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1.  [No title available] 
PMCID: PMC3883807  PMID: 23536326
2.  Increasing our understanding of human cognition through the study of Fragile X Syndrome 
Developmental neurobiology  2013;74(2):147-177.
Fragile-X Syndrome (FXS) is considered the most common form of inherited intellectual disability. It is caused by reductions in the expression level or function of a single protein, the Fragile-X Mental Retardation Protein (FMRP), a translational regulator which binds to approximately 4% of brain messenger RNAs. Accumulating evidence suggests that FXS is a complex disorder of cognition, involving interactions between genetic and environmental influences, leading to difficulties in acquiring key life skills including motor skills, language and proper social behaviors. Since many FXS patients also present with one or more features of autism spectrum disorders (ASDs), insights gained from studying the monogenic basis of FXS could pave the way to a greater understanding of underlying features of multigenic ASDs. Here we present an overview of the FXS and FMRP field with the goal of demonstrating how loss of a single protein involved in translational control affects multiple stages of brain development and leads to debilitating consequences on human cognition. We also focus on studies which have rescued or improved FXS symptoms in mice using genetic or therapeutic approaches to reduce protein expression. We end with a brief description of how deficits in translational control are implicated in FXS and certain cases of ASDs, with many recent studies demonstrating that ASDs are likely caused by increases or decreases in the levels of certain key synaptic proteins. The study of FXS and its underlying single genetic cause offers an invaluable opportunity to study how a single gene influences brain development and behavior.
doi:10.1002/dneu.22096
PMCID: PMC4216185  PMID: 23723176
Fragile X Syndrome; cognition; FMRP; synapses; connectivity; local protein synthesis; plasticity; FXR1P; FXR2P
3.  Distinct roles of Drosophila cacophony and Dmca1D Ca2+ channels in synaptic homeostasis: Genetic interactions with slowpoke Ca2+-activated BK channels in presynaptic excitability and postsynaptic response 
Developmental neurobiology  2013;74(1):10.1002/dneu.22120.
Ca2+ influx through voltage-activated Ca2+ channels and its feedback regulation by Ca2+-activated K+ (BK) channels is critical in Ca2+-dependent cellular processes, including synaptic transmission, growth and homeostasis. Here we report differential roles of cacophony (CaV2) and Dmca1D (CaV1) Ca2+ channels in synaptic transmission and in synaptic homeostatic regulations induced by slowpoke (slo) BK channel mutations. At Drosophila larval neuromuscular junctions (NMJs), a well-established homeostatic mechanism of transmitter release enhancement is triggered by experimentally suppressing postsynaptic receptor response. In contrast, a distinct homeostatic adjustment is induced by slo mutations. To compensate for the loss of BK channel control presynaptic Sh K+ current is upregulated to suppress transmitter release, coupled with a reduction in quantal size. We demonstrate contrasting effects of cac and Dmca1D channels in decreasing transmitter release and muscle excitability, respectively, consistent with their predominant pre- vs. post-synaptic localization. Antibody staining indicated reduced postsynaptic GluRII receptor subunit density and altered ratio of GluRII A and B subunits in slo NMJs, leading to quantal size reduction. Such slo-triggered modifications were suppressed in cac;;slo larvae, correlated with a quantal size reversion to normal in double mutants, indicating a role of cac Ca2+ channels in slo-triggered homeostatic processes. In Dmca1D;slo double mutants, the quantal size and quantal content were not drastically different from those of slo, although Dmca1D suppressed the slo-induced satellite bouton overgrowth. Taken together, cac and Dmca1D Ca2+ channels differentially contribute to functional and structural aspects of slo-induced synaptic modifications.
doi:10.1002/dneu.22120
PMCID: PMC3859705  PMID: 23959639
Synaptic transmission; cacophony (CaV2); Dmca1D (CaV1); slowpoke (BK); synaptic homeostasis; EJPs; mEJPs; spontaneous vesicle release; larval neuromuscular junction (NMJ)
4.  Shifts in the Vascular endothelial growth factor (Vegf) isoforms result in transcriptome changes correlated with early neural stem cell proliferation and differentiation in mouse forebrain 
Developmental neurobiology  2013;74(1):63-81.
Regulation of neural stem cell (NSC) fate decisions is critical during the transition from a multicellular mammalian forebrain neuroepithelium to the multi-layered neocortex. Forebrain development requires coordinated vascular investment alongside NSC differentiation. Vascular endothelial growth factor A (Vegf) has proven to be a pleiotrophic gene whose multiple protein isoforms regulate a broad range of effects in neurovascular systems. To test the hypothesis that the Vegf isoforms (120, 164, and 188) are required for normal forebrain development, we analyzed the forebrain transcriptome of mice expressing specific Vegf isoforms, Vegf120, VegfF188, or a combination of Vegf120/188. Transcriptome analysis identified differentially expressed genes in embryonic day (E) 9.5 forebrain, a time point preceding dramatic neuroepithelial expansion and vascular investment in the telencephalon. Meta-analysis identified gene pathways linked to chromosome-level modifications, cell fate regulation, and neurogenesis that were altered in Vegf isoform mice. Based on these gene network shifts, we predicted that NSC populations would be affected in later stages of forebrain development. In the E11.5 telencephalon, we quantified mitotic cells [Phospho-Histone H3 (pHH3)-positive] and intermediate progenitor cells (Tbr2/Eomes-positive), observing quantitative and qualitative shifts in these populations. We observed qualitative shifts in cortical layering at P0, particularly with Ctip2-positive cells in layer V. The results identify a suite of genes and functional gene networks that can be used to further dissect the role of Vegf in regulating NSC differentiation and downstream consequences for NSC fate decisions.
