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1.  Modulation of neurite outgrowth by activation of calcium-permeable kainate receptors expressed by rat nociceptive-like dorsal root ganglion neurons 
Developmental neurobiology  2011;71(10):818-835.
Neurite outgrowth is a fundamental step in establishing proper neuronal connections in the developing central nervous system. Dynamic control of outgrowth has been attributed to changes in growth cone Ca2+ levels in response to extracellular cues. Here we have investigated a possible role for Ca2+ permeable kainate (KA) receptors in regulating neurite outgrowth of nociceptive-like dorsal root ganglion (DRG) neurons. To identify KA receptor subunits likely to be involved, we used quantitative RT-PCR on acutely dissociated DRG and dorsal horn neurons. DRG neurons expressed more GluK1, particularly the GluK1b spice variant, than dorsal horn neurons. Conversely, dorsal horn neurons expressed more GluK2, particularly GluK2a, than DRG neurons. Further, an RNA editing assay indicated that the majority of GluK1 and GluK2 mRNA transcripts in DRG were unedited. Imaging Ca2+ transients following application of a KA receptor agonist to DRG and dorsal horn co-cultures revealed increases in intracellular Ca2+ in the growth cones of DRG neurons. In the majority of cases, this increase in Ca2+ was partly or completely blocked by Joro spider toxin (JSTX), an antagonist for Ca2+-permeable AMPA and KA receptors. Treatment of DRG/dorsal horn co-cultures with KA for 18 hours suppressed neurite outgrowth while application of the rapidly desensitizing KA receptor agonist SYM 2081, the competitive AMPA/KA receptor antagonist, CNQX, and JSTX or philanthotoxin enhanced neurite outgrowth and prevented KA effects on neurite outgrowth. Thus, Ca2+ entry through KA receptors at the growth cone of DRG neurons may be an important regulator of neurite outgrowth.
doi:10.1002/dneu.20906
PMCID: PMC3973019  PMID: 21557511
Dorsal root ganglion; growth cone; microisland; neurite outgrowth; RNA editing
2.  REGULATION OF EPHRIN-A EXPRESSION IN COMPRESSED RETINOCOLLICULAR MAPS 
Developmental neurobiology  2012;73(4):274-296.
Retinotopic maps can undergo compression and expansion in response to changes in target size, but the mechanism underlying this compensatory process has remained a mystery. The discovery of ephrins as molecular mediators of Sperry’s chemoaffinity process allows a mechanistic approach to this important issue. In Syrian hamsters, neonatal, partial (PT) ablation of posterior superior colliculus (SC) leads to compression of the retinotopic map, independent of neural activity. Graded, repulsive EphA receptor/ephrin-A ligand interactions direct the formation of the retinocollicular map, but whether ephrins might also be involved in map compression is unknown. To examine whether map compression might be directed by changes in the ephrin expression pattern, we compared ephrin-A2 and ephrin-A5 mRNA expression between normal SC and PT SC using in situ hybridization and quantitative real-time PCR. We found that ephrin-A ligand expression in the compressed maps was low anteriorly and high posteriorly, as in normal animals. Consistent with our hypothesis, the steepness of the ephrin gradient increased in the lesioned colliculi. Interestingly, overall levels of ephrin-A2 and -A5 expression declined immediately after neonatal target damage, perhaps promoting axon outgrowth. These data establish a correlation between changes in ephrin-A gradients and map compression, and suggest that ephrin-A expression gradients may be regulated by target size. This in turn could lead to compression of the retinocollicular map onto the reduced target. These findings have important implications for mechanisms of recovery from traumatic brain injury.
doi:10.1002/dneu.22059
PMCID: PMC3595324  PMID: 23008269
3.  Organization of Myelin in the Mouse Somatosensory Barrel Cortex and the Effects of Sensory Deprivation 
Developmental neurobiology  2012;73(4):297-314.
In rodents, the barrel cortex is a specialized area within the somatosensory cortex that processes signals from the mystacial whiskers. We investigated the normal development of myelination in the barrel cortex of mice, as well as the effects of sensory deprivation on this pattern. Deprivation was achieved by trimming the whiskers on one side of the face every other day from birth. In control mice, myelin was not present until postnatal day 14 and did not show prominence until postnatal day 30; adult levels of myelination were reached by the end of the second postnatal month. Unbiased stereology was used to estimate axon density in the interbarrel septal region and barrel walls as well as the barrel centers. Myelin was significantly more concentrated in the interbarrel septa/barrel walls than in the barrel centers in both control and sensory-deprived conditions. Sensory deprivation did not impact the onset of myelination but resulted in a significant decrease in myelinated axons in the barrel region and decreased the amount of myelin ensheathing each axon. Visualization of the oligodendrocyte nuclear marker Olig2 revealed a similar pattern of myelin as seen using histochemistry, but with no significant changes in Olig2+ nuclei following sensory deprivation. Consistent with the anatomical results showing less myelination, local field potentials revealed slower rise times following trimming. Our results suggest that myelination develops relatively late and can be influenced by sensory experience.
doi:10.1002/dneu.22060
PMCID: PMC3725810  PMID: 23047707
myelin; barrel cortex; activity dependent; whiskers; sensory deprivation
4.  Isolation of a Novel Rat Neural Progenitor Clone that Expresses Dlx Family Transcription Factors and Gives Rise to Functional GABAergic Neurons in Culture 
Developmental neurobiology  2012;72(6):805-820.
