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ABSTRACT: Arginine-vasopressin (AVP) and the vasopressin V1a receptor (V1aR) acting within the forebrain are involved in social behavior in adult animals. Much less is known about the function of V1aR in neurobehavioral development. In the present study, at post-natal day 8 (P8) in neonatal C57BL/6J mice, we map V1aR and use an olfactory exposure paradigm to assess a role for V1aR on olfactory preferences. In addition to V1aR in the lateral septum and ventral tegmental area, we observe V1aR in the neocortex and hippocampus, not typically observed in adult mice, implicating a developmental sensitive period for V1aR to modulate these brain areas in an experience-dependent manner. Males and females were tested on P8 for orienting preferences after exposure to a non-social odor, presented either when the mother was in the home cage (contingent) or when the mother had been removed from the home cage (not contingent). Wild-type female mice show a selective orienting bias toward the exposed odor, but only in the contingent condition. Males did not show orienting bias after either training condition. Female Avpr1a(-/-) mice showed strong familiar odor bias, regardless of the training condition. This finding led us to test the ability of AVP to diminish odor bias in females. Central application of AVP eliminated odor bias in Avpr1a(+/+), but not Avpr1a(-/-) female mice. Together, these data indicate that AVP acting at V1aR eliminates the expression of familiar odor bias in neonatal mice. This suggests a developmental role for AVP on familiarity bias, which has implications for species-typical life history trajectories of social learning and natal dispersal.
Hormones and Behavior 12/2012; · 3.87 Impact Factor
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ABSTRACT: Corticothalamic (CT) feedback outnumbers thalamocortical projections, and regulates sensory information processing at the level of the thalamus. It is well established that EphA7, a member of EphA receptor family, is involved in the topographic mapping of CT projections. The aim of the present study is to dissect the precise impact of EphA7 on each step of CT growth. We used in utero electroporation-mediated EphA7 overexpression in developing somatosensory CT axons to dissect EphA7/ephrin-A-dependent mechanisms involved in regulating both initial targeting and postnatal growth of the CT projections. Our data revealed that topographic maps of cortical afferents in the ventrobasal complex and medial part of the posterior complex in the thalamus become discernible shortly after birth and are fully established by the second postnatal week. This process starts with the direct ingrowth of the CT axons to the designated areas within target thalamic nuclei and by progressive increase of axonal processes in the terminal zones. Large-scale overproduction and elimination of exuberant widespread axonal branches outside the target zone was not observed. Each developmental event was coordinated by spatially and temporally different responsiveness of CT axons to the ephrin-A gradient in thalamic nuclei, as well as by the matching levels of EphA7 in CT axons and ephrin-As in thalamic nuclei. These results support the concept that the topographic connections between the maps in the cerebral cortex and corresponding thalamic nuclei are genetically pre-specified to a large extent, and established by precise spatio-temporal molecular mechanisms that involve the Eph family of genes. J. Comp. Neurol., 2012. © 2012 Wiley Periodicals, Inc.
The Journal of Comparative Neurology 07/2012; · 3.81 Impact Factor
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ABSTRACT: Arginine-vasopressin (AVP) and the vasopressin 1a receptor (V1aR) modulate social behavior and learning and memory in adult animals. Both functions depend upon the normal emergence of the balance of excitation and inhibition (E/I balance) in the neocortex. Here, we tested the hypothesis that V1aR signaling and E/I balance converge through the influence of the neuropeptide on interneuron number achieved in the neocortex. Postnatal mapping of forebrain V1aR binding in male and female mice revealed a transient expression of high levels of receptor in the neocortex and hippocampus in the second and third post-natal weeks. Receptor binding levels in these cortical structures fell dramatically in the adult, maintaining high levels of expression subcortically. Surprisingly, we observed sex differences in the number of calbindin interneurons, and a contribution of V1aR to the number of parvalbumin-immunoreactive neurons in the adult mouse neocortex. These data suggest that individual differences in developmentally transient V1aR signaling and even sex may alter the development of E/I balance in the neocortex, with long-lasting influence on information processing.