doi:10.1002/dneu.22130
PMCID: PMC4096862  PMID: 24124161
neural development; forebrain; VEGF; Pax6; Tbr2; neurogenesis
5.  Castration-Induced Upregulation of Muscle ERα Supports Estrogen Sensitivity of Motoneuron Dendrites in a Sexually Dimorphic Neuromuscular System 
Developmental neurobiology  2013;73(12):10.1002/dneu.22118.
The spinal cord of rats contains the sexually dimorphic motoneurons of the spinal nucleus of the bulbocavernosus (SNB). In males, SNB dendrites fail to grow after castration, but androgen or estrogen treatment supports dendritic growth in castrated males. Estrogenic support of SNB dendrite growth is mediated by estrogen receptors (ER) in the target muscle. ERα expression in cells lacking a basal lamina (referred to as “extra-muscle fiber cells”) of the SNB target musculature coincides with the period of estrogen-dependent SNB dendrite growth. In the SNB target muscle, extra-muscle fiber ERα expression declines with age and is typically absent after postnatal (P) day 21 (P21). Given that estradiol downregulates ERα in skeletal muscle, we tested the hypothesis that depleting gonadal hormones would prevent the postnatal decline in ERα expression in the SNB target musculature. We castrated male rats at P7 and assessed ERα immunolabeling at P21; ERα expression was significantly greater in castrated males compared with normal animals. Because ERα expression in SNB target muscles mediates estrogen-dependent SNB dendrogenesis, we further hypothesized that the castration-induced increase in muscle ERα would heighten the estrogen sensitivity of SNB dendrites. Male rats were castrated at P7 and treated with estradiol from P21 to P28; estradiol treatment in castrates resulted in dendritic hypertrophy in SNB motoneurons compared with normal males. We conclude that early castration results in an increase in ERα expression in the SNB target muscle, and this upregulation of ERα supports estrogen sensitivity of SNB dendrites, allowing for hypermasculinization of SNB dendritic arbors.
doi:10.1002/dneu.22118
PMCID: PMC3828751  PMID: 23939785
gonadal hormones; motoneurons; dendrites; spinal cord; rat
6.  Neural stem cell apoptosis after low methylmercury (MeHg) exposures in postnatal hippocampus produce persistent cell loss and adolescent memory deficits 
Developmental neurobiology  2013;73(12):10.1002/dneu.22119.
The developing brain is particularly sensitive to exposures to environmental contaminants. In contrast to the adult, the developing brain contains large numbers of dividing neuronal precursors, suggesting that they may be vulnerable targets. The postnatal day 7 (P7) rat hippocampus has populations of both mature neurons in the CA1-3 region as well as neural stem cells (NSC) in the dentate gyrus (DG) hilus, that actively produce new neurons that migrate to the granule cell layer (GCL). Using this well-characterized NSC population, we examined the impact of low levels of MeHg on proliferation, neurogenesis, and subsequent adolescent learning and memory behavior. Assessing a range of exposures, we found that a single subcutaneous injection of 0.6μg/g MeHg in P7 rats induced caspase activation in proliferating NSC of the hilus and GCL. This acute NSC death had lasting impact on the DG at P21, reducing cell numbers in the hilus by 22% and the GCL by 27%, as well as reductions in neural precursor proliferation by 25%. In contrast, non-proliferative CA1-3 pyramidal neuron cell number was unchanged. Furthermore, animals exposed to P7 MeHg exhibited an adolescent spatial memory deficit as assessed by Morris water maze. These results suggest that environmentally relevant levels of MeHg exposure may decrease NSC populations and, despite ongoing neurogenesis, the brain may not restore the hippocampal cell deficits, which may contribute to hippocampal-dependent memory deficits during adolescence.
doi:10.1002/dneu.22119
PMCID: PMC3874131  PMID: 23959606
Neural stem cell; apoptosis; methylmercury; hippocampus; development
7.  Visual Circuit Assembly in Drosophila 
Developmental neurobiology  2011;71(12):1286-1296.
