Atp1a3‐deficient heterozygous mice show lower rank in the hierarchy and altered social behavior

Atp1a3 is the Na‐pump alpha3 subunit gene expressed mainly in neurons of the brain. Atp1a3‐deficient heterozygous mice (Atp1a3^+/?) show altered neurotransmission and deficits of motor function after stress loading. To understand the function of Atp1a3 in a social hierarchy, we evaluated social behaviors (social interaction, aggression, social approach and social dominance) of Atp1a3^+/? and compared the rank and hierarchy structure between Atp1a3^+/? and wild‐type mice within a housing cage using the round‐robin tube test and barbering observations. Formation of a hierarchy decreases social conflict and promote social stability within the group. The hierarchical rank is a reflection of social dominance within a cage, which is heritable and can be regulated by specific genes in mice. Here we report: (1) The degree of social interaction but not aggression was lower in Atp1a3^+/? than wild‐type mice, and Atp1a3^+/? approached Atp1a3^+/? mice more frequently than wild type. (2) The frequency of barbering was lower in the Atp1a3^+/? group than in the wild‐type group, while no difference was observed in the mixed‐genotype housing condition. (3) Hierarchy formation was not different between Atp1a3^+/? and wild type. (4) Atp1a3^+/? showed a lower rank in the mixed‐genotype housing condition than that in the wild type, indicating that Atp1a3 regulates social dominance. In sum, Atp1a3^+/? showed unique social behavior characteristics of lower social interaction and preference to approach the same genotype mice and a lower ranking in the hierarchy.     

New insights and therapeutic opportunities for progranulin-deficient frontotemporal dementia

Frontotemporal dementia (FTD) is the second most common form of dementia. It affects the frontal and temporal lobes of the brain and has a highly heterogeneous clinical representation with patients presenting with a wide range of behavioral, language, and executive dysfunctions. Etiology of FTD is complex and consists of both familial and sporadic cases. Heterozygous mutations in the GRN gene, resulting in GRN haploinsufficiency, cause progranulin (PGRN)-deficient FTD characterized with cytoplasmic mislocalization of TAR DNA-binding protein 43 kDa (TDP-43) aggregates. GRN codes for PGRN, a secreted protein that is also localized in the endolysosomes and plays a critical role in regulating lysosomal homeostasis. How PGRN deficiency modulates immunity and causes TDP-43 pathology and FTD-related neurodegeneration remains an active area of intense investigation. In the current review, we discuss some of the significant progress made in the past two years that links PGRN deficiency with microglial-associated neuroinflammation, TDP-43 pathology, and lysosomal dysfunction. We also review the opportunities and challenges toward developing therapies and biomarkers to treat PGRN-deficient FTD.     

Decreased aggression and increased repetitive behavior in Pten haploinsufficient mice

Aggression is an aspect of social behavior that can be elevated in some individuals with autism spectrum disorder (ASD) and a concern for peers and caregivers. Mutations in Phosphatase and tensin homolog (PTEN), one of several ASD risk factors encoding negative regulators of the PI3K–Akt–mTOR pathway, have been reported in individuals with ASD and comorbid macrocephaly. We previously showed that a mouse model of Pten germline haploinsufficiency (Pten^+/?) has selective deficits, primarily in social behavior, along with broad overgrowth of the brain. Here, we further examine the social behavior of Pten^+/? male mice in the resident–intruder test of aggression, using a comprehensive behavioral analysis to obtain an overall picture of the agonistic, non‐agonistic and non‐social behavior patterns of Pten^+/? mice during a free interaction with a novel conspecific. Pten^+/? male mice were involved in less aggression than their wild‐type littermates. Pten^+/? mice also performed less social investigation, including anogenital investigation and approaching and/or attending to the intruder, which is consistent with our previous finding of decreased sociability in the social approach test. In contrast to these decreases in social behaviors, Pten^+/? mice showed increased digging. In summary, we report decreased aggression and increased repetitive behavior in Pten^+/? mice, thus extending our characterization of this model of an ASD risk factor that features brain overgrowth and social deficits.     