GABAergic interneurons are lost in conditions including epilepsy and CNS injury, but there are few culture models available to study their function. Towards the goal of obtaining renewable sources of GABAergic neurons, we used the molecular profile of a functionally-incomplete GABAergic precursor clone to screen 17 new clones isolated from GFP+ rat E14.5 cortex and ganglionic eminence (GE) that were generated by viral introduction of v-myc. The clones grow as neurospheres in medium with FGF2, and after withdrawal of FGF2 they exhibit varying patterns of differentiation. Transcriptional profiling and qPCR indicated that one clone (GE6) expresses high levels of mRNAs encoding Dlx1, 2, 5 and 6, glutamate decarboxylases, and presynaptic proteins including neuropeptide Y and somatostatin. Protein expression confirmed that GE6 is a progenitor with restricted differentiation giving rise mostly to neurons with GABAergic markers. In co-cultures with hippocampal neurons, GE6 neurons became electrically excitable and received both inhibitory and excitatory synapses. After withdrawal of FGF2 in cultures of GE6 alone, neurons matured to express βIII-tubulin, and staining for synaptophysin and vesicular GABA transporter (VGAT) were robust after 1-2 weeks of differentiation. GE6 neurons also became electrically excitable and displayed synaptic activity, but synaptic currents were carried by chloride and were blocked by bicuculline. The results suggest that the GE6 clone, which is ventrally derived from the GE, resembles GABAergic interneuron progenitors that migrate into the developing forebrain. This is the first report of a relatively stable fetal clone that can be differentiated into GABAergic interneurons with functional synapses.
doi:10.1002/dneu.20977
PMCID: PMC3968925  PMID: 21913335
neuronal progenitor; v-myc; GABA; GABAergic development
5.  Jelly Belly Trans-Synaptic Signaling to Anaplastic Lymphoma Kinase Regulates Neurotransmission Strength and Synapse Architecture 
Developmental neurobiology  2012;73(3):189-208.
In Drosophila the secreted signaling molecule Jelly Belly (Jeb) activates Anaplastic Lymphoma Kinase (Alk), a receptor tyrosine kinase, in multiple developmental and adult contexts. We have shown previously that Jeb and Alk are highly enriched at Drosophila synapses within the CNS neuropil and neuromuscular junction (NMJ) and postulated a conserved intercellular signaling function. At the embryonic and larval NMJ Jeb is localized in the motor neuron presynaptic terminal whereas Alk is concentrated in the muscle postsynaptic domain surrounding boutons, consistent with anterograde trans-synaptic signaling. Here, we show by functional inhibition of Jeb-Alk signaling that neurotransmission is regulated by Jeb secretion. Jeb is a novel negative regulator of neuromuscular transmission. Reduction or inhibtion of Alk function results in enhanced synaptic transmission. Activation of Alk conversely inhibits synaptic transmission. Restoration of wildtype postsynaptic Alk expression in Alk partial loss-of-function mutants rescues NMJ transmission phenotypes and confirms that postsynaptic Alk regulates NMJ transmission. The effects of impaired Alk signaling on neurotransmission are observed in the absence of associated changes in NMJ structure. Complete removal of Jeb in motor neurons, however, disrupts both presynaptic bouton architecture and postsynaptic differentiation. Non-physiologic activation of Alk signaling also negatively regulates NMJ growth. Activation of Jeb-Alk signaling triggers the Ras-MAP kinase cascade in both pre- and postsynaptic compartments. These novel roles for Jeb-Alk signaling in the modulation of synaptic function and structure have potential implications for recently reported Alk functions in human addiction, retention of spatial memory, cognitive dysfunction in neurofibromatosis and the pathogenesis of amyotrophic lateral sclerosis.
doi:10.1002/dneu.22056
PMCID: PMC3565053  PMID: 22949158
Trans-Synaptic Signaling; Synaptic Inhibition; Anaplastic lymphoma kinase; Glutamatergic Synapse; Neuromuscular Junction; Drosophila
6.  Developmental mechanisms that regulate retinal ganglion cell dendritic morphology 
Developmental neurobiology  2011;71(12):1297-1309.