Both insect and vertebrate visual circuits are organized into orderly arrays of columnar and layered synaptic units that correspond to the array of photoreceptors in the eye. Recent genetic studies in Drosophila have yielded insights into the molecular and cellular mechanisms that pattern the layers and columns and establish specific connections within the synaptic units. A sequence of inductive events and complex cellular interactions coordinates the assembly of visual circuits. Photoreceptor-derived ligands, such as hedgehog and Jelly-Belly, induce target development and expression of specific adhesion molecules, which in turn serve as guidance cues for photoreceptor axons. Afferents are directed to specific layers by adhesive afferent-target interactions mediated by leucine-rich repeat proteins and cadherins, which are restricted spatially and/or modulated dynamically. Afferents are restricted to their topographically appropriate columns by repulsive interactions between afferents and by autocrine Activin signalling. Finally, Dscam-mediated repulsive interactions between target neuron dendrites ensure appropriate combinations of post-synaptic elements at synapses. Essentially all of these Drosophila molecules have vertebrate homologs, some of which are known to carry out analogous functions. Thus, the studies of Drosophila visual circuit development would shed light on neural circuit assembly in general.
doi:10.1002/dneu.20894
PMCID: PMC4245071  PMID: 21538922
8.  Postsynaptic Assembly: A Role for Wnt Signaling 
Developmental Neurobiology  2013;74(8):818-827.
Synapse formation requires the coordinated formation of the presynaptic terminal, containing the machinery for neurotransmitter release, and the postsynaptic side that possesses the machinery for neurotransmitter reception. For coordinated pre- and postsynaptic assembly signals across the synapse are required. Wnt secreted proteins are well-known synaptogenic factors that promote the recruitment of presynaptic components in diverse organisms. However, recent studies demonstrate that Wnts act directly onto the postsynaptic side at both central and peripheral synapses to promote postsynaptic development and synaptic strength. This review focuses on the role of Wnts in postsynaptic development at central synapses and the neuromuscular junction. © 2013 The Authors. Developmental Neurobiology Published by Wiley Periodicals, Inc. Develop Neurobiol 74: 818–827, 2014
doi:10.1002/dneu.22138
PMCID: PMC4237178  PMID: 24105999
neuromuscular junction; excitatory and inhibitory synapse; dendritic spines; synaptic plasticity
9.  Axonal Protein Synthesis and the Regulation of Primary Afferent Function 
Developmental Neurobiology  2013;74(3):269-278.
Local protein synthesis has been demonstrated in the peripheral processes of sensory primary afferents and is thought to contribute to the maintenance of the neuron, to neuronal plasticity following injury and also to regeneration of the axon after damage to the nerve. The mammalian target of rapamycin (mTOR), a master regulator of protein synthesis, integrates a variety of cues that regulate cellular homeostasis and is thought to play a key role in coordinating the neuronal response to environmental challenges. Evidence suggests that activated mTOR is expressed by peripheral nerve fibers, principally by A-nociceptors that rapidly signal noxious stimulation to the central nervous system, but also by a subset of fibers that respond to cold and itch. Inhibition of mTOR complex 1 (mTORC1) has shown that while the acute response to noxious stimulation is unaffected, more complex aspects of pain processing including the setting up and maintenance of chronic pain states can be disrupted suggesting a route for the generation of new drugs for the control of chronic pain. Given the role of mTORC1 in cellular homeostasis, it seems that systemic changes in the physiological state of the body such as occur during illness are likely to modulate the sensitivity of peripheral sensory afferents through mTORC1 signaling pathways. © 2013 Wiley Periodicals, Inc. Develop Neurobiol 74: 269–278, 2014
doi:10.1002/dneu.22133
PMCID: PMC4237183  PMID: 24085547
local translation; the mammalian target of rapamycin complex 1 (mTORC1); pain; itch; nociceptors
10.  Progressive Effects of N-myc Deficiency on Proliferation, Neurogenesis, and Morphogenesis in the Olfactory Epithelium 
Developmental Neurobiology  2013;74(6):643-656.
N-myc belongs to the myc proto-oncogene family, which is involved in numerous cellular processes such as proliferation, growth, apoptosis, and differentiation. Conditional deletion of N-myc in the mouse nervous system disrupted brain development, indicating that N-myc plays an essential role during neural development. How the development of the olfactory epithelium and neurogenesis within are affected by the loss of N-myc has, however, not been determined. To address these issues, we examined an N-mycFoxg1Cre conditional mouse line, in which N-myc is depleted in the olfactory epithelium. First changes in N-myc mutants were detected at E11.5, with reduced proliferation and neurogenesis in a slightly smaller olfactory epithelium. The phenotype was more pronounced at E13.5, with a complete lack of Hes5-positive progenitor cells, decreased proliferation, and neurogenesis. In addition, stereological analyses revealed reduced cell size of post-mitotic neurons in the olfactory epithelium, which contributed to a smaller olfactory pit. Furthermore, we observed diminished proliferation and neurogenesis also in the vomeronasal organ, which likewise was reduced in size. In addition, the generation of gonadotropin-releasing hormone neurons was severely reduced in N-myc mutants. Thus, diminished neurogenesis and proliferation in combination with smaller neurons might explain the morphological defects in the N-myc depleted olfactory structures. Moreover, our results suggest an important role for N-myc in regulating ongoing neurogenesis, in part by maintaining the Hes5-positive progenitor pool. In summary, our results provide evidence that N-myc deficiency in the olfactory epithelium progressively diminishes proliferation and neurogenesis with negative consequences at structural and cellular levels. © 2013 The Authors. Developmental Neurobiology Published by Wiley Periodicals, Inc. Develop Neurobiol 74: 643–656, 2014
doi:10.1002/dneu.22162
PMCID: PMC4237195  PMID: 24376126
neurogenesis; N-myc; olfactory epithelium; vomeronasal organ; mouse
11.  Increasing our Understanding of Human Cognition Through the Study of Fragile X Syndrome 
Developmental Neurobiology  2013;74(2):147-177.