Heterozygous loss of epilepsy gene KCNQ2 alters social,repetitive and exploratory behaviors

KCNQ/K_v7 channels conduct voltage‐dependent outward potassium currents that potently decrease neuronal excitability. Heterozygous inherited mutations in their principle subunits K_v7.2/KCNQ2 and K_v7.3/KCNQ3 cause benign familial neonatal epilepsy whereas patients with de novo heterozygous K_v7.2 mutations are associated with early‐onset epileptic encephalopathy and neurodevelopmental disorders characterized by intellectual disability, developmental delay and autism. However, the role of K_v7.2‐containing K_v7 channels in behaviors especially autism‐associated behaviors has not been described. Because pathogenic K_v7.2 mutations in patients are typically heterozygous loss‐of‐function mutations, we investigated the contributions of K_v7.2 to exploratory, social, repetitive and compulsive‐like behaviors by behavioral phenotyping of both male and female KCNQ2^+/? mice that were heterozygous null for the KCNQ2 gene. Compared with their wild‐type littermates, male and female KCNQ2^+/? mice displayed increased locomotor activity in their home cage during the light phase but not the dark phase and showed no difference in motor coordination, suggesting hyperactivity during the inactive light phase. In the dark phase, KCNQ2^+/? group showed enhanced exploratory behaviors, and repetitive grooming but decreased sociability with sex differences in the degree of these behaviors. While male KCNQ2^+/? mice displayed enhanced compulsive‐like behavior and social dominance, female KCNQ2^+/? mice did not. In addition to elevated seizure susceptibility, our findings together indicate that heterozygous loss of K_v7.2 induces behavioral abnormalities including autism‐associated behaviors such as reduced sociability and enhanced repetitive behaviors. Therefore, our study is the first to provide a tangible link between loss‐of‐function K_v7.2 mutations and the behavioral comorbidities of K_v7.2‐associated epilepsy.     

Ankyrin Repeat‐rich Membrane Spanning/Kidins220 protein regulates dendritic branching and spine stability in vivo

The development of nervous system connectivity depends upon the arborization of dendritic fields and the stabilization of dendritic spine synapses. It is well established that neuronal activity and the neurotrophin BDNF modulate these correlated processes. However, the downstream mechanisms by which these extrinsic signals regulate dendritic development and spine stabilization are less well known. Here we report that a substrate of BDNF signaling, the Ankyrin Repeat‐rich Membrane Spanning (ARMS) protein or Kidins220, plays a critical role in the branching of cortical and hippocampal dendrites and in the turnover of cortical spines. In the barrel somatosensory cortex and the dentate gyrus, regions where ARMS/Kidins220 is highly expressed, no difference in the complexity of dendritic arbors was observed in 1‐month‐old adolescent ARMS/Kidins220^+/? mice compared to wild‐type littermates. However, at 3 months of age, young adult ARMS/Kidins220^+/? mice exhibited decreased dendritic complexity. This suggests that ARMS/Kidins220 does not play a significant role in the initial formation of dendrites but, rather, is involved in the refinement or stabilization of the arbors later in development. In addition, at 1 month of age, the rate of spine elimination was higher in ARMS/Kidins220^+/? mice than in wild‐type mice, suggesting that ARMS/Kidins220^+/? levels regulate spine stability. Taken together, these data suggest that ARMS/Kidins220 is important for the growth of dendritic arbors and spine stability during an activity‐ and BDNF‐dependent period of development. © 2009 Wiley Periodicals, Inc. Develop Neurobiol 2009     

Impairment of insulin signalling in peripheral tissue fails to extend murine lifespan

Impaired insulin/IGF1 signalling has been shown to extend lifespan in model organisms ranging from yeast to mammals. Here we sought to determine the effect of targeted disruption of the insulin receptor (IR) in non‐neuronal tissues of adult mice on the lifespan. We induced hemizygous (PerIRKO^+/?) or homozygous (PerIRKO^?/?) disruption of the IR in peripheral tissue of 15‐weeks‐old mice using a tamoxifen‐inducible Cre transgenic mouse with only peripheral tissue expression, and subsequently monitored glucose metabolism, insulin signalling and spontaneous death rates over 4 years. Complete peripheral IR disruption resulted in a diabetic phenotype with increased blood glucose and plasma insulin levels in young mice. Although blood glucose levels returned to normal, and fat mass was reduced in aged PerIRKO^?/? mice, their lifespan was reduced. By contrast, heterozygous disruption had no effect on lifespan. This was despite young male PerIRKO^+/? mice showing reduced fat mass and mild increase in hepatic insulin sensitivity. In conflict with findings in metazoans like Caenorhabditis elegans and Drosophila melanogaster, our results suggest that heterozygous impairment of the insulin signalling limited to peripheral tissues of adult mice fails to extend lifespan despite increased systemic insulin sensitivity, while homozygous impairment shortens lifespan.     