Neuroscience 07/2012; 222:20-8. · 3.38 Impact Factor
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ABSTRACT: BackgroundIn an effort to identify genes that specify the mammalian forebrain, we used a comparative approach to identify mouse homologs
of transcription factors expressed in developing Caenorhabditis elegans GABAergic neurons. A cell-specific microarray profiling study revealed a set of transcription factors that are highly expressed
in embryonic C. elegans GABAergic neurons.
ResultsBioinformatic analyses identified mouse protein homologs of these selected transcripts and their expression pattern was mapped
in the mouse embryonic forebrain by in situ hybridization. A review of human homologs indicates several of these genes are potential candidates in neurodevelopmental
disorders.
ConclusionsOur comparative approach has revealed several novel candidates that may serve as future targets for studies of mammalian forebrain
development.
Neural Development 04/2012; 5(1):1-14. · 3.70 Impact Factor
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ABSTRACT: Auditory stimulus representations are dynamically maintained by ascending and descending projections linking the auditory cortex (Actx), medial geniculate body (MGB), and inferior colliculus. Although the extent and topographic specificity of descending auditory corticofugal projections can equal or surpass that of ascending corticopetal projections, little is known about the molecular mechanisms that guide their development. Here, we used in utero gene electroporation to examine the role of EphA receptor signaling in the development of corticothalamic (CT) and corticocollicular connections. Early in postnatal development, CT axons were restricted to a deep dorsal zone (DDZ) within the MGB that expressed low levels of the ephrin-A ligand. By hearing onset, CT axons had innervated surrounding regions of MGB in control-electroporated mice but remained fixed within the DDZ in mice overexpressing EphA7. In vivo neurophysiological recordings demonstrated a corresponding reduction in spontaneous firing rate, but no changes in sound-evoked responsiveness within MGB regions deprived of CT innervation. Structural and functional CT disruption occurred without gross alterations in thalamocortical connectivity. These data demonstrate a potential role for EphA/ephrin-A signaling in the initial guidance of corticofugal axons and suggest that "genetic rewiring" may represent a useful functional tool to alter cortical feedback without silencing Actx.
Cerebral Cortex 04/2012; · 6.54 Impact Factor
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ABSTRACT: Serotonin (5-hydroxytryptamine, 5-HT) signaling is thought to modulate nervous system development. Genetic and pharmacological studies support the idea that altered 5-HT signaling during development can have enduring consequences on brain function and behavior. Recently, we discovered that 5-HT can modulate thalamic axon guidance in vitro and in vivo. Embryonic thalamic axons transiently express the 5-HT transporter (SERT; Slc6a4) and accumulate 5-HT, suggesting that the SERT activity of these axons may regulate 5-HT-modulated guidance cues. We tested whether pharmacologically blocking SERT using selective 5-HT reuptake inhibitors (SSRIs) would impact the action of 5-HT on thalamic axon responses to netrin-1 in vitro. Surprisingly, we observed that two high-affinity SSRIs, racemic citalopram ((RS)-CIT) and paroxetine, affect the outgrowth of embryonic thalamic axons, but differ with respect to their dependence on SERT blockade. Using a recently developed 'citalopram insensitive' transgenic mouse line and in vitro pharmacology, we show that the effect of (RS)-CIT effect is SERT independent, but rather arises from R-CIT activation of the orphan sigma-1 receptor(σ1, Oprs1). Our results reveal a novel σ1 activity in modulating axon guidance and a 5-HT independent action of a widely prescribed SSRI. By extension, (RS)-CIT and possibly other structurally similar SSRIs may have other off-target actions that can impact neural development and contribute to therapeutic efficacy or side effects.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 03/2012; 37(8):1879-84. · 6.99 Impact Factor
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Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 01/2012; 37(1):299-300. · 6.99 Impact Factor
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ABSTRACT: Across the first year of life, infants achieve remarkable success in their ability to interact in the social world. The hierarchical nature of circuit and skill development predicts that the emergence of social behaviors may depend upon an infant's early abilities to detect contingencies, particularly socially-relevant associations. Here, we examined whether individual differences in the rate of associative learning at one month of age is an enduring predictor of social, imitative, and discriminative behaviors measured across the human infant's first year. One-month learning rate was predictive of social behaviors at 5, 9, and 12 months of age as well as face-evoked discriminative neural activity at 9 months of age. Learning was not related to general cognitive abilities. These results underscore the importance of early contingency learning and suggest the presence of a basic mechanism underlying the ontogeny of social behaviors.