Fragile X Syndrome (FXS) is considered the most common form of inherited intellectual disability. It is caused by reductions in the expression level or function of a single protein, the Fragile X Mental Retardation Protein (FMRP), a translational regulator which binds to approximately 4% of brain messenger RNAs. Accumulating evidence suggests that FXS is a complex disorder of cognition, involving interactions between genetic and environmental influences, leading to difficulties in acquiring key life skills including motor skills, language, and proper social behaviors. Since many FXS patients also present with one or more features of autism spectrum disorders (ASDs), insights gained from studying the monogenic basis of FXS could pave the way to a greater understanding of underlying features of multigenic ASDs. Here we present an overview of the FXS and FMRP field with the goal of demonstrating how loss of a single protein involved in translational control affects multiple stages of brain development and leads to debilitating consequences on human cognition. We also focus on studies which have rescued or improved FXS symptoms in mice using genetic or therapeutic approaches to reduce protein expression. We end with a brief description of how deficits in translational control are implicated in FXS and certain cases of ASDs, with many recent studies demonstrating that ASDs are likely caused by increases or decreases in the levels of certain key synaptic proteins. The study of FXS and its underlying single genetic cause offers an invaluable opportunity to study how a single gene influences brain development and behavior. © 2013 The Authors. Developmental Neurobiology Published by Wiley Periodicals, Inc. Develop Neurobiol 74: 147–177, 2014
doi:10.1002/dneu.22096
PMCID: PMC4216185  PMID: 23723176
Fragile X Syndrome; cognition; FMRP; synapses; connectivity; local protein synthesis; plasticity; FXR1P; FXR2P
12.  Wnt5a Evokes Cortical Axon Outgrowth and Repulsive Guidance by Tau Mediated Reorganization of Dynamic Microtubules 
Developmental Neurobiology  2013;74(8):797-817.
Wnt5a guides cortical axons in vivo by repulsion and in vitro evokes cortical axon outgrowth and repulsion by calcium signaling pathways. Here we examined the role of microtubule (MT) reorganization and dynamics in mediating effects of Wnt5a. Inhibiting MT dynamics with nocodazole and taxol abolished Wnt5a evoked axon outgrowth and repulsion of cultured hamster cortical neurons. EGFP-EB3 labeled dynamic MTs visualized in live cell imaging revealed that growth cone MTs align with the nascent axon. Wnt5a increased axon outgrowth by reorganization of dynamic MTs from a splayed to a bundled array oriented in the direction of axon extension, and Wnt5a gradients induced asymmetric redistribution of dynamic MTs toward the far side of the growth cone. Wnt5a gradients also evoked calcium transients that were highest on the far side of the growth cone. Calcium signaling and the reorganization of dynamic MTs could be linked by tau, a MT associated protein that stabilizes MTs. Tau is phosphorylated at the Ser 262 MT binding site by CaMKII, and is required for Wnt5a induced axon outgrowth and repulsive turning. Phosphorylation of tau at Ser262 is known to detach tau from MTs to increase their dynamics. Using transfection with tau constructs mutated at Ser262, we found that this site is required for the growth and guidance effects of Wnt5a by mediating reorganization of dynamic MTs in cortical growth cones. Moreover, CaMKII inhibition also prevents MT reorganization required for Wnt5a induced axon outgrowth, thus linking Wnt/calcium signaling to tau mediated MT reorganization during growth cone behaviors.
doi:10.1002/dneu.22102
PMCID: PMC4087151  PMID: 23818454
Wnt5a; axon growth and guidance; microtubules; tau; calcium signaling
13.  CNP/cGMP Signaling Regulates Axon Branching and Growth by Modulating Microtubule Polymerization 
Developmental neurobiology  2013;73(9):673-687.
The peptide hormone CNP has recently been found to positively regulate axon branching and growth via activation of cGMP signaling in embryonic dorsal root ganglion (DRG) neurons, but the cellular mechanisms mediating the regulation of these developmental processes have not been established. In this study, we provide evidence linking CNP/cGMP signaling to microtubule dynamics via the microtubule regulator CRMP2. First, phosphorylation of CRMP2 can be suppressed by cGMP activation in embryonic DRG neurons, and non-phosphorylated CRMP2 promotes axon branching and growth. In addition, real time analysis of growing microtubule ends indicates a similar correlation of CRMP2 phosphorylation and its activity in promoting microtubule polymerization rates and durations in COS cells and DRG growth cones. Moreover, direct activation of cGMP signaling leads to increased assembly of dynamic microtubules in DRG growth cones. Finally, low doses of a microtubule depolymerization drug nocodazole block CNP/cGMP-dependent axon branching and growth. Taken together, our results support a critical role of microtubule dynamics in mediating CNP/cGMP regulation of axonal development.
doi:10.1002/dneu.22078
PMCID: PMC4229251  PMID: 23420620
axon branching and growth; microtubule dynamics; CNP/cGMP; DRG axons; CRMP2
14.  Cell Replacement Therapies for Nervous System Regeneration 
Developmental neurobiology  2012;72(2):145-152.