Enhanced axon outgrowth and improved long‐distance axon regeneration in sprouty2 deficient mice

Sprouty (Spry) proteins are negative feedback inhibitors of receptor tyrosine kinase signaling. Downregulation of Spry2 has been demonstrated to promote elongative axon growth of cultured peripheral and central neurons. Here, we analyzed Spry2 global knockout mice with respect to axon outgrowth in vitro and peripheral axon regeneration in vivo. Neurons dissociated from adult Spry2 deficient sensory ganglia revealed stronger extracellular signal‐regulated kinase activation and enhanced axon outgrowth. Prominent axon elongation was observed in heterozygous Spry2^+/? neuron cultures, whereas homozygous Spry2^?/? neurons predominantly exhibited a branching phenotype. Following sciatic nerve crush, Spry2^+/? mice recovered faster in motor but not sensory testing paradigms (Spry2^?/? mice did not tolerate anesthesia required for nerve surgery). We attribute the improvement in the rotarod test to higher numbers of myelinated fibers in the regenerating sciatic nerve, higher densities of motor endplates in hind limb muscles and increased levels of GAP‐43 mRNA, a downstream target of extracellular regulated kinase signaling. Conversely, homozygous Spry2^?/? mice revealed enhanced mechanosensory function (von Frey's test) that was accompanied by an increased innervation of the epidermis, elevated numbers of nonmyelinated axons and more IB4‐positive neurons in dorsal root ganglia. The present results corroborate the functional significance of receptor tyrosine kinase signaling inhibitors for axon outgrowth during development and nerve regeneration and propose Spry2 as a novel potential target for pharmacological inhibition to accelerate long‐distance axon regeneration in injured peripheral nerves. © 2014 Wiley Periodicals, Inc. Develop Neurobiol 75: 217–231, 2015     

The Evolution of the Secreted Regulatory Protein Progranulin

Progranulin is a secreted growth factor that is active in tumorigenesis, wound repair, and inflammation. Haploinsufficiency of the human progranulin gene, GRN, causes frontotemporal dementia. Progranulins are composed of chains of cysteine-rich granulin modules. Modules may be released from progranulin by proteolysis as 6kDa granulin polypeptides. Both intact progranulin and some of the granulin polypeptides are biologically active. The granulin module occurs in certain plant proteases and progranulins are present in early diverging metazoan clades such as the sponges, indicating their ancient evolutionary origin. There is only one Grn gene in mammalian genomes. More gene-rich Grn families occur in teleost fish with between 3 and 6 members per species including short-form Grns that have no tetrapod counterparts. Our goals are to elucidate progranulin and granulin module evolution by investigating (i): the origins of metazoan progranulins (ii): the evolutionary relationships between the single Grn of tetrapods and the multiple Grn genes of fish (iii): the evolution of granulin module architectures of vertebrate progranulins (iv): the conservation of mammalian granulin polypeptide sequences and how the conserved granulin amino acid sequences map to the known three dimensional structures of granulin modules. We report that progranulin-like proteins are present in unicellular eukaryotes that are closely related to metazoa suggesting that progranulin is among the earliest extracellular regulatory proteins still employed by multicellular animals. From the genomes of the elephant shark and coelacanth we identified contemporary representatives of a precursor for short-from Grn genes of ray-finned fish that is lost in tetrapods. In vertebrate Grns pathways of exon duplication resulted in a conserved module architecture at the amino-terminus that is frequently accompanied by an unusual pattern of tandem nearly identical module repeats near the carboxyl-terminus. Polypeptide sequence conservation of mammalian granulin modules identified potential structure-activity relationships that may be informative in designing progranulin based therapeutics.     

Mapping genetic modifiers of survival in a mouse model of Dravet syndrome

Epilepsy is a common neurological disorder affecting approximately 1% of the population. Mutations in voltage‐gated sodium channels are responsible for several monogenic epilepsy syndromes. More than 800 mutations in the voltage‐gated sodium channel SCN1A have been reported in patients with generalized epilepsy with febrile seizures plus and Dravet syndrome. Heterozygous loss‐of‐function mutations in SCN1A result in Dravet syndrome, a severe infant‐onset epileptic encephalopathy characterized by intractable seizures, developmental delays and increased mortality. A common feature of monogenic epilepsies is variable expressivity among individuals with the same mutation, suggesting that genetic modifiers may influence clinical severity. Mice with heterozygous deletion of Scn1a (Scn1a^+/?) model a number of Dravet syndrome features, including spontaneous seizures and premature lethality. Phenotype severity in Scn1a^+/? mice is strongly dependent on strain background. On the 129S6/SvEvTac strain Scn1a^+/? mice exhibit no overt phenotype, whereas on the (C57BL/6J × 129S6/SvEvTac)F1 strain Scn1a^+/? mice exhibit spontaneous seizures and early lethality. To systematically identify loci that influence premature lethality in Scn1a^+/? mice, we performed genome scans on reciprocal backcrosses. Quantitative trait locus mapping revealed modifier loci on mouse chromosomes 5, 7, 8 and 11. RNA‐seq analysis of strain‐dependent gene expression, regulation and coding sequence variation provided a list of potential functional candidate genes at each locus. Identification of modifier genes that influence survival in Scn1a^+/? mice will improve our understanding of the pathophysiology of Dravet syndrome and may suggest novel therapeutic strategies for improved treatment of human patients.     