One of the fundamental features of retinal ganglion cells (RGCs) is that dendrites of individual RGCs are confined to one or a few narrow strata within the inner plexiform layer (IPL), and each RGC synapses only with a small group of presynaptic bipolar and amacrine cells with axons/dendrites ramified in the same strata to process distinct visual features. The underlying mechanisms which control the development of this laminar-restricted distribution pattern of RGC dendrites have been extensively studied, and it is still an open question whether the dendritic pattern of RGCs is determined by molecular cues or by activity-dependent refinement. Accumulating evidence suggests that both molecular cues and activity-dependent refinement might regulate RGC dendrites in a cell subtype-specific manner. However, identification of morphological subtypes of RGCs before they have achieved their mature dendritic pattern is a major challenge in the study of RGC dendritic development. This problem is now being circumvented through the use of molecular markers in genetically engineered mouse lines to identify RGC subsets early during development. Another unanswered fundamental question in the study of activity-dependent refinement of RGC dendrites is how changes in synaptic activity lead to the changes in dendritic morphology. Recent studies have started to shed light on the molecular basis of activity-dependent dendritic refinement of RGCs by showing that some molecular cascades control the cytoskeleton reorganization of RGCs.
doi:10.1002/dneu.20900
PMCID: PMC3923654  PMID: 21542137
retinal ganglion cells; retinal development; synaptic activity; dendritic morphology; synaptic connection
7.  Ethanol Influences on Bax Associations with Mitochondrial Membrane Proteins in Neonatal Rat Cerebellum 
Developmental neurobiology  2012;73(2):127-141.
These studies investigated interactions taking place at the mitochondrial membrane in neonatal rat cerebellum following ethanol exposure, and focused on interactions between pro-apoptotic Bax and proteins of the permeability transition pore (PTP), voltage-dependent anion channel (VDAC), and adenine nucleotide translocator (ANT), of the outer and inner mitochondrial membranes, respectively. Cultured cerebellar granule cells were used to assess the role of these interactions in ethanol neurotoxicity. Analyses were made at the age of maximal cerebellar ethanol vulnerability (P4), compared to the later age of relative resistance (P7), to determine whether differential ethanol sensitivity was mirrored by differences in these molecular interactions. We found that following ethanol exposure, Bax pro-apoptotic associations with both VDAC and ANT were increased, particularly at the age of greater ethanol sensitivity, and these interactions were sustained at this age for at least two hours post-exposure. Since Bax:VDAC interactions disrupt protective VDAC interactions with mitochondrial hexokinase (HXK), we also assessed VDAC:HXK associations following ethanol treatment, and found such interactions were altered by ethanol treatment, but only at two-hours post-exposure, and only in the P4, ethanol-sensitive cerebellum. Ethanol neurotoxicity in cultured neuronal preparations was abolished by pharmacological inhibition of both VDAC and ANT interactions with Bax, but not by a Bax channel blocker. Therefore, we conclude that at this age, within the constraints of our experimental model, a primary mode of Bax-induced initiation of the apoptosis cascade following ethanol insult involves interactions with proteins of the PTP complex, and not channel formation independent of PTP constituents.
doi:10.1002/dneu.22042
PMCID: PMC3480559  PMID: 22767450
Ethanol; fetal alcohol syndrome; apoptosis; mitochondria; cerebellum
8.  The Sox gene Dichaete is expressed in local interneurons and functions in development of the Drosophila adult olfactory circuit 
Developmental neurobiology  2012;73(2):107-126.
In insects, the primary sites of integration for olfactory sensory input are the glomeruli in the antennal lobes. Here, axons of olfactory receptor neurons synapse with dendrites of the projection neurons that relay olfactory input to higher brain centers, such as the mushroom bodies and lateral horn. Interactions between olfactory receptor neurons and projection neurons are modulated by excitatory and inhibitory input from a group of local interneurons. While significant insight has been gleaned into the differentiation of olfactory receptor and projection neurons, much less is known about the development and function of the local interneurons. We have found that Dichaete, a conserved Sox HMG box gene, is strongly expressed in a cluster of LAAL cells located adjacent to each antennal lobe in the adult brain. Within these clusters, Dichaete protein expression is detected in both cholinergic and GABAergic local interneurons. In contrast, Dichaete expression is not detected in mature or developing projection neurons, or developing olfactory receptor neurons. Analysis of novel viable Dichaete mutant alleles revealed misrouting of specific projection neuron dendrites and axons, and alterations in glomeruli organization. These results suggest non-cell autonomous functions of Dichaete in projection neuron differentiation as well as a potential role for Dichaete-expressing local interneurons in development of the adult olfactory circuitry.
doi:10.1002/dneu.22038
PMCID: PMC3517933  PMID: 22648855
Drosophila Sox gene; olfactory circuit; antennal lobes; local interneurons
9.  New transgenic reporters identify somatosensory neuron subtypes in larval zebrafish 
Developmental neurobiology  2012;73(2):152-167.
