10; CFC: nWT = nAP2γ KO = [Student's t-test and Two-way ANOVA; *** p < 0.001; ** p < 0.01; * p < 0.05; Statistical summary in Supplementary file 1]. Abbreviations: WT, wild-type; AP2γ KO, AP2γ heterozygous knockout mice. The OF, the and the NSF tests were performed to evaluate anxiety-like behavior. In the test, AP2γ KO mice showed a a decrease in the distance traveled in the anxiogenic center of the = Figure with no in locomotor activity as denoted by similar (Figure supplement 1A). In the test, AP2γ KO mice time in the WT mice (Figure These results are in agreement with results from the NSF test, AP2γ KO mice increased latency to reach and feed from the food pellet (Figure and in appetite drive were observed between since in the food assessment (Figure supplement The test and TST were then performed to examine the adaptive behavior to cope with inescapable WT and AP2γ KO mice exhibit similar immobility time in (Figure and TST (Figure These observations suggest that anxiety-like behavior promoted by constitutive AP2γ deficiency persist in adult mice, with no in behavior. memory performance was evaluated by the and ORT revealed a a decrease in the to the object of AP2γ KO when compared to WT mice = Figure no alterations were observed in the object (Figure In the results were similar to juvenile mice. AP2γ KO adult mice were not to between the two since showed no of object WT animals a of time the of object (Figure to behavior in the was and WT and AP2γ KO performed (Figure AP2γ KO mice exhibited reduced behavior when to a conditioning - (Figure no alterations in behavior were observed in (Figure in the (Figure These along with the results from the suggest that adult AP2γ KO mice have deficits in contextual memory and an The were also subjected to the test for evaluation of spatial memory (Figure In the memory that on hippocampal et al., AP2γ KO and WT mice exhibit similar performance to reach the hidden platform along the days (Figure and the platform was to the to assess behavior a task that not only in hippocampal neurogenesis and 2017; et al., but also in prefrontal cortical and adult AP2γ KO mice time in the new WT animals (Figure suggesting that constitutive AP2γ deficiency leads to behavioral analysis of the to reach the escape platform et al., 2021; et al., 2009; and Mateus-Pinheiro et al., 2017; et al., revealed that AP2γ KO mice the from to hippocampal-dependent (Figure suggesting an of hippocampal function. differences were in the memory task (Figure supplement 1A and Figure 5 with 1 supplement see all Download asset Open asset performance of adult mice in the Morris water maze test. (A and B) memory was assessed as the escape latency to find a hidden and platform in test day. (C) In the last day, animals were subjected to a task to test behavioral (D) of to find the platform during spatial memory evaluation to its of the hippocampus Hippocampal of used for WT (E) and AP2γ KO mice, by The of along with the of and length are for (G) WT and AP2γ KO mice. Data presented as mean ± SEM. nWT = 10; nAP2γ KO = measures ANOVA and t-test; ***p < 0.001; Statistical summary in Supplementary file 1]. Abbreviations: WT, wild-type; AP2γ KO, AP2γ heterozygous knockout mice. these results that AP2γ constitutive deficiency not only early postnatal hippocampal neurogenesis but also These neurogenic in emotional and memory deficits that persist in the adult mice, together with impairments in behavioral flexibility and object location recognition impairments that emerge during adulthood. adult AP2γ KO mice exhibit anxiety-like behavior, impairments, and in behavioral flexibility Moreover, to the relevance of the hippocampus and to behavioral tests assessed and behavioral flexibility in adult mice, the functional of these brain is to be by constitutive and heterozygous deficiency of AP2γ. Adult functional is by AP2γ constitutive and heterozygous deficiency the impact of AP2γ deficiency on emotional behavior and we s
Source: eLife
Language: English
Subfield: Developmental Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,500
OpenAlex ID: W4200523633