Adult-born Dentate Granule Cells Research Articles

Egr1 Expression Is Correlated With Synaptic Activity but Not Intrinsic Membrane Properties in Mouse Adult-Born Dentate Granule Cells.

The discovery of adult-born granule cells (aDGCs) in the dentate gyrus of the hippocampus has raised questions regarding how they develop, incorporate into the hippocampal circuitry, and contribute to learning and memory. Here, we used patch-clamp electrophysiology to investigate the intrinsic and synaptic excitability of mouse aDGCs as they matured, enabled by using a tamoxifen-induced genetic label to birth date the aDGCs at different animal ages. Importantly, we also undertook immunofluorescence studies of the expression of the immediate early gene Egr1 and compared these findings with the electrophysiology data in the same animals. We examined two groups of animals, with aDGC birthdating when the mice were 2 months and at 7-9 months of age. In both groups, cells 4 weeks old had lower thresholds for current-evoked action potentials than older cells but fired fewer spikes during long current pulses and responded more poorly to synaptic activation. aDGCs born in both 2 and 7-9-month-old mice matured in their intrinsic excitability and synaptic properties from 4-12 weeks postgenesis, but this occurred more slowly for the older age animals. Interestingly, this pattern of intrinsic excitability changes did not correlate with the pattern of Egr1 expression. Instead, the development of Egr1 expression was correlated with the frequency of spontaneous excitatory postsynaptic currents. These results suggest that in order for aDGCs to fully participate in hippocampal circuitry, as indicated by Egr1 expression, they must have developed enough synaptic input, in spite of the greater input resistance and reduced firing threshold that characterizes young aDGCs.

TAAR1 in dentate gyrus is involved in chronic stress-induced impairments in hippocampal plasticity and cognitive function

Multiple lines of evidence suggest that the trace amine-associated receptor 1 (TAAR1) holds promise as a potential target for stress-related disorders, such as treating major depressive disorder (MDD). The role of TAAR1 in the regulation of adult neurogenesis is recently supported by transcriptomic data. However, it remains unknown whether TAAR1 in dentate gyrus (DG) mediate chronic stress-induced negative effects on hippocampal plasticity and related behavior in mice. The present study consisted of a series of experiments using RNAscope, genetic approaches, behavioral tests, immunohistochemical staining, Golgi-Cox technique to unravel the effects of TAAR1 on alterations of dentate neuronal plasticity and cognitive function in the chronic social defeat stress model. The mice subjected to chronic defeat stress exhibited a noteworthy decrease in the mRNA level of TAAR1 in DG. Additionally, they exhibited compromised social memory and spatial object recognition memory, as well as impaired proliferation and maturation of adult-born dentate granule cells. Moreover, the selective knockout TAAR1 in DG mostly mimicked the cognitive function deficits and neurogenesis impairment induced by chronic stress. Importantly, the administration of the selective TAAR1 partial agonist RO5263397 during stress exposure attenuated the adverse effects of chronic stress on cognitive function, adult neurogenesis, dendritic arborization, and the synapse number of dentate neurons in DG. In summary, our findings suggest that TAAR1 plays a crucial role in mediating the detrimental effects of chronic stress on hippocampal plasticity and cognition. TAAR1 agonists exhibit therapeutic potential for individuals suffering from cognitive impairments associated with MDD.

GSK-3β orchestrates the inhibitory innervation of adult-born dentate granule cells in vivo

Adult hippocampal neurogenesis enhances brain plasticity and contributes to the cognitive reserve during aging. Adult hippocampal neurogenesis is impaired in neurological disorders, yet the molecular mechanisms regulating the maturation and synaptic integration of new neurons have not been fully elucidated. GABA is a master regulator of adult and developmental neurogenesis. Here we engineered a novel retrovirus encoding the fusion protein Gephyrin:GFP to longitudinally study the formation and maturation of inhibitory synapses during adult hippocampal neurogenesis in vivo. Our data reveal the early assembly of inhibitory postsynaptic densities at 1 week of cell age. Glycogen synthase kinase 3 Beta (GSK-3β) emerges as a key regulator of inhibitory synapse formation and maturation during adult hippocampal neurogenesis. GSK-3β-overexpressing newborn neurons show an increased number and altered size of Gephyrin+ postsynaptic clusters, enhanced miniature inhibitory postsynaptic currents, shorter and distanced axon initial segments, reduced synaptic output at the CA3 and CA2 hippocampal regions, and impaired pattern separation. Moreover, GSK-3β overexpression triggers a depletion of Parvalbumin+ interneuron perineuronal nets. These alterations might be relevant in the context of neurological diseases in which the activity of GSK-3β is dysregulated.