The adult brain was thought to be a slowly decaying organ, a sophisticated but flawed machine condemned to inevitable decline. Today we know that the brain is more plastic than previously assumed, as most prominently demonstrated by the constitutive birth of new neurons that occurs in selected regions of the adult brain, even in humans. However, the overall modest capacity for endogenous repair of the central nervous system (CNS) has sparked interest in understanding the barriers to neuronal regeneration and in developing novel approaches to enable neuronal and circuit repair for therapeutic benefit in neurodegenerative disorders and traumatic injuries. Scientists recently assembled in Baeza, a picturesque town in the south of Spain, to discuss aspects of CNS regeneration. The picture that emerged shows how an integrated view of developmental and adult neurogenesis may inform the manipulation of neural progenitors, differentiated cells, and pluripotent stem cells for therapeutic benefit and foster new understanding of the inner limits of brain plasticity.
doi:10.1002/dneu.20897
PMCID: PMC4226408  PMID: 21557508
neural stem cells; regeneration; adult neurogenesis
15.  Embryonic Origins of the Mouse Superior Olivary Complex 
Developmental neurobiology  2013;73(5):384-398.
Many areas of the central nervous system are organized into clusters of cell groups, with component cell groups exhibiting diverse but related functions. One such cluster, the superior olivary complex (SOC), is located in the ventral auditory brainstem in mammals. The SOC is an obligatory contact point for most projection neurons of the ventral cochlear nucleus and plays central roles in many aspects of monaural and binaural information processing. Despite their important interrelated functions, little is known about the embryonic origins of SOC nuclei, due in part to a paucity of developmental markers to distinguish individual cell groups. In this report, we present a collection of novel markers for the developing SOC nuclei in mice, including the transcription factors FoxP1, MafB, and Sox2, and the lineage-marking transgenic line En1-Cre. We use these definitive markers to examine the rhombic lip and rhombomeric origins of SOC nuclei and demonstrate that they can serve to uniquely identify SOC nuclei and subnuclei in newborn pups. The markers are also useful in identifying distinct nuclear domains within the presumptive SOC as early as embryonic day (E) 14.5, well before morphological distinction of individual nuclei is evident. These findings indicate that the mediolateral and dorsoventral position of SOC nuclei characteristic of the adult brainstem is established during early neurogenesis.
doi:10.1002/dneu.22069
PMCID: PMC4217651  PMID: 23303740
auditory brainstem; fate mapping; lineage; rhombomere; superior olivary complex
16.  Expression of Kv1.3 potassium channels regulates density of cortical interneurons 
Developmental neurobiology  2013;73(11):10.1002/dneu.22105.
The Kv1.3 protein is a member of the large family of voltage-dependent K+ subunits (Kv channels), which assemble to form tetrameric membrane-spanning channels that provide a selective pore for the conductance of K+ across the cell membrane. Kv1.3 differs from most other Kv channels in that deletion of Kv1.3 gene produces very striking changes in development and structure of the olfactory bulb, where Kv1.3 is expressed at high levels, resulting in a lower threshold for detection of odors, an increased number of synaptic glomeruli and alterations in the levels of a variety of neuronal signaling molecules. Because Kv1.3 is also expressed in the cerebral cortex, we have now examined the effects of deletion of the Kv1.3 gene on the expression of interneuron populations of the cerebral cortex. Using unbiased stereology we found an increase in the number of parvalbumin (PV) cells in whole cerebral cortex of Kv1.3−/− mice relative to that in wild type mice, and a decrease in the number of calbindin (CB), calretinin (CR), neuropeptide Y (NPY), vasoactive intestinal peptide (VIP) and somatostatin (SOM) interneurons. These changes are accompanied by a decrease in the cortical volume such that the cell density of PV interneurons is significantly increased and that of SOM neurons is decreased in Kv1.3−/− animals. Our studies suggest that, as in the olfactory bulb, Kv1.3 plays a unique role in neuronal differentiation and/or survival of interneuron populations and that expression of Kv1.3 is required for normal cortical function.
doi:10.1002/dneu.22105
PMCID: PMC3829632  PMID: 23821603
Potassium channels; Kv1.3; interneurons; cerebral cortex; CDP
17.  Rhythmic Cortical Neurons Increase their Oscillations and Sculpt Basal Ganglia Signaling During Motor Learning 
Developmental neurobiology  2013;73(10):754-768.