PLoS ONE 01/2012; 7(1):e30511. · 4.09 Impact Factor
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ABSTRACT: Although infants display preferences for social stimuli early in their lives, we know relatively little about the mechanisms of infant learning about the social world. In the current set of studies, 1-month-old infants underwent an adapted eyeblink conditioning paradigm to examine learning to both 'social' and non-social cues. While infants were asleep, they were presented with either a 'social' stimulus (a female voice) or one of two non-social stimuli (tone or backward voice) followed by an airpuff presented to the eyelid. Infants in the experimental groups displayed increased learning across trials, regardless of stimulus type. However, infants conditioned to the 'social' stimulus showed increased learning compared to infants conditioned to either of the non-social stimuli. These results suggest a mechanism by which learning about the social world occurs early in life and the power of ecologically valid cues in facilitating that learning.
Developmental Science 09/2011; 14(5):1134-41. · 3.89 Impact Factor
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ABSTRACT: Autism spectrum disorder (ASD) is a highly heritable, behaviorally defined, heterogeneous disorder of unknown pathogenesis. Several genetic risk genes have been identified, including the gene encoding the receptor tyrosine kinase MET, which regulates neuronal differentiation and growth. An ASD-associated polymorphism disrupts MET gene transcription, and there are reduced levels of MET protein expression in the mature temporal cortex of subjects with ASD. To address the possible neurodevelopmental contribution of MET to ASD pathogenesis, we examined the expression and transcriptional regulation of MET by a transcription factor, FOXP2, which is implicated in regulation of cognition and language, two functions altered in ASD. MET mRNA expression in the midgestation human fetal cerebral cortex is strikingly restricted, localized to portions of the temporal and occipital lobes. Within the cortical plate of the temporal lobe, the pattern of MET expression is highly complementary to the expression pattern of FOXP2, suggesting the latter may play a role in repression of gene expression. Consistent with this, MET and FOXP2 also are reciprocally expressed by differentiating normal human neuronal progenitor cells (NHNPs) in vitro, leading us to assess whether FOXP2 transcriptionally regulates MET. Indeed, FOXP2 binds directly to the 5' regulatory region of MET, and overexpression of FOXP2 results in transcriptional repression of MET. The expression of MET in restricted human neocortical regions, and its regulation in part by FOXP2, is consistent with genetic evidence for MET contributing to ASD risk.
Journal of Neuroscience 08/2011; 31(32):11437-42. · 7.11 Impact Factor
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ABSTRACT: Autism spectrum disorder (ASD) is characterized by core deficits in social behavior, communication, and behavioral flexibility. Several lines of evidence indicate that oxytocin, signaling through its receptor (OXTR), is important in a wide range of social behaviors. In attempts to determine whether genetic variations in the oxytocin signaling system contribute to ASD susceptibility, seven recent reports indicated association of common genetic polymorphisms in the OXTR gene with ASD. Each involved relatively small sample sizes (57 to 436 families) and, where it was examined, failed to identify association of OXTR polymorphisms with measures of social behavior in individuals with ASD. We report genetic association analysis of 25 markers spanning the OXTR locus in 1,238 pedigrees including 2,333 individuals with ASD. Association of three markers previously implicated in ASD susceptibility, rs2268493 (P = 0.043), rs1042778 (P = 0.037), and rs7632287 (P = 0.016), was observed. Further, these genetic markers were associated with multiple core ASD phenotypes, including social domain dysfunction, measured by standardized instruments used to diagnose and describe ASD. The data suggest association of OXTR genetic polymorphisms with ASD, although the results should be interpreted with caution because none of the significant associations would survive appropriate correction for multiple comparisons. However, the current findings of association in a large independent cohort are consistent with previous results, and the biological plausibility of participation of the oxytocin signaling system in modulating social disruptions characteristic of ASD, suggest that functional polymorphisms of OXTR may contribute to ASD risk in a subset of families.