Adult-born neurons in critical period maintain hippocampal seizures via local aberrant excitatory circuits

Temporal lobe epilepsy (TLE), one common type of medically refractory epilepsy, is accompanied with altered adult-born dentate granule cells (abDGCs). However, the causal role of abDGCs in recurrent seizures of TLE is not fully understood. Here, taking advantage of optogenetic and chemogenetic tools to selectively manipulate abDGCs in a reversible manner, combined with Ca2+ fiber photometry, trans-synaptic viral tracing, in vivo/vitro electrophysiology approaches, we aimed to test the role of abDGCs born at different period of epileptogenic insult in later recurrent seizures in mouse TLE models. We found that abDGCs were functionally inhibited during recurrent seizures. Optogenetic activation of abDGCs significantly extended, while inhibition curtailed, the seizure duration. This seizure-modulating effect was attributed to specific abDGCs born at a critical early phase after kindled status, which experienced specific type of circuit re-organization. Further, abDGCs extended seizure duration via local excitatory circuit with early-born granule cells (ebDGCs). Repeated modulation of “abDGC-ebDGC” circuit may easily induce a change of synaptic plasticity, and achieve long-term anti-seizure effects in both kindling and kainic acid-induced TLE models. Together, we demonstrate that abDGCs born at a critical period of epileptogenic insult maintain seizure duration via local aberrant excitatory circuits, and inactivation of these aberrant circuits can long-termly alleviate severity of seizures. This provides a deeper and more comprehensive understanding of the potential pathological changes of abDGCs circuit and may be helpful for the precise treatment in TLE.

GRM2 Regulates Functional Integration of Adult-Born DGCs by Paradoxically Modulating MEK/ERK1/2 Pathway.

Metabotropic glutamate receptor 2 (GRM2) is highly expressed in hippocampal dentate granule cells (DGCs), regulating synaptic transmission and hippocampal functions. Newborn DGCs are continuously generated throughout life and express GRM2 when they are mature. However, it remained unclear whether and how GRM2 regulates the development and integration of these newborn neurons. We discovered that the expression of GRM2 in adult-born DGCs increased with neuronal development in mice of both sexes. Lack of GRM2 caused developmental defects of DGCs and impaired hippocampus-dependent cognitive functions. Intriguingly, our data showed that knockdown of Grm2 resulted in decreased b/c-Raf kinases and paradoxically led to an excessive activation of MEK/ERK1/2 pathway. Inhibition of MEK ameliorated the developmental defects caused by Grm2 knockdown. Together, our results indicate that GRM2 is necessary for the development and functional integration of newborn DGCs in the adult hippocampus through regulating the phosphorylation and activation state of MEK/ERK1/2 pathway.SIGNIFICANCE STATEMENT Metabotropic glutamate receptor 2 (GRM2) is highly expressed in mature dentate granule cells (DGCs) in the hippocampus. It remains unclear whether GRM2 is required for the development and integration of adult-born DGCs. We provided in vivo and in vitro evidence to show that GRM2 regulates the development of adult-born DGCs and their integration into existing hippocampal circuits. Lack of GRM2 in a cohort of newborn DGCs impaired object-to-location memory in mice. Moreover, we revealed that GRM2 knockdown paradoxically upregulated MEK/ERK1/2 pathway by suppressing b/c-Raf in developing neurons, which is likely a common mechanism underlying the regulation of the development of neurons expressing GRM2. Thus, Raf/MEK/ERK1/2 pathway could be a potential target for brain diseases related to GRM2 abnormality.

Adult hippocampal neurogenesis in Alzheimer's disease: A roadmap to clinical relevance.