The function and modulation of neural circuits underlying motor skill may involve rhythmic oscillations (Feller, 1999; Marder and Goaillard, 2006; Churchland et al., 2012). In the proposed pattern generator for birdsong, the cortical nucleus HVC, the frequency and power of oscillatory bursting during singing increases with development (Crandall et al., 2007; Day et al., 2009). We examined the maturation of cellular activity patterns that underlie these changes. Single unit ensemble recording combined with antidromic identification (Day et al., 2011) was used to study network development in anesthetized zebra finches. Autocovariance quantified oscillations within single units. A subset of neurons oscillated in the theta/alpha/mu/beta range (8–20 Hz), with greater power in adults compared to juveniles. Across the network, the normalized oscillatory power in the 8–20 Hz range was greater in adults than juveniles. In addition, the correlated activity between rhythmic neuron pairs increased with development. We next examined the functional impact of the oscillators on the output neurons of HVC. We found that the firing of oscillatory neurons negatively correlated with the activity of cortico-basal ganglia neurons (HVCXs), which project to Area X (the song basal ganglia). If groups of oscillators work together to tonically inhibit and precisely control the spike timing of adult HVCXs with coordinated release from inhibition, then the activity of HVCXs in juveniles should be decreased relative to adults due to uncorrelated, tonic inhibition. Consistent with this hypothesis, HVCXs had lower activity in juveniles. These data reveal network changes that shape cortical-to-basal ganglia signaling during motor learning.
doi:10.1002/dneu.22098
PMCID: PMC4036633  PMID: 23776169
mu rhythm; oscillation; development; vocal learning; speech
18.  Programming and Reprogramming Neuronal Subtypes in the Central Nervous System 
Developmental neurobiology  2012;72(7):1085-1098.
Recent discoveries in nuclear reprogramming have challenged the dogma that the identity of terminally differentiated cells cannot be changed. The identification of molecular mechanisms that reprogram differentiated cells to a new identity carries profound implications for regenerative medicine across organ systems. The central nervous system (CNS) has historically been considered to be largely immutable. However, recent studies indicate that even the adult CNS is imparted with the potential to change under the appropriate stimuli. Here, we review current knowledge regarding the capability of distinct cells within the CNS to reprogram their identity and consider the role of developmental signals in directing these cell fate decisions. Finally, we discuss the progress and current challenges of using developmental signals to precisely direct the generation of individual neuronal subtypes in the postnatal CNS and in the dish.
doi:10.1002/dneu.22018
PMCID: PMC4123849  PMID: 22378700
directed differentiation; reprogramming; cellular replacement; corticospinal motor neurons
19.  Arachidonic acid closes innexin/pannexin channels and thereby inhibits microglia cell movement to a nerve injury 
Developmental neurobiology  2013;73(8):621-631.
Pannexons are membrane channels formed by pannexins and are permeable to ATP. They have been implicated in various physiological and pathophysiological processes. Innexins, the invertebrate homologues of the pannexins, form innexons. Nerve injury induces calcium waves in glial cells, releasing ATP through glial pannexon/innexon channels. The ATP then activates microglia. More slowly, injury releases arachidonic acid (ArA). The present experiments show that ArA itself reduced the macroscopic membrane currents of innexin- and of pannexin-injected oocytes; ArA also blocked K+-induced release of ATP. In leeches, whose large glial cells have been favorable for studying control of microglia migration, ArA blocked glial dye-release and, evidently, ATP-release. A physiological consequence in the leech was block of microglial migration to nerve injuries. Exogenous ATP (100 μM) reversed the effect, for ATP causes activation and movement of microglia after nerve injury, but nitric oxide directs microglia to the lesion. It was not excluded that metabolites of ArA may also inhibit the channels. But for all these effects, ArA and its non-metabolizable analogue eicosatetraynoic acid (ETYA) were indistinguishable. Therefore, ArA itself is an endogenous regulator of pannexons and innexons. ArA thus blocks release of ATP from glia after nerve injury and thereby, at least in leeches, stops microglia at lesions.
doi:10.1002/dneu.22088
PMCID: PMC3710304  PMID: 23650255
neuroglia; microglia; pannexin/innexin; adenosine triphosphate; nerve injury; arachidonic acid
20.  Androgen Action at the Target Musculature Regulates Brain-Derived Neurotrophic Factor Protein in the Spinal Nucleus of the Bulbocavernosus 
Developmental neurobiology  2013;73(8):587-598.
We have previously demonstrated that brain-derived neurotrophic factor (BDNF) interacts with testosterone to regulate dendritic morphology of motoneurons in the highly androgen-sensitive spinal nucleus of the bulbocavernosus (SNB). Additionally, in adult male rats testosterone regulates BDNF in SNB motoneurons and its target muscle, the bulbocavernosus (BC). Because BDNF is retrogradely transported from skeletal muscles to spinal motoneurons, we hypothesized that testosterone could regulate BDNF in SNB motoneurons by acting locally at the BC muscle. To test this hypothesis, we restricted androgen manipulation to the SNB target musculature. After castration, BDNF immunolabeling in SNB motoneurons was maintained at levels similar to those of gonadally intact males by delivering testosterone treatment directly to the BC muscle. When the same implant was placed interscapularly in castrated males it was ineffective in supporting BDNF immunolabeling in SNB motoneurons. Furthermore, BDNF immunolabeling in gonadally intact adult males given the androgen receptor blocker hydroxyflutamide delivered directly to the BC muscle was decreased compared with that of gonadally intact animals that had the same hydroxyflutamide implant placed interscapularly, or when compared with castrated animals that had testosterone implants at the muscle. These results demonstrate that the BC musculature is a critical site of action for the androgenic regulation of BDNF in SNB motoneurons and that it is both necessary and sufficient for this action. Furthermore, the local action of androgens at the BC muscle in regulating BDNF provides a possible mechanism underlying the interactive effects of testosterone and BDNF on motoneuron morphology.