To analyze somatosensory neuron diversity in larval zebrafish, we identified several enhancers from the zebrafish and pufferfish genomes and used them to create five new reporter transgenes. Sequential deletions of three of these enhancers identified small sequence elements sufficient to drive expression in zebrafish trigeminal and Rohon-Beard (RB) neurons. One of these reporters, using the Fru.p2x3-2 enhancer, highlighted a somatosensory neuron subtype that expressed both the p2rx3a and pkcα genes. Comparison with a previously described trpA1b reporter revealed that it highlighted the same neurons as the Fru.p2x3-2 reporter. To determine whether neurons of this subtype possess characteristic peripheral branching morphologies or central axon projection patterns, we analyzed the morphology of single neurons. Surprisingly, although these analyses revealed diversity in peripheral axon branching and central axon projection, PKCα/p2rx3a/trpA1b-expressing RB cells did not possess obvious characteristic morphological features, suggesting that even within this molecularly defined subtype, individual neurons may possess distinct properties. The new transgenes created in this study will be powerful tools for further characterizing the molecular, morphological, and developmental diversity of larval somatosensory neurons.
doi:10.1002/dneu.22049
PMCID: PMC3541445  PMID: 22865660
zebrafish; somatosensation; trigeminal; Rohon-Beard; peripheral axon; central axon; transgenic reporter
10.  CRITICAL PERIOD FOR ESTROGEN-DEPENDENT MOTONEURON DENDRITE GROWTH IS COINCIDENT WITH ERα EXPRESSION IN TARGET MUSCULATURE 
Developmental neurobiology  2012;73(1):72-84.
The spinal cord of rats contains the sexually dimorphic, steroid-sensitive motoneurons of the spinal nucleus of the bulbocavernosus (SNB). In males, SNB dendrite growth is dependent on gonadal steroids: dendrite growth is inhibited after castration, but supported in androgen- or estrogen-treated castrated males. Furthermore, estrogenic support of SNB dendrite growth is mediated by estrogen action at the target musculature, inhibited by estrogen receptor (ER) blockade at the muscle, and supported by local estradiol treatment However, this estrogenic support is restricted to the early postnatal period, after which the morphology of SNB dendrites is insensitive to estrogens. To test if the developmentally restricted effects of estrogens on SNB dendrite growth coincides with the transient expression of ER in the target musculature, ERα expression was assessed during development and in adulthood. ERα expression in extra-muscle fiber cells was greatest from postnatal day 7 (P7) to P14, and declined after P21. Because this pattern of ERα expression coincided with the period of estrogen-dependent dendrite growth, we tested if limiting hormone exposure to the period of maximal ERα expression in extra-muscle fiber cells could fully support estrogen-dependent SNB dendrite growth. We restricted estradiol treatment in castrated males from P7-P21, and assessed SNB dendritic morphology at P28. Treating castrates with estradiol implants at the muscle from P7-P21 supported dendrite growth to normal levels through P28. These data suggest that the transient ERα expression in target muscle could potentially define the critical period for estrogen-dependent dendrite growth in SNB motoneurons.
doi:10.1002/dneu.22040
PMCID: PMC3480967  PMID: 22678724
gonadal hormones; motoneurons; dendrites; spinal cord; rat
11.  Dynamics of presynaptic protein recruitment induced by local presentation of artificial adhesive contacts 
Developmental neurobiology  2012;73(1):98-106.
Here we introduce a novel approach to induce and observe the formation of presynaptic compartments in axons through a combination of Atomic Force Microscopy (AFM) and fluorescence microscopy. First, we use a poly-D-lysine coated bead attached to an AFM tip to induce the recruitment of two synaptic proteins, bassoon and synaptophysin, and measure their absolute arrival times to the presynaptic department. We find that bassoon arrives before synaptophysin. Second, we observed the formation of very long (several 10s of µm), structured, protein-containing membranous strings as the AFM tip was withdrawn from the axon. It is conceivable that these strings might be a novel mechanism by which new neurites or branch points along existing neurites may be generated in situ.
doi:10.1002/dneu.22037
PMCID: PMC3518747  PMID: 22648784
Atomic force microscope; synaptogenesis; poly-D-lysine; presynaptic site; protein recruitment
12.  Reciprocal actions of ATF5 and Shh in proliferation of cerebellar granule neuron progenitor cells 
Developmental neurobiology  2012;72(6):10.1002/dneu.20979.
Precise regulation of neuroprogenitor cell proliferation and differentiation is required for successful brain development, but the factors that contribute to this are only incompletely understood. The transcription factor ATF5 promotes proliferation of cerebral cortical neuroprogenitor cells and its down-regulation permits their differentiation. Here, we examine the expression and regulation of ATF5 in cerebellar granule neuron progenitor cells (CGNPs) as well as the role of ATF5 in the transition of CGNPs to post-mitotic cerebellar granule neurons (GCNs). We find that ATF5 is expressed by proliferating CGNPs in both the embryonic and post-natal cerebellar external granule layer (EGL) and in the rhombic lip, the embryonic structure from which the EGL arises. In contrast, ATF5 is undetectable in post-mitotic GCNs. In highly enriched dissociated cultures of CGNPs and CGNs, ATF5 is expressed only in CGNPs. Constitutive ATF5 expression in CGNPs does not affect their proliferation or exit from the cell cycle. In contrast, in presence of sonic hedgehog (Shh), a mitogen for CGNPs, constitutively expressed ATF5 promotes CGNP proliferation and delays their cell cycle exit and differentiation. Conversely, ATF5 loss-of-function conferred by a dominant-negative form of ATF5, significantly diminishes Shh-stimulated CGNP proliferation and promotes differentiation. In parallel with its stimulation of CGNP proliferation, Shh enhances ATF5 expression by what appeared to be a post-transcriptional mechanism involving protein stabilization. These findings indicate a reciprocal interaction between ATF5 and Shh in which Shh stimulates ATF5 expression and in which ATF5 contributes to Shh-stimulated CGNP expansion.