Adult hippocampal neurogenesis (AHN) drops sharply during early stages of Alzheimer's disease (AD), via unknown mechanisms, and correlates with cognitive status in AD patients. Understanding AHN regulation in AD could provide a framework for innovative pharmacological interventions. We here combine molecular, behavioral, and clinical data and critically discuss the multicellular complexity of the AHN niche in relation to AD pathophysiology. We further present a roadmap toward a better understanding of the role of AHN in AD by probing the promises and caveats of the latest technological advancements in the field and addressing the conceptual and methodological challenges ahead.

Adult-born dentate granule cells promote hippocampal population sparsity

The dentate gyrus (DG) gates neocortical information flow to the hippocampus. Intriguingly, the DG also produces adult-born dentate granule cells (abDGCs) throughout the lifespan, but their contribution to downstream firing dynamics remains unclear. Here, we show that abDGCs promote sparser hippocampal population spiking during mnemonic processing of novel stimuli. By combining triple-(DG-CA3-CA1) ensemble recordings and optogenetic interventions in behaving mice, we show that abDGCs constitute a subset of high-firing-rate neurons with enhanced activity responses to novelty and strong modulation by theta oscillations. Selectively activating abDGCs in their 4–7-week post-birth period increases sparsity of hippocampal population patterns, whereas suppressing abDGCs reduces this sparsity, increases principal cell firing rates and impairs novel object recognition with reduced dimensionality of the network firing structure, without affecting single-neuron spatial representations. We propose that adult-born granule cells transiently support sparser hippocampal population activity structure for higher-dimensional responses relevant to effective mnemonic information processing.

Kainate receptors regulate the functional properties of young adult-born dentate granule cells.

SUMMARYBoth inhibitory and excitatory neurotransmitter receptors can influence maturation and survival of adult-born neurons in the dentate gyrus; nevertheless, how these two neurotransmitter systems affect integration of new neurons into the existing circuitry is still not fully characterized. Here, we demonstrate that glutamate receptors of the kainate receptor (KAR) subfamily are expressed in adult-born dentate granule cells (abDGCs) and that, through their interaction with GABAergic signaling mechanisms, they alter the functional properties of adult-born cells during a critical period of their development. Both the intrinsic properties and synaptic connectivity of young abDGCs were affected. Timed KAR loss in a cohort of young adult-born neurons in mice disrupted their performance in a spatial discrimination task but not in a hippocampal-dependent fear conditioning task. Together, these results demonstrate the importance of KARs in the proper functional development of young abDGCs.

Activation of 6–8-week-old new mature adult-born dentate granule cells contributes to anxiety-like behavior

Adult-born dentate granule cells (aDGCs) at 4–6 weeks of age are particularly excitable but subsequently develop the quiet properties of mature cells. Most existing studies have focused on the hyperactivity of 4–6-week-old aDGCs or neurogenesis, which confers stress resilience or buffers stress responses. However, the function of the quiet property of new mature aDGCs remains unclear. Here we used a retrovirus expressing cre recombinase in combination with an associated-adenovirus to specifically interfere with the activity of new mature aDGCs, and estimated anxiety-like behaviors by the open-field test and elevated plus maze test, antidepressant-like behaviors by the tail suspension test, and spatial memory by the Barnes maze test. We found that sustained hyperactivity of 6–8-week-old, but not 8–10-week-old, aDGCs induced anxiety-like behaviors, and suppression of the activity of 6–8-week-old aDGCs disturbed spatial memory. Meanwhile, sustained hyperactivity of 6–8-week-old aDGCs induced activation of mature dentate gyrus (DG) neurons and inhibition of immature aDGCs. Additionally, the mice showing anxiety-like behaviors induced by chronic mild immobilization stress exhibited increased activity in 6–8-week-old aDGCs. Furthermore, the sustained hyperactivity of mature DG neurons also induced anxiety-like behaviors and decreased the activity of immature aDGCs. Our results combined show that the excitation of 6–8-week-old new mature aDGCs, which prohibits them from normally entering the resting state, determines anxiety-like behavior, while the maintenance of normal excitation ability of 6–8-week-old new mature aDGCs confers memory. Our results suggests that strategies aimed at inhibiting unusual hyperactive new mature aDGCs at a restricted time window may protect against stress-related psychiatric disorders, such as anxiety and depression.