Journal of Neurodevelopmental Disorders 06/2011; 3(2):101-12. · 3.06 Impact Factor
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ABSTRACT: The validity for assigning disorder risk to an autism spectrum disorder (ASD) candidate gene comes from convergent genetic, clinical, and developmental neurobiology data. Here, we review these lines of evidence from multiple human genetic studies, and non-human primate and mouse experiments that support the conclusion that the MET receptor tyrosine kinase (RTK) functions to influence synapse development in circuits relevant to certain core behavioral domains of ASD. There is association of both common functional alleles and rare copy number variants that impact levels of MET expression in the human cortex. The timing of Met expression is linked to axon terminal outgrowth and synaptogenesis in the developing rodent and primate forebrain, and both in vitro and in vivo studies implicate this RTK in dendritic branching, spine maturation, and excitatory connectivity in the neocortex. This impact can occur in a cell-nonautonomous fashion, emphasizing the unique role that Met plays in specific circuits relevant to ASD.
Journal of Neurodevelopmental Disorders 04/2011; 3(3):282-92. · 3.06 Impact Factor
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ABSTRACT: Serotonin (5-hydroxytryptamine or 5-HT) is thought to regulate neurodevelopmental processes through maternal-fetal interactions that have long-term mental health implications. It is thought that beyond fetal 5-HT neurons there are significant maternal contributions to fetal 5-HT during pregnancy but this has not been tested empirically. To examine putative central and peripheral sources of embryonic brain 5-HT, we used Pet1(-/-) (also called Fev) mice in which most dorsal raphe neurons lack 5-HT. We detected previously unknown differences in accumulation of 5-HT between the forebrain and hindbrain during early and late fetal stages, through an exogenous source of 5-HT which is not of maternal origin. Using additional genetic strategies, a new technology for studying placental biology ex vivo and direct manipulation of placental neosynthesis, we investigated the nature of this exogenous source. We uncovered a placental 5-HT synthetic pathway from a maternal tryptophan precursor in both mice and humans. This study reveals a new, direct role for placental metabolic pathways in modulating fetal brain development and indicates that maternal-placental-fetal interactions could underlie the pronounced impact of 5-HT on long-lasting mental health outcomes.
Nature 04/2011; 472(7343):347-50. · 36.28 Impact Factor
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ABSTRACT: Local hyperconnectivity in the neocortex is a hypothesized pathophysiological state in autism spectrum disorder (ASD). MET, a receptor tyrosine kinase that regulates dendrite and spine morphogenesis, has been established as a risk gene for ASD. Here, we analyzed the synaptic circuit organization of identified pyramidal neurons in the anterior frontal cortex of mice with a dorsal pallium-derived, conditional knock-out (cKO) of Met. Synaptic mapping by glutamate uncaging identified layer 2/3 as the main source of local excitatory input to layer 5 projection neurons in controls. In both cKO and heterozygotes, this pathway was stronger by a factor of approximately 2. This increase was both sublayer and projection-class specific, restricted to corticostriatal neurons in upper layer 5B and not neighboring corticopontine neurons. Paired recordings in cKO slices demonstrated increased unitary connectivity. We propose that excitatory hyperconnectivity in specific neocortical microcircuits constitutes a physiological basis for Met-mediated ASD risk.