doi:10.1002/dneu.20979
PMCID: PMC3857133  PMID: 22095825
ATF5; sonic hedgehog (Shh); cerebellum; cerebellar granule neuron progenitor cells; cerebellar granule neurons; external granule layer (EGL)
13.  C. elegans dystroglycan coordinates responsiveness of follower axons to dorsal/ventral and anterior/posterior guidance cues 
Developmental neurobiology  2012;72(12):1498-1515.
Neural development in metazoans is characterized by the establishment of initial process tracts by pioneer axons and the subsequent extension of follower axons along these pioneer processes. Mechanisms governing the fidelity of follower extension along pioneered routes are largely unknown. In C. elegans, formation of the right angle-shaped lumbar commissure connecting the lumbar and preanal ganglia is an example of pioneer/follower dynamics. We find that the dystroglycan ortholog DGN-1 mediates the fidelity of follower lumbar commissure axon extension along the pioneer axon route. In dgn-1 mutants, the axon of the pioneer PVQ neuron faithfully establishes the lumbar commissure, but axons of follower lumbar neurons, such as PVC, frequently bypass the lumbar commissure and extend along an oblique trajectory directly toward the preanal ganglion. In contrast, disruption of the UNC-6/netrin guidance pathway principally perturbs PVQ ventral guidance to pioneer the lumbar commissure. Loss of DGN-1 in unc-6 mutants has a quantitatively similar effect on follower axon guidance regardless of PVQ axon route, indicating that DGN-1 does not mediate follower/pioneer adhesion. Instead, DGN-1 appears to block premature responsiveness of follower axons to a preanal ganglion-directed guidance cue which mediates ventral-to-anterior reorientation of lumbar commissure axons. Deletion analysis shows that only the most N-terminal DGN-1 domain is required for these activities. These studies suggest that dystroglycan modulation of growth cone responsiveness to conflicting guidance cues is important for restricting follower axon extension to the tracts laid down by pioneers.
doi:10.1002/dneu.22011
PMCID: PMC3507465  PMID: 22275151
14.  Sleep contributes to dendritic spine formation and elimination in the developing mouse somatosensory cortex 
Developmental neurobiology  2012;72(11):1391-1398.
Sleep is maximal during early postnatal life when rapid and extensive synapse remodeling occurs. It remains unknown whether and how sleep affects synapse development and plasticity. Using transcranial two-photon microscopy, we examined the formation and elimination of fluorescently-labeled dendritic spines and filopodia of layer 5 pyramidal neurons in the barrel cortex of 3-week old mice during wakefulness and sleep. We observed high turnover of dendritic protrusions over 2 hours in both wake and sleep states. The formation rate of dendritic spines or filopodia over 2 hours was comparable between the two states. The elimination rate of dendritic spines or filopodia was lower during 2-hour wakefulness than during 2-hour sleep. Similar results were observed on dendritic protrusion dynamics over 12-hour light/dark cycle when mice spent more time asleep or awake. The substantial remodeling of dendritic protrusions during the sleep state supports the notion that sleep plays an important role in the development and plasticity of synaptic connections in the mouse cortex.
doi:10.1002/dneu.20996
PMCID: PMC3404222  PMID: 22058046
Sleep; two-photon imaging; dendritic spine; filopodia
15.  Changes in Notch signaling coordinates maintenance and differentiation of the Drosophila larval optic lobe neuroepithelia 
Developmental neurobiology  2012;72(11):1376-1390.
A dynamic balance between stem cell maintenance and differentiation paces generation of post-mitotic progeny during normal development and maintenance of homeostasis. Recent studies show that Notch plays a key role in regulating the identity of neuroepithelial stem cells, which generate terminally differentiated neurons that populate the adult optic lobe via the intermediate progenitor cell type called neuroblast. Thus, understanding how Notch controls neuroepithelial cell maintenance and neuroblast formation will provide critical insight into the intricate regulation of stem cell function during tissue morphogenesis. Here, we showed that a low level of Notch signaling functions to maintain the neuroepithelial cell identity by suppressing the expression of pointedP1 gene through the transcriptional repressor Anterior open. Increased Notch signaling, which coincides with transient cell cycle arrest but precedes the expression of PointedP1 in cells near the medial edge of neuroepithelia, defines transitioning neuroepithelial cells that are in the process of acquiring the neuroblast identity. Transient up-regulation of Notch signaling in transitioning neuroepithelial cells decreases their sensitivity to PointedP1 and prevents them from becoming converted into neuroblasts prematurely. Down-regulation of Notch signaling combined with a high level of PointedP1 trigger a synchronous conversion from transitioning neuroepithelial cells to immature neuroblasts at the medial edge of neuroepithelia. Thus, changes in Notch signaling orchestrate a dynamic balance between maintenance and conversion of neuroepithelial cells during optic lobe neurogenesis.
