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.

Impaired endothelium-mediated cerebrovascular reactivity promotes anxiety and respiration disorders in mice.

Carbon dioxide (CO2), the major product of metabolism, has a strong impact on cerebral blood vessels, a phenomenon known as cerebrovascular reactivity. Several vascular risk factors such as hypertension or diabetes dampen this response, making cerebrovascular reactivity a useful diagnostic marker for incipient vascular pathology, but its functional relevance, if any, is still unclear. Here, we found that GPR4, an endothelial H+ receptor, and endothelial Gαq/11 proteins mediate the CO2/H+ effect on cerebrovascular reactivity in mice. CO2/H+ leads to constriction of vessels in the brainstem area that controls respiration. The consequential washout of CO2, if cerebrovascular reactivity is impaired, reduces respiration. In contrast, CO2 dilates vessels in other brain areas such as the amygdala. Hence, an impaired cerebrovascular reactivity amplifies the CO2 effect on anxiety. Even at atmospheric CO2 concentrations, impaired cerebrovascular reactivity caused longer apneic episodes and more anxiety, indicating that cerebrovascular reactivity is essential for normal brain function. The site-specific reactivity of vessels to CO2 is reflected by regional differences in their gene expression and the release of vasoactive factors from endothelial cells. Our data suggest the central nervous system (CNS) endothelium as a target to treat respiratory and affective disorders associated with vascular diseases.

Effects of p75NTR deficiency on cholinergic innervation of the amygdala and anxiety-like behavior.

The p75 neurotrophin receptor (p75NTR) is a low-affinity receptor that is capable of binding neurotrophins. Two different p75NTR knockout mouse lines are available either with a deletion in Exon III (p75NTRExIII-/- ) or in Exon IV (p75NTRExIV-/- ). In p75NTRExIII knockout mice, only the full-length p75NTR is deleted, whereas in p75NTRExIV knockout mice, the full-length as well as the truncated isoform of the receptor is deleted. Deletion of p75NTR has been shown to affect, among others, the septohippocampal cholinergic innervation pattern and neuronal plasticity within the hippocampus. We hypothesize that deletion of p75NTR also alters the morphology and physiology of a further key structure of the limbic system, the amygdala. Our results indicate that deletion of p75NTR also increases cholinergic innervation in the basolateral amygdala in adult as well as aged p75NTRExIII-/- and p75NTRExIV-/- mice. The p75NTRExIV-/- mice did not display altered long-term potentiation (LTP) in the basolateral amygdala as compared to age-matched control littermates. However, p75NTRExIII-/- mice display stronger LTP in the basolateral amygdala compared to age-matched controls. Bath-application of K252a (a trk antagonist) did not inhibit the induction of LTP in the basolateral amygdala, but reduced the level of LTP in p75NTRExIII-/- mice to levels seen in respective controls. Moreover, p75NTRExIII-/- mice display altered behavior in the dark/light box. Thus, deletion of p75NTR in mice leads to physiological and morphological changes in the amygdala and altered behavior that is linked to the limbic system.

Assessing the Cognitive Translational Potential of a Mouse Model of the 22q11.2 Microdeletion Syndrome.

A chromosomal microdeletion at the 22q11.2 locus is associated with extensive cognitive impairments, schizophrenia and other psychopathology in humans. Previous reports indicate that mouse models of the 22q11.2 microdeletion syndrome (22q11.2DS) may model the genetic basis of cognitive deficits relevant for neuropsychiatric disorders such as schizophrenia. To assess the models usefulness for drug discovery, a novel mouse (Df(h22q11)/+) was assessed in an extensive battery of cognitive assays by partners within the NEWMEDS collaboration (Innovative Medicines Initiative Grant Agreement No. 115008). This battery included classic and touchscreen-based paradigms with recognized sensitivity and multiple attempts at reproducing previously published findings in 22q11.2DS mouse models. This work represents one of the most comprehensive reports of cognitive functioning in a transgenic animal model. In accordance with previous reports, there were non-significant trends or marginal impairment in some tasks. However, the Df(h22q11)/+ mouse did not show comprehensive deficits; no robust impairment was observed following more than 17 experiments and 14 behavioral paradigms. Thus - within the current protocols - the 22q11.2DS mouse model fails to mimic the cognitive alterations observed in human 22q11.2 deletion carriers. We suggest that the 22q11.2DS model may induce liability for cognitive dysfunction with additional "hits" being required for phenotypic expression.