Journal of Neuroscience 04/2011; 31(15):5855-64. · 7.11 Impact Factor
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ABSTRACT: Candidate risk genes for autism spectrum disorder (ASD) have been identified, but the challenge of determining their contribution to pathogenesis remains. We previously identified two ASD risk genes encoding the receptor tyrosine kinase MET and the urokinase plasminogen activator receptor (PLAUR), which is thought to modulate availability of the MET ligand. We also reported a role for Met signaling in cortical interneuron development in vitro and a reduction of these neurons in uPAR (mouse ortholog of PLAUR) null mice, suggesting that disruption of either gene impacts cortical development similarly. Here, we modify this conclusion, reporting that interneuron numbers are unchanged in the neocortex of Met(fx/fx) / Dlx5/6(cre) mice, in which Met is ablated from cells arising from the ventral telencephalon (VTel). Consistent with this, Met transcript is not detected in the VTel during interneuron genesis and migration; furthermore, during the postnatal period of interneuron maturation, Met is co-expressed in glutamatergic projection neurons, but not interneurons. Low levels of Met protein are expressed in the VTel at E12.5 and E14.5, likely reflecting the arrival of Met containing corticofugal axons. Met expression, however, is induced in E12.5 VTel cells after 2 days in vitro, perhaps underlying discrepancies between observations in vitro and in Met(fx/fx) / Dlx5/6(cre) mice. We suggest that, in vivo, Met impacts the development of cortical projection neurons, whereas uPAR influences interneuron maturation. An altered balance between excitation and inhibition has been postulated as a biological mechanism for ASD; this imbalance could arise from different risk genes differentially affecting either or both elements.
Autism Research 02/2011; 4(1):68-83. · 3.69 Impact Factor
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ABSTRACT: The neuronal transcription splicing factor, A2BP1, has been implicated in a variety of neurodevelopmental disorders; however, the role of A2BP1 in brain development and gene regulatory function remains to be explicated. Here, we map A2bp1 gene expression, focusing on the developing forebrain of the C57BL6J mouse. Early in forebrain development, A2bp1 expression is highly reminiscent of the expression of genes marking postmitotic GABAergic cells emanating from the ventral telencephalon during migration to the dorsal pallium. Ventral pallial expression remains low after the migratory period. Broader dorsal pallial expression becomes more evident late prenatally and early postnatally. This is paralleled by dense, restricted expression in the ventrobasal dorsal thalamic complex and mid-hypothalamic region. Outside of the forebrain, there is significant expression in motor pathways. These data indicate that A2BP1 mutations may clinically affect very selective forebrain neuron types from early periods of development.
Developmental Neuroscience 02/2011; 33(1):64-74. · 3.63 Impact Factor
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ABSTRACT: Met receptor tyrosine kinase signaling regulates the growth and development of axons and may contribute to the wiring of cortical and limbic circuits in the rodent forebrain. Whether the orthologous MET receptor functions similarly in the developing primate forebrain is not known but is of considerable interest considering the association of variant MET alleles with social and communication phenotypes in autism. To begin addressing this question, we compared Met/MET protein expression in the developing mouse and rhesus macaque forebrain. There was a strong temporal conservation of expression during the time of rapid axon development and the onset of robust synapse formation. Expression patterns of Met/MET in limbic-related structures were almost identical between species. In marked contrast, there was highly divergent expression in the neocortex. In mouse, Met was broadly distributed throughout neocortex. In the macaque, robust MET expression was largely restricted to the posterior cingulate, inferior temporal, posterior parietal, and visual cortices, including face processing regions. The pattern is consistent with the importance of vision in the social repertoire of the primate. Collectively, these data suggest a conserved developmental function of the MET receptor in wiring together limbic and neocortical circuits that facilitate species-appropriate responses, including social behavior.