doi:10.1002/dneu.20995
PMCID: PMC3407541  PMID: 22038743
16.  Immune system gene dysregulation in autism & schizophrenia 
Developmental neurobiology  2012;72(10):1277-1287.
Gene*environment interactions play critical roles in the emergence of autism and schizophrenia pathophysiology. In both disorders, recent genetic association studies have provided evidence for disease-linked variation in immune system genes and post-mortem gene expression studies have shown extensive chronic immune abnormalities in brains of diseased subjects. Furthermore, peripheral biomarker studies revealed that both innate and adaptive immune systems are dysregulated. In both disorders symptoms of the disease correlate with the immune system dysfunction; yet, in autism this process appears to be chronic and sustained, while in schizophrenia it is exacerbated during acute episodes. Furthermore, since immune abnormalities endure into adulthood and anti-inflammatory agents appear to be beneficial, it is likely that these immune changes actively contribute to disease symptoms. Modeling these changes in animals provided further evidence that prenatal maternal immune activation alters neurodevelopment and leads to behavioral changes that are relevant for autism and schizophrenia. The converging evidence strongly argues that neurodevelopmental immune insults and genetic background critically interact and result in increased risk for either autism or schizophrenia. Further research in these areas may improve prenatal health screening in genetically at-risk families and may also lead to new preventive and/or therapeutic strategies.
doi:10.1002/dneu.22044
PMCID: PMC3435446  PMID: 22753382
schizophrenia; autism; immune; environment; maternal immune activation
17.  Epidemiologic studies of exposure to prenatal infection and risk of schizophrenia and autism 
Developmental neurobiology  2012;72(10):1272-1276.
In this review, we provide a synopsis of work on the epidemiologic evidence for prenatal infection in the etiology of schizophrenia and autism. In birth cohort studies conducted by our group and others, in utero exposure to infectious agents, prospectively obtained following biomarker assays of archived maternal sera and by obstetric records was related to an elevated risk of schizophrenia. Thus far, it has been demonstrated that prenatal exposure to influenza, elevated toxoplasma antibody, genital/reproductive infections, rubella, and other pathogens are associated with schizophrenia. Anomalies of the immune system, including enhanced maternal cytokine levels are also related to schizophrenia. Some evidence also suggests that maternal infection and immune dysfunction may be associated with autism. Although replication is required, these findings suggest that public health interventions targeting infectious exposures have the potential for preventing cases of schizophrenia and autism. Moreover, this work has stimulated translational research on the neurobiological and genetic determinants of these conditions.
doi:10.1002/dneu.22024
PMCID: PMC3435457  PMID: 22488761
schizophrenia; infection; influenza; epidemiology; toxoplasmosis; birth cohort
18.  NEUROIMMUNE MECHANISMS IN FETAL ALCOHOL SPECTRUM DISORDER 
Developmental neurobiology  2012;72(10):1302-1316.
Fetal alcohol spectrum disorder (FASD) is a major health concern worldwide and results from maternal consumption of alcohol during pregnancy. It produces tremendous individual, social, and economic losses. This review will first summarize the structural, functional and behavior changes seen in FASD. The development of the neuroimmune system will be then be described with particular emphasis on the role of microglial cells in the normal regulation of homeostatic function in the central nervous system (CNS) including synaptic transmission. The impact of alcohol on the neuroimmune system in the developing CNS will be discussed in the context of several key immune molecules and signaling pathways involved in neuroimmune mechanisms that contribute to FASD. This review concludes with a summary of the development of early therapeutic approaches utilizing immunosuppressive drugs to target alcohol-induced pathologies. The significant role played by neuroimmune mechanisms in alcohol addiction and pathology provides a focus for future research aimed at understanding and treating the consequences of FASD.
doi:10.1002/dneu.22035
PMCID: PMC3435481  PMID: 22623427
Microglia; CNS development; Fetal alcohol syndrome; Fetal alcohol spectrum disorders; Toll-like receptor
19.  Maternal and Fetal Anti-brain Antibodies in Development and Disease 
Developmental neurobiology  2012;72(10):1327-1334.