doi:10.1002/dneu.22083
PMCID: PMC4030717  PMID: 23512738
neurotrophic factors; bulbocavernosus; testosterone; SNB
21.  Wnt5a Evokes Cortical Axon Outgrowth and Repulsive Guidance by Tau Mediated Reorganization of Dynamic Microtubules 
Developmental neurobiology  2013;74(8):797-817.
Wnt5a guides cortical axons in vivo by repulsion and in vitro evokes cortical axon outgrowth and repulsion by calcium signaling pathways. Here we examined the role of microtubule (MT) reorganization and dynamics in mediating effects of Wnt5a. Inhibiting MT dynamics with nocodazole and taxol abolished Wnt5a evoked axon outgrowth and repulsion of cultured hamster cortical neurons. EGFP-EB3 labeled dynamic MTs visualized in live cell imaging revealed that growth cone MTs align with the nascent axon. Wnt5a increased axon outgrowth by reorganization of dynamic MTs from a splayed to a bundled array oriented in the direction of axon extension, and Wnt5a gradients induced asymmetric redistribution of dynamic MTs toward the far side of the growth cone. Wnt5a gradients also evoked calcium transients that were highest on the far side of the growth cone. Calcium signaling and the reorganization of dynamic MTs could be linked by tau, a MT associated protein that stabilizes MTs. Tau is phosphorylated at the Ser 262 MT binding site by CaMKII, and is required for Wnt5a induced axon outgrowth and repulsive turning. Phosphorylation of tau at Ser262 is known to detach tau from MTs to increase their dynamics. Using transfection with tau constructs mutated at Ser262, we found that this site is required for the growth and guidance effects of Wnt5a by mediating reorganization of dynamic MTs in cortical growth cones. Moreover, CaMKII inhibition also prevents MT reorganization required for Wnt5a induced axon outgrowth, thus linking Wnt/calcium signaling to tau mediated MT reorganization during growth cone behaviors.
doi:10.1002/dneu.22102
PMCID: PMC4087151  PMID: 23818454
Wnt5a; axon growth and guidance; microtubules; tau; calcium signaling
22.  ARMS/Kidins220 regulates dendritic branching and spine stability in vivo 
Developmental neurobiology  2009;69(9):547-557.
The development of nervous system connectivity depends upon the arborization of dendritic fields and the stabilization of dendritic spine synapses. It is well established that neuronal activity and the neurotrophin BDNF modulate these correlated processes. However, the downstream mechanisms by which these extrinsic signals regulate dendritic development and spine stabilization are less well known. Here we report that a substrate of BDNF signaling, the Ankyrin Repeat-rich Membrane Spanning protein (ARMS) or Kidins220, plays a critical role in the branching of cortical and hippocampal dendrites and in the turnover of cortical spines. In the barrel somatosensory cortex and the dentate gyrus, regions where ARMS/Kidins220 is highly expressed, no difference in the complexity of dendritic arbors was observed in 1-month-old adolescent ARMS/Kidins220+/− mice compared to wild-type littermates. However, at 3 months of age, young adult ARMS/Kidins220+/− mice exhibited decreased dendritic complexity. This suggests that ARMS/Kidins220 does not play a significant role in the initial formation of dendrites but, rather, is involved in the refinement or stabilization of the arbors later in development. In addition, at 1 month of age the rate of spine elimination was higher in ARMS/Kidins220+/− mice than in wild-type mice, suggesting that adolescent ARMS/Kidins220+/− mice exhibit reduced spine stability. Taken together, these data suggest that ARMS/Kidins220 is important for the growth of dendritic arbors and spine stability during an activity- and BDNF-dependent period of development.
doi:10.1002/dneu.20723
PMCID: PMC4098644  PMID: 19449316
spines; dendritic arbors; barrel cortex; dentate gyrus
23.  Curiosity and Cure: Translational Research Strategies for Neural Repair-Mediated Rehabilitation 
Developmental neurobiology  2007;67(9):1133-1147.