A functional model of adult dentate gyrus neurogenesis.

In adult dentate gyrus neurogenesis, the link between maturation of newborn neurons and their function, such as behavioral pattern separation, has remained puzzling. By analyzing a theoretical model, we show that the switch from excitation to inhibition of the GABAergic input onto maturing newborn cells is crucial for their proper functional integration. When the GABAergic input is excitatory, cooperativity drives the growth of synapses such that newborn cells become sensitive to stimuli similar to those that activate mature cells. When GABAergic input switches to inhibitory, competition pushes the configuration of synapses onto newborn cells toward stimuli that are different from previously stored ones. This enables the maturing newborn cells to code for concepts that are novel, yet similar to familiar ones. Our theory of newborn cell maturation explains both how adult-born dentate granule cells integrate into the preexisting network and why they promote separation of similar but not distinct patterns.

Kainate Receptors Regulate the Functional Properties of Young Adult-Born Dentate Granule Cells

Both inhibitory and excitatory neurotransmitter receptors can influence maturation and survival of adult-born neurons in the dentate gyrus; yet how these two neurotransmitter systems affect integration of new neurons into the existing circuitry are still not fully characterized. Here we demonstrate that glutamate receptors of the kainate receptor (KAR) subfamily are expressed in adult-born dentate granule cells (abDGCs) and that through their interaction with GABAergic signaling mechanisms alter the functional maturation of adult-born cells during a critical period of their development. Both the intrinsic properties and synaptic connectivity of young abDGCs were affected. Timed KAR loss in a cohort of young adult-born neurons in mice disrupted their performance in a spatial discrimination task but not in a hippocampal-dependent fear conditioning task. Together these results demonstrate the importance of KARs in the proper functional development of young abDGCs.

Enhancing adult neurogenesis promotes contextual fear memory discrimination and activation of hippocampal-dorsolateral septal circuits

Hippocampal circuitry is continuously modified by integration of adult-born dentate granule cells (DGCs). Prior work has shown that enhancing adult hippocampal neurogenesis decreases interference or overlap or conflict between ensembles of similar contexts and promotes discrimination of a shock-associated context from a similar, neutral context. However, the impact of enhanced integration of adult-born neurons on hippocampal network activity or downstream circuits such as the dorsolateral septum that mediate defensive behavioral responses is poorly understood. Here, we first replicated our finding that genetic expansion of the population of adult-born dentate granule cells (8 weeks and younger) promotes contextual fear discrimination. We found that enhanced contextual fear discrimination is associated with greater c-Fos expression in discrete hippocampal subfields along the proximo-distal and dorsoventral axis. Examination of the dorsolateral septum revealed an increase in activation of somatostatin expressing neurons consistent with recent characterization of these cells as calibrators of defensive behavior. Together, these findings begin to shed light on how genetically enhancing adult hippocampal neurogenesis affects activity of hippocampal-dorsolateral septal circuits.

Early Dendritic Morphogenesis of Adult-Born Dentate Granule Cells Is Regulated by FHL2.

Dentate granule cells (DGCs), the progeny of neural stem cells (NSCs) in the sub-granular zone of the dentate gyrus (DG), must develop and functionally integrate with the mature cohort of neurons in order to maintain critical hippocampal functions throughout adulthood. Dysregulation in the continuum of DGC development can result in aberrant morphology and disrupted functional maturation, impairing neuroplasticity of the network. Yet, the molecular underpinnings of the signaling involved in adult-born DGC maturation including dendritic growth, which correlates with functional integration, remains incompletely understood. Given the high metabolic activity in the dentate gyrus (DG) required to achieve continuous neurogenesis, we investigated the potential regulatory role of a cellular metabolism-linked gene recently implicated in NSC cycling and neuroblast migration, called Four and a half LIM domain 2 (FHL2). The FHL2 protein modulates numerous pathways related to proliferation, migration, survival and cytoskeletal rearrangement in peripheral tissues, interacting with the machinery of the sphingosine-1-phosphate pathway, also known to be highly active especially in the hippocampus. Yet, the potential relevance of FHL2 to adult-born DGC development remains unknown. To elucidate the role of FHL2 in DGC development in the adult brain, we first confirmed the endogenous expression of FHL2 in NSCs and new granule cells within the DG, then engineered viral vectors for genetic manipulation experiments, investigating morphological changes in early stages of DGC development. Overexpression of FHL2 during early DGC development resulted in marked sprouting and branching of dendrites, while silencing of FHL2 increased dendritic length. Together, these findings suggest a novel role of FHL2 in adult-born DGC morphological maturation, which may open up a new line of investigation regarding the relevance of this gene in physiology and pathologies of the hippocampus such as mesial temporal lobe epilepsy (MTLE).