Facilitated c-Fos Induction in Mice Deficient for the AMPA Receptor-Associated Protein Ckamp44.

The recently identified Cystine-knot containing AMPAR-associated protein (Ckamp44) represents a novel AMPAR-related protein that critically controls AMPAR-mediated currents and short-term plasticity. However, the effects of the lack of this protein at network level are not entirely understood. Here we used c-Fos brain mapping to analyse whether the excitatory/inhibitory balance is altered in the absence of the Ckamp44. We found that Ckamp44(-/-) mice treated with an NMDAR antagonist exhibited a very robust c-Fos expression pattern, similar with that seen in mice lacking the GluN2A subunit of NMDAR treated with the same compound. This finding is unexpected, in particular, since Ckamp44 expression is strongest in dentate gyrus granule cells and less abundant in the rest of the brain.

Minocycline exacerbates apoptotic neurodegeneration induced by the NMDA receptor antagonist MK-801 in the early postnatal mouse brain.

NMDA receptor (NMDAR) antagonists induce in perinatal rodent cortical apoptosis and protracted schizophrenia-like alterations ameliorated by antipsychotic treatment. The broad-spectrum antibiotic minocycline elicits antipsychotic and neuroprotective effects. Here we tested, if minocycline protects also against apoptosis triggered by the NMDAR antagonist MK-801 at postnatal day 7. Surprisingly, minocycline induced widespread cortical apoptosis and exacerbated MK-801-triggered cell death. In some areas such as the subiculum, the pro-apoptotic effect of minocycline was even more pronounced than that elicited by MK-801. These data reveal among antipsychotics unique pro-apoptotic properties of minocycline, raising concerns regarding consequences for brain development and the use in children.

APP and APLP2 are essential at PNS and CNS synapses for transmission, spatial learning and LTP.

Despite its key role in Alzheimer pathogenesis, the physiological function(s) of the amyloid precursor protein (APP) and its proteolytic fragments are still poorly understood. Previously, we generated APPsα knock-in (KI) mice expressing solely the secreted ectodomain APPsα. Here, we generated double mutants (APPsα-DM) by crossing APPsα-KI mice onto an APLP2-deficient background and show that APPsα rescues the postnatal lethality of the majority of APP/APLP2 double knockout mice. Surviving APPsα-DM mice exhibited impaired neuromuscular transmission, with reductions in quantal content, readily releasable pool, and ability to sustain vesicle release that resulted in muscular weakness. We show that these defects may be due to loss of an APP/Mint2/Munc18 complex. Moreover, APPsα-DM muscle showed fragmented post-synaptic specializations, suggesting impaired postnatal synaptic maturation and/or maintenance. Despite normal CNS morphology and unaltered basal synaptic transmission, young APPsα-DM mice already showed pronounced hippocampal dysfunction, impaired spatial learning and a deficit in LTP that could be rescued by GABA(A) receptor inhibition. Collectively, our data show that APLP2 and APP are synergistically required to mediate neuromuscular transmission, spatial learning and synaptic plasticity.

Phenotype of mice with inducible ablation of GluA1 AMPA receptors during late adolescence: relevance for mental disorders.

Adolescence is characterized by important molecular and anatomical changes with relevance for the maturation of brain circuitry and cognitive function. This time period is of critical importance in the emergence of several neuropsychiatric disorders accompanied by cognitive impairment, such as affective disorders and schizophrenia. The molecular mechanisms underlying these changes at neuronal level during this specific developmental stage remains however poorly understood. GluA1-containing AMPA receptors, which are located predominantly on hippocampal neurons, are the primary molecular determinants of synaptic plasticity. We investigated here the consequences of the inducible deletion of GluA1 AMPA receptors in glutamatergic neurons during late adolescence. We generated mutant mice with a tamoxifen-inducible deletion of GluA1 under the control of the CamKII promoter for temporally and spatially restricted gene manipulation. GluA1 ablation during late adolescence induced cognitive impairments, but also marked hyperlocomotion and sensorimotor gating deficits. Unlike the global genetic deletion of GluA1, inducible GluA1 ablation during late adolescence resulted in normal sociability. Deletion of GluA1 induced redistribution of GluA2 subunits, suggesting AMPA receptor trafficking deficits. Mutant animals showed increased hippocampal NMDA receptor expression and no change in striatal dopamine concentration. Our data provide new insight into the role of deficient AMPA receptors specifically during late adolescence in inducing several cognitive and behavioral alterations with possible relevance for neuropsychiatric disorders.