Recent evidence has emerged indicating that the maternal immune response can have a substantial deleterious impact on prenatal development (Croen et al., 2008). The maternal immune response is largely sequestered from the fetus. Maternal antibodies, specifically immunoglobulin G (IgG), are passed to the fetus to provide passive immunity throughout much of pregnancy. However, both protective and pathogenic autoantibodies have equal access to the fetus (Goines and Van de Water, 2010). If the mother has an underlying autoimmune disease or has reactivity to fetal antigens, autoantibodies produced before or during pregnancy can target tissues in the developing fetus. One such tissue is the fetal brain. The blood brain barrier (BBB) is developing during the fetal period allowing maternal antibodies to have direct access to the brain during gestation (Diamond et al., 2009; Braunschweig et al., 2011). It has been proposed that brain injury by circulating brain–specific maternal autoantibodies might underlie multiple congenital, developmental disorders (Lee et al., 2009). In this review, we will discuss the current state of research in the area of maternal autoantibodies and the development of autism.
doi:10.1002/dneu.22052
PMCID: PMC3478666  PMID: 22911883
20.  Protocadherin-17 Function in Zebrafish Retinal Development 
Developmental neurobiology  2013;73(4):259-273.
Cadherin cell adhesion molecules play crucial roles in vertebrate development including the development of the retina. Most studies have focused on examining functions of classic cadherins (e.g. N-cadherin) in retinal development. There is little information on the function of protocadherins in the development of the vertebrate visual system. We previously showed that protocadherin-17 mRNA was expressed in developing zebrafish retina during critical stages of the retinal development. To gain insight into protocadherin-17 function in the formation of the retina, we analyzed eye development and differentiation of retinal cells in zebrafish embryos injected with protocadherin-17 specific antisense morpholino oligonucleotides (MOs). Protocadherin-17 knockdown embryos (pcdh17 morphants) had significantly reduced eyes due mainly to decreased cell proliferation. Differentiation of several retinal cell types (e.g. retinal ganglion cells) was also disrupted in the pcdh17 morphants. Phenotypic rescue was achieved by injection of protocadherin-17 mRNA. Injection of a vivo-protocadherin-17 MO into one eye of embryonic zebrafish resulted in similar eye defects. Our results suggest that protocadherin-17 plays an important role in the normal formation of the zebrafish retina.
doi:10.1002/dneu.22053
PMCID: PMC3579003  PMID: 22927092
cell adhesion molecules; eye; retinal cells differentiation; optic nerve
21.  The Dynamic Role of Bone Morphogenetic Proteins in Neural Stem Cell Fate and Maturation 
Developmental neurobiology  2012;72(7):1068-1084.
The bone morphogenetic proteins (BMPs) are a group of powerful morphogens that are critical for development of the nervous system. The effects of BMP signaling on neural stem cells are myriad and dynamic, changing with each stage of development. During early development inhibition of BMP signaling differentiates neuroectoderm from ectoderm, and BMP signaling helps to specify neural crest. Thus modulation of BMP signaling underlies formation of both the central and peripheral nervous systems. BMPs secreted from dorsal structures then form a gradient which helps pattern the dorsal–ventral axis of the developing spinal cord and brain. During forebrain development BMPs sequentially induce neurogenesis and then astrogliogenesis and participate in neurite outgrowth from immature neurons. BMP signaling also plays a critical role in maintaining adult neural stem cell niches in the subventricular zone (SVZ) and subgranular zone (SGZ). BMPs are able to exert such diverse effects through closely regulated temporospatial expression and interaction with other signaling pathways.
doi:10.1002/dneu.22022
PMCID: PMC3773925  PMID: 22489086
BMP; neural stem cells; patterning; neurogenesis; gliogenesis
22.  Primary cilia and Gli3 activity regulate cerebral cortical size 
Developmental neurobiology  2012;72(9):1196-1212.
During neural development, patterning, neurogenesis and overall growth are highly regulated and coordinated between different brain regions. Here, we show that primary cilia and the regulation of Gli activity, are necessary for the normal expansion of the cerebral cortex. We show that loss of Kif3a, an important functional component of primary cilia, leads to the degeneration of primary cilia, marked overgrowth of the cortex, and altered cell cycle kinetics within cortical progenitors. The G1 phase of the cell cycle is shortened through a mechanism likely involving reduced Gli3 activity and a resulting increase in expression of cyclin D1 and Fgf15. The defects in Gli3 activity alone are sufficient to accelerate cell cycle kinetics and cause the molecular changes seen in brains that lack cilia. Finally, we show that levels of full-length and repressor Gli3 proteins are tightly regulated during normal development and correlate with changes in expression of two known Shh-target genes, CyclinD1 and Fgf15, and with the normal lengthening of the cell cycle during corticogenesis. These data suggest that Gli3 activity is regulated through the primary cilium to control cell cycle length in the cortex and thus determine cortical size.
doi:10.1002/dneu.20985
PMCID: PMC3350755  PMID: 21976438
Kif3a; cilia; Gli3; proliferation; cell cycle
23.  EphB signaling regulates target innervation in the developing and deafferented auditory brainstem 
Developmental neurobiology  2012;72(9):1243-1255.