Loss of TREM2 rescues hyperactivation of microglia,but not lysosomal deficits and neurotoxicity in models of progranulin deficiency

Haploinsufficiency of the progranulin (PGRN)‐encoding gene (GRN) causes frontotemporal lobar degeneration (GRN‐FTLD) and results in microglial hyperactivation, TREM2 activation, lysosomal dysfunction, and TDP‐43 deposition. To understand the contribution of microglial hyperactivation to pathology, we used genetic and pharmacological approaches to suppress TREM2‐dependent transition of microglia from a homeostatic to a disease‐associated state. Trem2 deficiency in Grn KO mice reduced microglia hyperactivation. To explore antibody‐mediated pharmacological modulation of TREM2‐dependent microglial states, we identified antagonistic TREM2 antibodies. Treatment of macrophages from GRN‐FTLD patients with these antibodies led to reduced TREM2 signaling due to its enhanced shedding. Furthermore, TREM2 antibody‐treated PGRN‐deficient microglia derived from human‐induced pluripotent stem cells showed reduced microglial hyperactivation, TREM2 signaling, and phagocytic activity, but lysosomal dysfunction was not rescued. Similarly, lysosomal dysfunction, lipid dysregulation, and glucose hypometabolism of Grn KO mice were not rescued by TREM2 ablation. Synaptic loss and neurofilament light‐chain (NfL) levels, a biomarker for neurodegeneration, were further elevated in the Grn/Trem2 KO cerebrospinal fluid (CSF). These findings suggest that TREM2‐dependent microglia hyperactivation in models of GRN deficiency does not promote neurotoxicity, but rather neuroprotection.     

Detailed analysis of paternal knockout Grb10 mice suggests effects on stability of social behavior,rather than social dominance

Imprinted genes are highly expressed in monoaminergic regions of the midbrain and their functions in this area are thought to have an impact on mammalian social behaviors. One such imprinted gene is Grb10, of which the paternal allele is generally recognized as mediating social dominance behavior. However, there has been no detailed study of social dominance in Grb10 ^+/p mice. Moreover, the original study examined tube‐test behavior in isolated mice 10 months of age. Isolation testing favors more territorial and aggressive behaviors, and does not address social dominance strategies employed in group housing contexts. Furthermore, isolation stress impacts midbrain function and dominance related behavior, often through alterations in monoaminergic signaling. Thus, we undertook a systematic study of Grb10 ^+/p social rank and dominance behavior within the cage group, using a number of convergent behavioral tests. We examined both male and female mice to account for sex differences and tested cohorts aged 2, 6 and 10 months to examine any developments related to age. We found group‐housed Grb10 ^+/p mice do not show evidence of enhanced social dominance, but cages containing Grb10 ^+/p and wild‐type mice lacked the normal correlation between three different measures of social rank. Moreover, a separate study indicated isolation stress induced inconsistent changes in tube test behavior. Taken together, these data suggest future research on Grb10 ^+/p mice should focus on the stability of social behaviors, rather than dominance per se.     