Impact of adolescent GluA1 AMPA receptor ablation in forebrain excitatory neurons on behavioural correlates of mood disorders.

Glutamatergic dysfunctions have recently been postulated to play a considerable role in mood disorders. However, molecular mechanisms underlying these effects have been poorly deciphered. Previous work demonstrated the contribution of GluA1-containing AMPA receptors (AMPAR) to a depression-like and anxiety-like phenotype. Here we investigated the effect of temporally and spatially restricted gene manipulation of GluA1 on behavioural correlates of mood disorders in mice. Here we show that tamoxifen-induced GluA1 deletion restricted to forebrain glutamatergic neurons of post-adolescent mice does not induce depression- and anxiety-like changes. This differs from the phenotype of mice with global AMPAR deletion suggesting that for mood regulation AMPAR may be particularly important on inhibitory interneurons or already early in development.

Hippocampal serotonin-1A receptor function in a mouse model of anxiety induced by long-term voluntary wheel running.

We have recently demonstrated that, in C57/Bl6 mice, long-term voluntary wheel running is anxiogenic, and focal hippocampal irradiation prevents the increase in anxiety-like behaviors and neurobiological changes in the hippocampus induced by wheel running. Evidence supports a role of hippocampal 5-HT1A receptors in anxiety. Therefore, we investigated hippocampal binding and function of 5-HT1A receptors in this mouse model of anxiety. Four weeks of voluntary wheel running resulted in hippocampal subregion-specific changes in 5-HT1A receptor binding sites and function, as measured by autoradiography of [(3) H] 8-hydroxy-2-(di-n-propylamino)tetralin binding and agonist-stimulated binding of [(35) S]GTPγS to G proteins, respectively. In the dorsal CA1 region, 5-HT1A receptor binding and function were not altered by wheel running or irradiation. In the dorsal dentate gyrus and CA2/3 region, 5-HT1A receptor function was decreased by not only running but also irradiation. In the ventral pyramidal layer, wheel running resulted in a decrease of 5-HT1A receptor function, which was prevented by irradiation. Neither irradiation nor wheel running affected 5-HT1A receptors in medial prefrontal cortex or in the dorsal or median raphe nuclei. Our data indicate that downregulation of 5-HT1A receptor function in ventral pyramidal layer may play a role in anxiety-like behavior induced by wheel running.

Pten ablation in adult dopaminergic neurons is neuroprotective in Parkinson's disease models.

Parkinson's disease (PD) is a progressive age-related movement disorder that results primarily from the selective loss of midbrain dopaminergic (DA) neurons. Symptoms of PD can be induced by genetic mutations or by DA neuron-specific toxins. A specific ablation of an essential factor controlling ribosomal RNA transcription, TifIa, in adult mouse DA neurons represses mTOR signaling and leads to progressive neurodegeneration and PD-like phenotype. Using an inducible Cre system in adult mice, we show here that the specific ablation of Pten in adult mouse DA neurons leads to activation of mTOR pathway and is neuroprotective in genetic (TifIa deletion) and neurotoxin-induced (MPTP or 6OHDA) mouse models of PD. Adult mice with DA neuron-specific Pten deletion exhibit elevated expression of tyrosine hydroxylase, a rate-limiting enzyme in the dopamine biosynthesis pathway, associated with increased striatal dopamine content, and increased mRNA levels of Foxa2, Pitx3, En1, Nurr1, and Lmx1b-the essential factors for maintaining physiological functions of adult DA neurons. Pten deletion attenuates the loss of tyrosine hydroxylase-positive cells after 6OHDA treatment, restores striatal dopamine in TifIa-knockout and MPTP-treated mice, and rescues locomotor impairments caused by TifIa loss. Inhibition of Pten-dependent functions in adult DA neurons may represent a promising PD therapy.