Clinicians who seek interventions for neural repair in patients with paralysis and other impairments may extrapolate the results of cell culture and rodent experiments into the framework of a preclinical study. These experiments, however, must be interpreted within the context of the model and the highly constrained hypothesis and manipulation being tested. Rodent models of repair for stroke and spinal cord injury offer examples of potential pitfalls in the interpretation of results from developmental gene activation, transgenic mice, endogeneous neurogenesis, cellular transplantation, axon regeneration and remyelination, dendritic proliferation, activity-dependent adaptations, skills learning, and behavioral testing. Preclinical experiments that inform the design of human trials ideally include a lesion of etiology, volume and location that reflects the human disease; examine changes induced by injury and by repair procedures both near and remote from the lesion; distinguish between reactive molecular and histologic changes versus changes critical to repair cascades; employ explicit training paradigms for the reacquisition of testable skills; correlate morphologic and physiologic measures of repair with behavioral measures of task reacquisition; reproduce key results in more than one laboratory, in different strains or species of rodent, and in a larger mammal; and generalize the results across several disease models, such as axonal regeneration in a stroke and spinal cord injury platform. Collaborations between basic and clinical scientists in the development of translational animal models of injury and repair can propel experiments for ethical bench-to-bedside therapies to augment the rehabilitation of disabled patients.
doi:10.1002/dneu.20514
PMCID: PMC4099053  PMID: 17514711
rehabilitation; stroke; spinal cord injury; neural repair; animal models
24.  Correlation between Electrophysiological Properties, Morphological Maturation, and Olig Gene Changes during Postnatal Motor Tract Development 
Developmental neurobiology  2013;73(9):713-722.
Background
Functional maturation of the nervous system in postnatal (PN) animals is a progressive process that may be assessed using evoked potentials of the auditory, visual, or somatosensory systems. This study investigated electrophysiological and histological changes as well as alterations of myelin relevant proteins of descending motor tracts in rat pups. MEP responses were recorded bi-weekly from postnatal (PN) week-1 to week-9 (adult).
Results
MEP latencies in PN week-1 rats averaged 23.7 milliseconds and became shorter during early maturation, stabilizing at 6.6 milliseconds at PN week-4. During maturation there was a rapid increase in the conduction velocity (CV). The CV increased from 2.8 ± 0.2 at PN week-1 to 35.2 ± 3.1 mm/ms at PN week-8 which represented functional maturation. Histology of the spinal cord and sciatic nerves revealed progressive axonal myelination. Expression of the oligodendrocyte precursor markers PDGFRα and NG2 were gradually down-regulated in spinal cords, and myelin-relevant proteins such as GalC, CNP, and MBP were increased during maturation. Oligodendrocyte-lineage markers Olig2 and MOG, specifically expressed in myelinated oligodendrocytes, peaked at approximately PN week-3 and were down-regulated thereafter. A similar expression pattern was also observed in neurofilament M/H subunits (NF-M/H). Noticeably, NF-M/H was extensively phosphorylated in adult spinal cords but not in neonatal spinal cords, suggesting an increase in axon diameter and myelin formation. Ultra-structural morphology of axon and myelin sheaths in the ventrolateral funiculus (VLF) showed axon myelination of the VLF axons (99.3%) at PN week-2, while only 44.6% were sheathed at PN week-1. Furthermore, increased axon diameter and myelin thickness in both the VLF and sciatic nerves were highly correlated to the CV (rs>0.95).
Conclusions
Results from this study indicate that MEPs may be a predicator for the morphological maturity and integrity of myelinated axons in descending motor tracts.
doi:10.1002/dneu.22094
PMCID: PMC4058424  PMID: 23696057
Motor evoked potentials; Conduction velocity; Ventrolateral funiculus; Spinal cord; Sciatic nerve; Maturation
25.  Differential Effects of RET and TRKB on Axonal Branching and Survival of Parasympathetic Neurons 
Developmental neurobiology  2012;73(1):45-59.
Interactions between neurons and their targets of innervation influence many aspects of neural development. To examine how synaptic activity interacts with neurotrophic signaling, we determined the effects of blocking neuromuscular transmission on survival and axonal outgrowth of ciliary neurons from the embryonic chicken ciliary ganglion. Ciliary neurons undergo a period of cell loss due to programmed cell death between embryonic Days (E) 8 and 14 and they innervate the striated muscle of the iris. The nicotinic antagonist d-tubocurarine (dTC) induces an increase in branching measured by counting neurofilament-positive voxels (NF-VU) in the iris between E14–17 while reducing ciliary neuron survival. Blocking ganglionic transmission with dihyro-β-erythroidin and α-methyllycacontine does not mimic dTC. At E8, many trophic factors stimulate neurite outgrowth and branching of neurons placed in cell culture; however, at E13, only GDNF stimulates branching selectively in cultured ciliary neurons. The GDNF-induced branching at E13 could be inhibited by BDNF. Blocking ret signaling in vivo with a dominant negative (dn)ret decreases survival of ciliary and choroid neurons at E14 and prevents dTC induced increases in NF-VU in the iris at E17. Blocking TRKB signaling with dn TRKB increases NF-VU in the iris at E17 and decreases neuronal survival at E17, but not at E14. Thus, RET promotes survival during programmed cell death in the ciliary ganglion and contributes to promoting branching when synaptic transmission is blocked while TRKB inhibits branching and promotes maintenance of neuronal survival. These studies highlight the multifunctional nature of trophic molecule function during neuronal development.
doi:10.1002/dneu.22036
PMCID: PMC4037150  PMID: 22648743
GDNF; BDNF; d-tubocurarine; iris; ciliary

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