Disentangling chemical and electrical effects of status epilepticus-induced dentate gyrus abnormalities

In rodents, status epilepticus (SE) triggered by chemoconvulsants can differently affect the proliferation and fate of adult-born dentate granule cells (DGCs). It is unknown whether abnormal neurogenesis results from intracellular signaling associated with drug-receptor interaction, paroxysmal activity, or both. To test the contribution of these factors, we systematically compared the effects of kainic acid (KA)- and pilocarpine (PL)-induced SE on the morphology and localization of DGCs generated before or after SE in the ipsi- and contralateral hippocampi of mice. Hippocampal insult was induced by unilateral intrahippocampal (ihpc) administration of KA or PL. We employed conditional doublecortin-dependent expression of the green fluorescent protein (GFP) to label adult-born cells committed to neuronal lineage either one month before (mature DGCs) or seven days after (immature DGCs) SE. Unilateral ihpc administration of KA and PL led to bilateral epileptiform discharges and focal and generalized behavioral seizures. However, drastic granule cell layer (GCL) dispersion occurred only in the ipsilateral side of KA injection, but not in PL-treated animals. Granule cell layer dispersion was accompanied by a significant reduction in neurogenesis after SE in the ipsilateral side of KA-treated animals, while neurogenesis increased in the contralateral side of KA-treated animals and both hippocampi of PL-treated animals. The ratio of ectopic neurons in the ipsilateral hippocampus was higher among immature as compared to mature neurons in the KA model (32.8% vs. 10.0%, respectively), while the occurrence of ectopic neurons in PL-treated animals was lower than 3% among both mature and immature DGCs. Collectively, our results suggest that KA- and PL-induced SE leads to distinct cellular alterations in mature and immature DGCs. We also show different local and secondary effects of KA or PL in the histological organization of the adult DG, suggesting that these unique epilepsy models may be complementary to our understanding of the disease.NEWroscience 2018.

Development of Depotentiation in Adult-Born Dentate Granule Cells.

Activity-dependent synaptic plasticity, i.e., long-term potentiation (LTP), long-term depression (LTD) and LTP reversal, is generally thought to make up the cellular mechanism underlying learning and memory in the mature brain, in which N-methyl-D-aspartate subtype of glutamate (NMDA) receptors and neurogenesis play important roles. LTP reversal may be the mechanism of forgetting and may mediate many psychiatric disorders, such as schizophrenia, but the specific mechanisms underlying these disorders remain unclear. In addition, LTP reversal during the development of adult-born dentate granule cells (DGCs) remains unknown. We found that the expression of the NMDA receptor subunits NR2A and NR2B displayed dynamic changes during the development of postnatal individuals and the maturation of adult-born neurons and was coupled with the change in LTP reversal. The susceptibility of LTP reversal progressively increases with the rise in the expression of NR2A during the development of postnatal individual and adult-born neurons. In addition, NMDA receptor subunits NR2A, but not NR2B, mediated LTP reversal in the DGCs of the mouse hippocampus.

Functions of adult-born neurons in hippocampal memory interference and indexing.