AMPA GluR-A receptor subunit mediates hippocampal responsiveness in mice exposed to stress.

Because stress represents a major precipitating event for psychiatric disorders, it is important to identify molecular mechanisms that may be altered in vulnerable individuals when exposed to stress. Here, we studied GluR-A(-/-) mice, animals with compromised AMPA receptor signaling, and characterized by a schizophrenic as well as depressive phenotype to investigate changes occurring in response to an acute stress. Wild-type and GluR-A(-/-) mice were exposed to a single immobilization stress and sacrificed immediately after the end of the stress for the analysis of activity regulated genes and of glutamatergic synapse responsiveness. The acute stress produced a marked increase in the hippocampal expression of Arc (activity-regulated cytoskeletal-associated protein) in GluR-A(-/-) , but not in wild-type mice, which was associated with a similar increase of phospho-CaMKII, a partner in the action of Arc. When looking at the glutamatergic response to stress in wild-type animals, we found that stress increased GluR-A phosphorylation on serine831, an effect that was paralleled by a significant increase of the phosphorylation of the main NMDA receptor subunits, that is, NR-1 and NR-2B. Conversely, the stress-induced modulation of NMDA receptor subunits was not observed in GluR-A(-/-) mice. We suggest that enhanced stress responsiveness in GluR-A(-/-) mice may be due, at least in part, to their inability to activate NMDA-mediated glutamatergic neurotransmission, suggesting that the integrity of AMPA/NMDA receptor function may be important for successful coping under stressful conditions.

Cre-Activation in ErbB4-Positive Neurons of Floxed Grin1/NMDA Receptor Mice Is Not Associated With Major Behavioral Impairment.

Extensive evidence suggests a dysfunction of the glutamate NMDA receptor (NMDAR) in schizophrenia, a severe psychiatric disorder with putative early neurodevelopmental origins, but clinical onset mainly during late adolescence. On the other hand, pharmacological models using NMDAR antagonists and the clinical manifestation of anti-NMDAR encephalitis indicate that NMDAR blockade/hypofunction can trigger psychosis also at adult stages, without any early developmental dysfunction. Previous genetic models of NMDAR hypofunction restricted to parvalbumin-positive interneurons indicate the necessity of an early postnatal impairment to trigger schizophrenia-like abnormalities, whereas the cellular substrates of NMDAR-mediated psychosis at adolescent/adult stages are unknown. Neuregulin 1 (NRG1) and its receptor ErbB4 represent schizophrenia-associated susceptibility factors that closely interact with NMDAR. To determine the neuronal populations implicated in "late" NMDAR-driven psychosis, we analyzed the effect of the inducible ablation of NMDARs in ErbB4-expressing cells in mice during late adolescence using a pharmacogenetic approach. Interestingly, the tamoxifen-inducible NMDAR deletion during this late developmental stage did not induce behavioral alterations resembling depression, schizophrenia or anxiety. Our data indicate that post-adolescent NMDAR deletion, even in a wider cell population than parvalbumin-positive interneurons, is also not sufficient to generate behavioral abnormalities resembling psychiatric disorders. Other neuronal substrates that have to be revealed by future studies, may underlie post-adolescent NMDAR-driven psychosis.

Voluntary exercise induces anxiety-like behavior in adult C57BL/6J mice correlating with hippocampal neurogenesis.