Dual Benefit of Reduced Cx43 on Atherosclerosis in LDL Receptor-Deficient Mice

Paracrine cell-to-cell interactions are crucial events during atherogenesis, however, little is known on the role of gap junctional communication during this process. We recently demonstrated increased expression of Cx43 in intimal smooth muscle cells and in a subset of endothelial cells covering the shoulder of atherosclerotic plaques. The purpose of this study was to examine the role of Cx43 in the development of atherosclerosis in vivo. Atherosclerosis-susceptible LDL receptor-deficient (LDLR^?/?) mice were intercrossed with mice heterozygous for Cx43 (Cx43^+/?mice). Male mice with normal (Cx43^+/+LDLR^?/?) or reduced (Cx43^+/?LDLR^?/?) Cx43 level of 10 weeks old were fed a cholesterol-rich diet (1.25%) for 14 weeks. Both groups of mice showed similar increases in serum lipids and body weight. Interestingly, the progression of atherosclerosis was reduced by 50% (P < 0.01) in the thoraco-abdominal aorta and in the aortic roots of Cx43^+/?LDLR^?/?mice compared with Cx43^+/+LDLR^?/?littermate controls. In addition, atheroma in Cx43^+/?LDLR^?/?mice contained fewer inflammatory cells and exhibited thicker fibrous caps with more collagen and smooth muscle cells, important features associated, in human, with stable atherosclerotic lesions. Thus, reducing Cx43 expression in mice provides beneficial effects on both the progression and composition of the atherosclerotic lesions.     

Neuroimmune dysfunction in frontotemporal dementia: Insights from progranulin and C9orf72 deficiency

Neuroimmune dysfunction is a cardinal feature of neurodegenerative diseases. But how immune dysregulation in the brain and peripheral organs contribute to neurodegeneration remains unclear. Here, we discuss the recent advances highlighting neuroimmune dysfunction as a key disease-driving factor in frontotemporal dementia (FTD). We provide an overview of the clinical observations supporting a high prevalence of autoimmune diseases in FTD patients with mutations in GRN or C9orf72. We then focus on a myriad of evidence from human genetic studies, mouse models, in vitro assays, and multi-omics platform, which indicate that haploinsufficiency in GRN and C9orf72 promotes neuroimmune dysfunction and contributes to neurodegeneration and premature death. These compelling data provide key insights to disease mechanisms, biomarker discovery, and therapeutic interventions for FTD (120 words).     

Mechanisms of Granulin Deficiency: Lessons from Cellular and Animal Models

The identification of causative mutations in the (pro)granulin gene (GRN) has been a major breakthrough in the research on frontotemporal dementia (FTD). So far, all FTD-associated GRN mutations are leading to neurodegeneration through a “loss-of-function” mechanism, encouraging researchers to develop a growing number of cellular and animal models for GRN deficiency. GRN is a multifunctional secreted growth factor, and loss of its function can affect different cellular processes. Besides loss-of-function (i.e., mostly premature termination codons) mutations, which cause GRN haploinsufficiency through reduction of GRN expression, FTD-associated GRN missense mutations have also been identified. Several of these missense mutations are predicted to increase the risk of developing neurodegenerative diseases through altering various key biological properties of GRN-like protein secretion, proteolytic processing, and neurite outgrowth. With the use of cellular and animal models for GRN deficiency, the portfolio of GRN functions has recently been extended to include functions in important biological processes like energy and protein homeostasis, inflammation as well as neuronal survival, neurite outgrowth, and branching. Furthermore, GRN-deficient animal models have been established and they are believed to be promising disease models as they show accelerated aging and recapitulate at least some neuropathological features of FTD. In this review, we summarize the current knowledge on the molecular mechanisms leading to GRN deficiency and the lessons we learned from the established cellular and animal models. Furthermore, we discuss how these insights might help in developing therapeutic strategies for GRN-associated FTD.     

Early‐onset aging and mitochondrial defects associated with loss of histone acetyltransferase 1 (Hat1)

Histone acetyltransferase 1 (Hat1) is responsible for the acetylation of newly synthesized histone H4 on lysines 5 and 12 during the process of chromatin assembly. To understand the broader biological role of Hat1, we have generated a conditional mouse knockout model of this enzyme. We previously reported that Hat1 is required for viability and important for mammalian development and genome stability. In this study, we show that haploinsufficiency of Hat1 results in a significant decrease in lifespan. Defects observed in Hat1^+/? mice are consistent with an early‐onset aging phenotype. These include lordokyphosis (hunchback), muscle atrophy, minor growth retardation, reduced subcutaneous fat, cancer, and paralysis. In addition, the expression of Hat1 is linked to the normal aging process as Hat1 mRNA and protein becomes undetectable in many tissues in old mice. At the cellular level, fibroblasts from Hat1 haploinsufficient embryos undergo early senescence and accumulate high levels of p21. Hat1^+/? mouse embryonic fibroblasts (MEFs) display modest increases in endogenous DNA damage but have significantly higher levels of reactive oxygen species (ROS). Consistently, further studies show that Hat1^?/? MEFs exhibit mitochondrial defects suggesting a critical role for Hat1 in mitochondrial function. Taken together, these data show that loss of Hat1 induces multiple hallmarks of early‐onset aging.     