The dentate gyrus-CA3 circuit of the hippocampus is continuously modified by the integration of adult-born dentate granule cells (abDGCs). All abDGCs undergo a prolonged period of maturation, during which they exhibit heightened synaptic plasticity and refinement of electrophysiological properties and connectivity. Consistent with theoretical models and the known functions of the dentate gyrus-CA3 circuit, acute or chronic manipulations of abDGCs support a role for abDGCs in the regulation of memory interference. In this Review, we integrate insights from studies that examine the maturation of abDGCs and their integration into the circuit with network mechanisms that support memory discrimination, consolidation and clearance. We propose that adult hippocampal neurogenesis enables the generation of a library of experiences, each registered in mature abDGC physiology and connectivity. Mature abDGCs recruit inhibitory microcircuits to support pattern separation and memory indexing.

Restrained Dendritic Growth of Adult-Born Granule Cells Innervated by Transplanted Fetal GABAergic Interneurons in Mice with Temporal Lobe Epilepsy.

The dentate gyrus (DG) is a region of the adult rodent brain that undergoes continuous neurogenesis. Seizures and loss or dysfunction of GABAergic synapses onto adult-born dentate granule cells (GCs) alter their dendritic growth and migration, resulting in dysmorphic and hyperexcitable GCs. Additionally, transplants of fetal GABAergic interneurons in the DG of mice with temporal lobe epilepsy (TLE) result in seizure suppression, but it is unknown whether increasing interneurons with these transplants restores GABAergic innervation to adult-born GCs. Here, we address this question by birth-dating GCs with retrovirus at different times up to 12 weeks after pilocarpine-induced TLE in adult mice. Channelrhodopsin 2 (ChR2)-enhanced yellow fluorescent protein (EYFP)-expressing medial-ganglionic eminence (MGE)-derived GABAergic interneurons from embryonic day (E)13.5 mouse embryos were transplanted into the DG of the TLE mice and GCs with transplant-derived inhibitory post-synaptic currents (IPSCs) were identified by patch-clamp electrophysiology and optogenetic interrogation. Putative synaptic sites between GCs and GABAergic transplants were also confirmed by intracellular biocytin staining, immunohistochemistry, and confocal imaging. 3D reconstructions of dendritic arbors and quantitative morphometric analyses were carried out in >150 adult-born GCs. GABAergic inputs from transplanted interneurons correlated with markedly shorter GC dendrites, compared to GCs that were not innervated by the transplants. Moreover, these effects were confined to distal dendritic branches and a short time window of six to eight weeks. The effects were independent of seizures as they were also observed in naïve mice with MGE transplants. These findings are consistent with the hypothesis that increased inhibitory currents over a smaller dendritic arbor in adult-born GCs may reduce their excitability and lead to seizure suppression.

Development of GABAergic Inputs Is Not Altered in Early Maturation of Adult Born Dentate Granule Neurons in Fragile X Mice.

Fragile X syndrome (FXS) is the most common form of inherited mental retardation and the most common known cause of autism. Loss of fragile X mental retardation protein (FMRP) in mice (Fmr1 KO) leads to altered synaptic and circuit maturation in the hippocampus that is correlated with alterations in hippocampal-dependent behaviors. Previous studies have demonstrated that loss of FMRP increased the rate of proliferation of progenitor cells and altered their fate specification in adult Fmr1 KO mice. While these studies clearly demonstrate a role for FMRP in adult neurogenesis in the hippocampus, it is not known whether the functional synaptic maturation and integration of adult-born dentate granule cells (abDGCs) into hippocampal circuits is affected in Fmr1 KO mice. Here, we used retroviral labeling to birthdate abDGCs in Fmr1 KO mice which allowed us to perform targeted patch clamp recording to measure the development of synaptic inputs to these neurons at precise time points after differentiation. The frequency and amplitude of spontaneous GABAergic events increased over the first three weeks after differentiation; however, this normal development of GABAergic synapses was not altered in Fmr1 KO mice. Furthermore, the relatively depolarized GABA reversal potential (EGABA) in immature abDGCs was unaffected by loss of FMRP as was the development of dendritic arbor of the adult generated neurons. These studies systematically characterized the functional development of abDGCs during the first four weeks after differentiation and demonstrate that the maturation of GABAergic synaptic inputs to these neurons is not grossly affected by the loss of FMRP.