Cerebral Cortex 12/2010; 21(7):1613-26. · 6.54 Impact Factor
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ABSTRACT: Human genetic findings and murine neuroanatomical expression mapping have intersected to implicate Met receptor tyrosine kinase signaling in the development of forebrain circuits controlling social and emotional behaviors that are atypical in autism-spectrum disorders (ASD). To clarify roles for Met signaling during forebrain circuit development in vivo, we generated mutant mice (Emx1(Cre)/Met(fx/fx)) with an Emx1-Cre-driven deletion of signaling-competent Met in dorsal pallially derived forebrain neurons. Morphometric analyses of Lucifer yellow-injected pyramidal neurons in postnatal day 40 anterior cingulate cortex (ACC) revealed no statistically significant changes in total dendritic length but a selective reduction in apical arbor length distal to the soma in Emx1(Cre)/Met(fx/fx) neurons relative to wild type, consistent with a decrease in the total tissue volume sampled by individual arbors in the cortex. The effects on dendritic structure appear to be circuit-selective, insofar as basal arbor length was increased in Emx1(Cre)/Met(fx/fx) layer 2/3 neurons. Spine number was not altered on the Emx1(Cre)/Met(fx/fx) pyramidal cell populations studied, but spine head volume was significantly increased (∼20%). Cell-nonautonomous, circuit-level influences of Met signaling on dendritic development were confirmed by studies of medium spiny neurons (MSN), which do not express Met but receive Met-expressing corticostriatal afferents during development. Emx1(Cre)/Met(fx/fx) MSN exhibited robust increases in total arbor length (∼20%). As in the neocortex, average spine head volume was also increased (∼12%). These data demonstrate that a developmental loss of presynaptic Met receptor signaling can affect postsynaptic morphogenesis and suggest a mechanism whereby attenuated Met signaling could disrupt both local and long-range connectivity within circuits relevant to ASD.
The Journal of Comparative Neurology 11/2010; 518(21):4463-78. · 3.81 Impact Factor
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Liu Sheng,
Xinxin Ding,
Marcus Ferguson,
Monique McCallister,
Raina Rhoades,
Mark Maguire,
Aramandla Ramesh,
Michael Aschner,
Daniel Campbell, Pat Levitt,
Darryl B Hood
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ABSTRACT: Gene by environment interactions (G × E) are thought to underlie neurodevelopmental disorder, etiology, neurodegenerative disorders, including the multiple forms of autism spectrum disorder. However, there is limited biological information, indicating an interaction between specific genes and environmental components. The present study focuses on a major component of airborne pollutants, polycyclic aromatic hydrocarbons (PAHs), such as benzo(a)pyrene [B(a)P], which negatively impacts cognitive development in children who have been exposed in utero. In our study, prenatal exposure of Cpr(lox/lox) timed-pregnant dams to B(a)P (0, 150, 300, and 600 μg/kg body weight via oral gavage) on embryonic day (E14-E17) consistent with our susceptibility-exposure paradigm was combined with the analysis of a replicated autism risk gene, the receptor tyrosine kinase, Met. The results demonstrate a dose-dependent increase in B(a)P metabolite generation in B(a)P-exposed Cpr(lox/lox) offspring. Additionally, a sustained persistence of hydroxy metabolites during the onset of synapse formation was noted, corresponding to the peak of Met expression. Prenatal B(a)P exposure also downregulated Met RNA and protein levels and dysregulated normal temporal patterns of expression during synaptogenesis. Consistent with these data, transcriptional cell-based assays demonstrated that B(a)P exposure directly reduces human MET promoter activity. Furthermore, a functional readout of in utero B(a)P exposure showed a robust reduction in novel object discrimination in B(a)P-exposed Cpr(lox/lox) offspring. These results confirm the notion that common pollutants, such as the PAH B(a)P, can have a direct negative impact on the regulated developmental expression of an autism risk gene with associated negative behavioral learning and memory outcomes.
Toxicological Sciences 10/2010; 118(2):625-34. · 4.65 Impact Factor
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ABSTRACT: Human cognitive and social-emotional behaviors are heterogeneous, underscoring the challenges in modeling pathogenesis in disorders of neurodevelopmental origin in which these domains are dysfunctional. In general, animal models for these disorders are built to emulate our understanding of the clinical diagnosis, with mixed results. We suggest the utility of model systems lies in the use of different strategies to perturb hierarchical circuit development, to examine the behavioral dimensions that are most impacted, and to discern the capacity for, and heterogeneity of, neuroadaptation that will then inform treatment strategies.
Neuron 09/2010; 67(5):702-12. · 14.74 Impact Factor