Several studies investigated the effect of physical exercise on emotional behaviors in rodents; resulting findings however remain controversial. Despite the accepted notion that voluntary exercise alters behavior in the same manners as antidepressant drugs, several studies reported opposite or no effects at all. In an attempt to evaluate the effect of physical exercise on emotional behaviors and brain plasticity, we individually housed C57BL/6J male mice in cages equipped with a running wheel. Three weeks after continuous voluntary running we assessed their anxiety- and depression-like behaviors. Tests included openfield, dark-light-box, elevated O-maze, learned helplessness, and forced swim test. We measured corticosterone metabolite levels in feces collected over a 24-h period and brain-derived neurotrophic factor (BDNF) in several brain regions. Furthermore, cell proliferation and adult hippocampal neurogenesis were assessed using Ki67 and Doublecortin. Voluntary wheel running induced increased anxiety in the openfield, elevated O-maze, and dark-light-box and higher levels of excreted corticosterone metabolites. We did not observe any antidepressant effect of running despite a significant increase of hippocampal neurogenesis and BDNF. These data are thus far the first to indicate that the effect of physical exercise in mice may be ambiguous. On one hand, the running-induced increase of neurogenesis and BDNF seems to be irrelevant in tests for depression-like behavior, at least in the present model where running activity exceeded previous reports. On the other hand, exercising mice display a more anxious phenotype and are exposed to higher levels of stress hormones such as corticosterone. Intriguingly, numbers of differentiating neurons correlate significantly with anxiety parameters in the openfield and dark-light-box. We therefore conclude that adult hippocampal neurogenesis is a crucial player in the genesis of anxiety.

Systematic analysis of severity in a widely used cognitive depression model for mice.

Animal models in psychiatric research are indispensable for insights into mechanisms of behaviour and mental disorders. Distress is an important aetiological factor in psychiatric diseases, especially depression, and is often used to mimic the human condition. Modern bioethics requires balancing scientific progress with animal welfare concerns. Therefore, scientifically based severity assessment of procedures is a prerequisite for choosing the least compromising paradigm according to the 3Rs principle. Evidence-based severity assessment in psychiatric animal models is scarce, particularly in depression research. Here, we assessed severity in a cognitive depression model by analysing indicators of stress and well-being, including physiological (body weight and corticosterone metabolite concentrations) and behavioural (nesting and burrowing behaviour) parameters. Additionally, a novel approach for objective individualised severity grading was employed using clustering of voluntary wheel running (VWR) behaviour. Exposure to the paradigm evoked a transient elevation of corticosterone, but neither affected body weight, nesting or burrowing behaviour. However, the performance in VWR was impaired after recurrent stress exposure, and the individual severity level increased, indicating that this method is more sensitive in detecting compromised welfare. Interestingly, the direct comparison to a somatic, chemically induced colitis model indicates less distress in the depression model. Further objective severity assessment studies are needed to classify the severity of psychiatric animal models in order to balance validity and welfare, reduce the stress load and thus promote refinement.

Effect of three different forms of handling on the variation of aggression-associated parameters in individually and group-housed male C57BL/6NCrl mice.

Mice are social animals hence group-housing of mice is preferred over individual housing. However, aggression in group-housed male mice under laboratory housing conditions is a well-known problem leading to serious health issues, including injury or death. Therefore, group-housed mice are frequently separated for welfare reasons. In this study, we investigated the effect of 3 different handling methods (tail, forceps, tube) in 2 different housing conditions (single vs. group) on the variance of aggression-associated parameters in male C57BL/6NCrl mice over 8 weeks. Blood glucose concentration, body weight, body temperature, plus number and severity of bite wounds and barbering intensity in group-housed mice were recorded. An assessment of nest complexity was also performed weekly. Feces were collected in week 3 and 7 for analysis of corticosterone metabolites. We also monitored the level of aggression by recording the behavior of group-housed animals after weekly cage cleaning. An open field test followed by a social novel object test, a light/dark box test, a hotplate and a resident-intruder test were performed at the end of the 8-week handling period. Post-mortem, we assessed organ weights. We found that forceps-handled mice, independent of the housing condition, had significantly higher levels of stress-induced-hyperthermia and enhanced aggression after cage cleaning, and they performed worse in the nest complexity test. In addition, handling male mice by the tail seems to be most effective to reduce aggressiveness after transferring animals into new cages, thereby representing an appropriate refinement.

Mice that under- or overexpress glucocorticoid receptors as models for depression or posttraumatic stress disorder.