Glutamic acid decarboxylase 67 haplodeficiency impairs social behavior in mice

Reduced glutamic acid decarboxylase (GAD)67 expression may be causally involved in the development of social withdrawal in neuropsychiatric states such as autism, schizophrenia and bipolar disorder. In this study, we report disturbance of social behavior in male GAD67 haplodeficient mice. GAD67^+/? mice, compared to GAD67^+/+ littermates, show reduced sociability and decreased intermale aggression, but normal nest building and urine marking behavior, as well as unchanged locomotor activity and anxiety‐like behavior. Moreover, the mutants display a reduced sensitivity to both social and non‐social odors, indicating a disturbance in the detection and/or processing of socially relevant olfactory stimuli. Indeed, we observed reduced activation of the lateral septum, medial preoptic area, bed nucleus of the stria terminalis, medial and cortical amygdala upon exposure of GAD67^+/? mice to social interaction paradigm, as indicated by c‐Fos immunohistochemistry. These data suggest a disturbance of stimulus processing in the brain circuitry controlling social behavior in GAD67^+/? mice, which may provide a useful model for studying the impact of a reduced GAD67 expression on alterations of social behavior related to neuropsychiatric disorders .     

Antidepressant‐like effects and basal immobility depend on age and serotonin transporter genotype

Monoamine uptake inhibitors are common treatments for depression; however, the therapeutic efficacy of these drugs varies widely. Two factors that are commonly linked to clinical outcome are age and serotonin transporter (SERT) genotype. Mouse models provide powerful tools to study consequences of age and genotype on antidepressant‐like efficacy; however, to date, systematic studies of this nature are lacking. Here, we used the tail suspension test (TST), a preclinical assay for antidepressant efficacy, to gain insight into age and SERT genotype dependency of immobility time in the TST under control conditions (saline injection) and in response to the tricyclic antidepressant, desipramine (DMI). Immobility after saline injection in juvenile, adolescent, adult, mature adult and middle‐aged mice (postnatal days 21, 28, 90, 210 and 300, respectively) significantly increased with age; however, the rate of increase was slower for SERT null (?/?) mice than for wild‐type (+/+) or heterozygote (+/?) mice. Desipramine reduced immobility across ages and SERT genotypes. Middle‐aged, but not adult, SERT^?/? mice were significantly more sensitive to DMI than age‐matched SERT^+/+ or SERT^+/? mice. Desipramine was less potent in middle‐aged SERT^+/+ and SERT^+/? mice than in adult SERT^+/+ or SERT^+/? mice. Regardless of age, DMI's maximal effects were greater in SERT^?/? mice than in SERT^+/+ or SERT^+/? mice. These results show that immobility time in the TST varies as a function of age and SERT genotype, underscoring the utility of the TST as a potential model to examine age‐ and SERT genotype‐dependent influences on antidepressant response.     

Not all water mazes are created equal: cyclin D2 knockout mice with constitutively suppressed adult hippocampal neurogenesis do show specific spatial learning deficits

Studies using the Morris water maze to assess hippocampal function in animals, in which adult hippocampal neurogenesis had been suppressed, have yielded seemingly contradictory results. Cyclin D2 knockout (Ccnd2^?/?) mice, for example, have constitutively suppressed adult hippocampal neurogenesis but had no overt phenotype in the water maze. In other paradigms, however, ablation of adult neurogenesis was associated with specific deficits in the water maze. Therefore, we hypothesized that the neurogenesis‐related phenotype might also become detectable in Ccnd2^?/? mice, if we used the exact setup and protocol that in our previous study had revealed deficits in mice with suppressed adult neurogenesis. Ccnd2^?/? mice indeed learned the task and developed a normal preference for the goal quadrant, but were significantly less precise for the exact goal position and were slower in acquiring efficient and spatially more precise search strategies. Upon goal reversal (when the hidden platform was moved to a new position) Ccnd2^?/? mice showed increased perseverance at the former platform location, implying that they were less flexible in updating the previously learned information. Both with respect to adult neurogenesis and behavioral performance, Ccnd2^+/? mice ranged between wild types and knockouts. Importantly, hippocampus‐dependent learning was not generally impaired by the mutation, but specifically functional aspects relying on precise and flexible encoding were affected. Whether ablation of adult neurogenesis causes a specific behavioral phenotype thus also depends on the actual task demands. The test parameters appear to be important variables influencing whether a task can pick up a contribution of adult neurogenesis to test performance.