Precision in auditory brainstem connectivity underlies sound localization. Cochlear activity is transmitted to the ventral cochlear nucleus (VCN) in the mammalian brainstem via the auditory nerve. VCN globular bushy cells project to the contralateral medial nucleus of the trapezoid body (MNTB), where specialized axons terminals, the calyces of Held, encapsulate MNTB principal neurons. The VCN-MNTB pathway is an essential component of the circuitry used to compute interaural intensity differences that are used for localizing sounds. When input from one ear is removed during early postnatal development, auditory brainstem circuitry displays robust anatomical plasticity. The molecular mechanisms that control the development of auditory brainstem circuitry and the developmental plasticity of these pathways are poorly understood. In this study we examined the role of EphB signaling in the development of the VCN-MNTB projection and in the reorganization of this pathway after unilateral deafferentation. We found that EphB2 and EphB3 reverse signaling are critical for the normal development of the projection from VCN to MNTB, but that successful circuit assembly most likely relies upon the coordinated function of many EphB proteins. We have also found that ephrin-B reverse signaling repels induced projections to the ipsilateral MNTB after unilateral deafferentation, suggesting that similar mechanisms regulate these two processes.
doi:10.1002/dneu.20990
PMCID: PMC3418463  PMID: 22021100
EphB; ephrin-B; VCN; MNTB; deafferentation
24.  Hindered submicron mobility and long-term storage of presynaptic dense-core granules revealed by single-particle tracking 
Developmental neurobiology  2012;72(9):1181-1195.
Dense-core granules (DCGs) are organelles found in neuroendocrine cells and neurons that house, transport, and release a number of important peptides and proteins. In neurons, DCG cargo can include the secreted neuromodulatory proteins tissue plasminogen activator (tPA) and/or brain-derived neurotrophic factor (BDNF), which play a key role in modulating synaptic efficacy in the hippocampus. This function has spurred interest in DCGs that localize to synaptic contacts between hippocampal neurons, and several studies recently have established that DCGs localize to, and undergo regulated exocytosis from, postsynaptic sites. To complement this work, we have studied presynaptically-localized DCGs in hippocampal neurons, which are much more poorly understood than their postsynaptic analogs. Moreover, to enhance relevance, we visualized DCGs via fluorescence labeling of exogenous and endogenous tPA and BDNF. Using single-particle tracking, we determined trajectories of more than 150 presynaptically-localized DCGs. These trajectories reveal that mobility of DCGs in presynaptic boutons is highly hindered and that storage is long-lived. We also computed mean-squared displacement curves, which can be used to elucidate mechanisms of transport. Over shorter time windows, most curves are linear, demonstrating that DCG transport in boutons is driven predominantly by diffusion. The remaining curves plateau with time, consistent with motion constrained by a submicron-sized corral. These results have relevance to recent models of presynaptic organization and to recent hypotheses about DCG cargo function. The results also provide estimates for transit times to the presynaptic plasma membrane that are consistent with measured times for onset of neurotrophin release from synaptically-localized DCGs.
doi:10.1002/dneu.20984
PMCID: PMC3512567  PMID: 21976424
Dense-core granule; presynaptic; transport; neuromodulator; hippocampus
25.  Members of the BMP, Shh and FGF morphogen families promote chicken statoacoustic ganglion neurite outgrowth and neuron survival in vitro 
Developmental neurobiology  2012;72(9):1213-1228.
Mechanosensory hair cells of the chicken inner ear are innervated by the peripheral processes of statoacoustic ganglion (SAG) neurons. Members of several morphogen families are expressed within and surrounding the chick inner ear during stages of SAG axon outgrowth and pathfinding. Based on their localized expression patterns, we hypothesized that BMPs, FGFs and Shh may function as guidance cues for growing axons and/or may function as trophic factors once axons have reached their targets. To test this hypothesis, three-dimensional collagen cultures were used to grow embryonic day 4 (E4) chick SAG explants for 24 hours in the presence of purified proteins or beads soaked in proteins. The density of neurite outgrowth was quantified to determine effects on neurite outgrowth. Explants displayed enhanced neurite outgrowth when cultured in the presence of purified BMP4, BMP7, a low concentration of Shh, FGF8, FGF10, or FGF19. In contrast, SAG neurons appeared unresponsive to FGF2. Collagen gel cultures were labeled with TUNEL and immunostained with anti-phospho-histone H3 to determine effects on neuron survival and proliferation, respectively. Treatments that increased neurite outgrowth also yielded significantly fewer apoptotic cells, with no effect on cell proliferation. When presented as focal sources, BMP4, Shh, and FGFs -8, -10, and -19 promoted asymmetric outgrowth from the ganglion in the direction of the beads. BMP7-soaked beads did not induce this response. These results suggest that a subset of morphogens enhance both survival and axon outgrowth of otic neurons.
doi:10.1002/dneu.20988
PMCID: PMC3582322  PMID: 22006861
BMP; FGF; inner ear; neurotrophic; Shh

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