Modern molecular and pathophysiological concepts suggest that glucocorticoid receptors (GRs) play a crucial role for the pathogenesis, course and therapy of affective or emotional disorders. Specifically, an impairment of GR signaling has been associated with major depression, whereas overactivity or hyperresponsiveness of GRs have been conceptualized for posttraumatic stress disorder (PTSD). Recently, several research groups have generated transgenic mouse strains that under- or overexpress GRs, respectively. These animals seem to represent valuable tools for studying the foregoing hypotheses. Indeed, first results indicate that mice with a deficit in GR expression show a depression-like behavioral phenotype as well as characteristic neuroendocrinological changes observed in depressive patients. Particularly, GR heterozygous mice with a 50% reduction of GR expression represent a model for combined effects of both genetic and environmental manipulations, since their depression-like behavior becomes only manifest after stress-exposure. Thus, the phenotype of this strain mimics the human situation in depressive disorders, in which individuals at risk are predisposed to develop depressive episodes after stress. It is currently less clear whether, and in which way, mice that overexpress GRs can serve as models for PTSD, or mimic at least specific aspects of the clinical syndrome. The latter strains have still to be subjected to specific tests analyzing conditioning and sensitization processes in fearful situations. So far, mice with compromised GR expression seem to be a good tool to further study molecular, pathophysiological and cellular/structural alterations that underlie specific behavioral features such as despair or helplessness. A major challenge is to decipher which signs and symptoms in patients correspond to these animal behavioral constructs, and to elucidate whether it is possible to gain insights from the animals' response to specific treatments for human therapy.

Evaluation of effects of previous exposure to an acute stressor before testing for depression-like behaviours in mice.

Test batteries are an essential and broadly used tool for behavioural phenotyping, especially with regard to mouse models of particular diseases, such as depression. Facing the problem of an often limited number of mutant animals, it therefore seems crucial to develop and optimise such test batteries in terms of an ideal throughput of subjects. This study aimed to characterize several common stressors, which are used for the investigation of depressive-like features with regard to their capability of each of them to affect performance in a subsequent behavioural test. Here we investigated swim-, restraint- and footshock-stress in male C57/BL6 mice, focusing on post-stress corticosterone elevations as well as potential effects on the behavioural level. The stressors increased circulating corticosterone levels when assessed 1 h after exposure. On the behavioural level, no test interactions could be detected, which suggests, that in general, combining these test conditions in experiments with a restricted availability of animals seems to be rather unproblematic.

Nature vs. nurture: can enrichment rescue the behavioural phenotype of BDNF heterozygous mice?

In earlier experiments we have demonstrated that group-housing in a rather impoverished "standard" environment can be a crucial stress factor in male C57Bl/6 mice. The present study aimed at investigating the effect of combining a probable genetic vulnerability--postulated by the "Neurotrophin Hypothesis of Depression"--with the potentially modulating influence of a stressful environment such as "impoverished" standard housing conditions. For that purpose mice with a partial deletion of brain-derived neurotrophic factor (BDNF) were group-housed under standard and enriched housing conditions and analysed in a well-established test battery for emotional behaviours. Standard group-housing affected emotional behaviour in male and female BDNF heterozygous mice, causing an increase in anxiety, changes in exploration as well as nociception. Providing the animals' cages with supplementary enrichment, however, led to a rescue of emotional alterations, which emphasises the significance of external factors and their relevance for a valid investigation of genetic aspects in these mutants as well as others, which may be examined in terms of stress-responsiveness or emotionality.

TDP-43 induces p53-mediated cell death of cortical progenitors and immature neurons.

TAR DNA-binding protein 43 (TDP-43) is a key player in neurodegenerative diseases including frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Accumulation of TDP-43 is associated with neuronal death in the brain. How increased and disease-causing mutant forms of TDP-43 induce cell death remains unclear. Here we addressed the role of TDP-43 during neural development and show that reduced TDP-43 causes defects in neural stem/progenitor cell proliferation but not cell death. However, overexpression of wild type and TDP-43A315T proteins induce p53-dependent apoptosis of neural stem/progenitors and human induced pluripotent cell (iPS)-derived immature cortical neurons. We show that TDP-43 induces expression of the proapoptotic BH3-only genes Bbc3 and Bax, and that p53 inhibition rescues TDP-43 induced cell death of embryonic mouse, and human cortical neurons, including those derived from TDP-43G298S ALS patient iPS cells. Hence, an increase in wild type and mutant TDP-43 induces p53-dependent cell death in neural progenitors developing neurons and this can be rescued. These findings may have important implications for accumulated or mutant TDP-43 induced neurodegenerative diseases.