Prenatal Exposure to Antipsychotics Disrupts the Plasticity of Dentate Neurons and Memory in Adult Male Mice.

BackgroundWith the growing use of second-generation antipsychotics for the treatment of a spectrum of psychiatric illnesses in pregnancy, concerns have been raised about the long-term impact of these medications on offspring neurodevelopment. However, preclinical and clinical evidence on the lasting effects of prenatal antipsychotic exposure is still sparse.MethodsRisperidone, a widely used second-generation antipsychotic, and haloperidol, a representative first-generation antipsychotic, were administered to pregnant C57BL/6N mice from embryonic day 6 to 16. Behavioral tests, immunohistochemical staining, Golgi-Cox technique, and western blot were used to determine the effects of prenatal antipsychotic exposure on the plasticity of the dentate gyrus and related behavior in adult male mice.ResultsBoth prenatal haloperidol- and risperidone-exposed mice showed recognition memory deficits but had no anxiety-related behavior. In addition, both prenatal haloperidol and risperidone exposure impaired the proliferation and maturation of adult-born dentate granule cells. We found that haloperidol exposure decreased dendritic length of dentate granule cells, while risperidone had no effect. However, both drugs inhibited dendrite branching in granule cells. Haloperidol exposure also significantly reduced total spine density in the middle dendritic segment of dentate gyrus. Prenatally risperidone-exposed mice only displayed a loss in thin and mushroom spines of infrapyramidal blade of dentate gyrus. Collectively, prenatal haloperidol exposure exerted more robust negative effects than risperidone.ConclusionThese data provide evidence for the long-term programming effects of early-life exposure to antipsychotics on hippocampal plasticity and behavior.

Repositioning of Somatic Golgi Apparatus Is Essential for the Dendritic Establishment of Adult-Born Hippocampal Neurons.

New dentate granule cells (DGCs) are continuously generated, and integrate into the preexisting hippocampal network in the adult brain. How an adult-born neuron with initially simple spindle-like morphology develops into a DGC, consisting of a single apical dendrite with further branches, remains largely unknown. Here, using retroviruses to birth date and manipulate newborn neurons, we examined initial dendritic formation and possible underlying mechanisms. We found that GFP-expressing newborn cells began to establish a DGC-like morphology at ∼7 d after birth, with a primary dendrite pointing to the molecular layer, but at this stage, with several neurites in the neurogenic zone. Interestingly, the Golgi apparatus, an essential organelle for neurite growth and maintenance, was dynamically repositioning in the soma of newborn cells during this initial integration stage. Two weeks after birth, by which time most neurites in the neurogenic zone were eliminated, a compact Golgi apparatus was positioned exclusively at the base of the primary dendrite. We analyzed the presence of Golgi-associated genes using single-cell transcriptomes of newborn DGCs, and among Golgi-related genes, found the presence of STK25 and STRAD, regulators of embryonic neuronal development. When we knocked down either of these two proteins, we found Golgi mislocalization and extensive aberrant dendrite formation. Furthermore, overexpression of a mutated form of STRAD, underlying the disorder polyhydramnios, megalencephaly, and symptomatic epilepsy, characterized by abnormal brain development and intractable epilepsy, caused similar defects in Golgi localization and dendrite formation in adult-born neurons. Together, our findings reveal a role for Golgi repositioning in regulating the initial integration of adult-born DGCs.SIGNIFICANCE STATEMENT Since the discovery of the continuous generation of new neurons in the adult hippocampus, extensive effort was directed toward understanding the functional contribution of these newborn neurons to the existing hippocampal circuit and associated behaviors, while the molecular mechanisms controlling their early morphological integration are less well understood. Dentate granule cells (DGCs) have a single, complex, apical dendrite. The events leading adult-born DGCs' to transition from simple spindle-like morphology to mature dendrite morphology are largely unknown. We studied establishment of newborn DGCs dendritic pattern and found it was mediated by a signaling pathway regulating precise localization of the Golgi apparatus. Furthermore, this Golgi-associated mechanism for dendrite establishment might be impaired in a human genetic epilepsy syndrome, polyhydramnios, megalencephaly, and symptomatic epilepsy.