Thalamocortical Axons Research Articles

Synaptic organization of thalamocortical axon collaterals in the perigeniculate nucleus and dorsal lateral geniculate nucleus

We examined the synaptic targets of large non-gamma-aminobutyric acid (GABA)-ergic profiles that contain round vesicles and dark mitochondria (RLD profiles) in the perigeniculate nucleus (PGN) and the dorsal lateral geniculate nucleus (dLGN). RLD profiles can provisionally be identified as the collaterals of thalamocortical axons, because their ultrastrucure is distinct from all other previously described dLGN inputs. We also found that RLD profiles are larger than cholinergic terminals and contain the type 2 vesicular glutamate transporter. RLD profiles are distributed throughout the PGN and are concentrated within the interlaminar zones (IZs) of the dLGN, regions distinguished by dense binding of Wisteria floribunda agglutinin (WFA). To determine the synaptic targets of thalamocortical axon collaterals, we examined RLD profiles in the PGN and dLGN in tissue stained for GABA. For the PGN, we found that all RLD profiles make synaptic contacts with GABAergic PGN somata, dendrites, and spines. In the dLGN, RLD profiles primarily synapse with GABAergic dendrites that contain vesicles (F2 profiles) and non-GABAergic dendrites in glomerular arrangements that include triads. Occasional synapses on GABAergic somata and proximal dendrites were also observed in the dLGN. These results suggest that correlated dLGN activity may be enhanced via direct synaptic contacts between thalamocortical cells, whereas noncorrelated activity (such as that occurring during binocular rivalry) could be suppressed via thalamocortical collateral input to PGN cells and dLGN interneurons.

Robust but delayed thalamocortical activation of dendritic-targeting inhibitory interneurons

GABA-releasing cortical interneurons are crucial for the neural transformations underlying sensory perception, providing "feedforward" inhibition that constrains the temporal window for synaptic integration. To mediate feedforward inhibition, inhibitory interneurons need to fire in response to ascending thalamocortical inputs, and most previous studies concluded that ascending inputs activate mainly or solely proximally targeting, parvalbumin-containing "fast-spiking" interneurons. However, when thalamocortical axons fire at frequencies that are likely to occur during natural exploratory behavior, activation of fast-spiking interneurons is rapidly and strongly depressed, implying the paradoxical conclusion that feedforward inhibition is absent when it is most needed. To address this issue, we took advantage of lines of transgenic mice in which either parvalbumin- or somatostatin-containing interneurons express GFP and recorded the responses of interneurons from both subtypes to thalamocortical stimulation in vitro. We report that during thalamocortical activation at behaviorally expected frequencies, fast-spiking interneurons were indeed activated only transiently because of rapid depression of their thalamocortical inputs, but a subset of layer 5 somatostatin-containing interneurons were robustly and persistently activated after a delay, due to the facilitation and temporal summation of their thalamocortical excitatory postsynaptic potentials. Somatostatin-containing interneurons are considered distally targeting. Thus, they are likely to provide delayed dendritic inhibition during exploratory behavior, contributing to the maintenance of a balance between cortical excitation and inhibition while leaving a wide temporal window open for synaptic integration and plasticity in distal dendrites.

Stem Cell Factor Functions as an Outgrowth-Promoting Factor to Enable Axon Exit from the Midline Intermediate Target

Commissural axons are attracted to the midline intermediate target by chemoattractants, but upon crossing the midline they switch off responsiveness to attractants and switch on responsiveness to midline repellents, which expel the axons from the midline and enable them to move on. Here we show that midline exit also requires the stimulation of axon outgrowth by Stem Cell Factor (SCF, also known as Steel Factor). SCF is expressed by midline floor plate cells, and its receptor Kit, a receptor tyrosine kinase, is expressed by commissural axons. In Steel and Kit mutant mice, the majority of commissural axons line up transiently at the contralateral edge of the floor plate, showing a delay in midline exit. In vitro, SCF selectively promotes outgrowth of postcrossing, but not precrossing, commissural axons. Our findings identify SCF as a guidance cue in the CNS, and provide evidence that exiting intermediate targets requires activation of outgrowth-promoting mechanisms.

The JIP1 Scaffold Protein Regulates Axonal Development in Cortical Neurons

SummaryThe development of neuronal polarity is essential for the determination of neuron connectivity and for correct brain function. The c-Jun N-terminal kinase (JNK)-interacting protein-1 (JIP1) is highly expressed in neurons and has previously been characterized as a regulator of JNK signaling. JIP1 has been shown to localize to neurites in various neuronal models, but the functional significance of this localization is not fully understood [1–4]. JIP1 is also a cargo of the motor protein kinesin-1, which is important for axonal transport [2, 4]. Here we demonstrate that before primary cortical neurons become polarized, JIP1 specifically localizes to a single neurite and that after axonal specification, it accumulates in the emerging axon. JIP1 is necessary for normal axonal development and promotes axonal growth dependent upon its binding to kinesin-1 and via a newly described interaction with the c-Abl tyrosine kinase. JIP1 associates with and is phosphorylated by c-Abl, and the mutation of the c-Abl phosphorylation site on JIP1 abrogates its ability to promote axonal growth. JIP1 is therefore an important regulator of axonal development and is a key target of c-Abl-dependent pathways that control axonal growth.

Vesicular glutamate transporters define two sets of glutamatergic afferents to the somatosensory thalamus and two thalamocortical projections in the mouse

The ventral posterior nucleus of the thalamus (VP) receives two major sets of excitatory inputs, one from the ascending somatosensory pathways originating in the dorsal horn, dorsal column nuclei, and trigeminal nuclei, and the other originating from the cerebral cortex. Both systems use glutamate as neurotransmitter, as do the thalamocortical axons relaying somatosensory information from the VP to the primary somatosensory cortex (SI). The synapses formed by these projection systems differ anatomically, physiologically, and in their capacity for short-term synaptic plasticity. Glutamate uptake into synaptic vesicles and its release at central synapses depend on two isoforms of vesicular glutamate transporters, VGluT1 and VGluT2. Despite ample evidence of their complementary distribution, some instances exist of co-localization in the same brain areas or at the same synapses. In the thalamus, the two transcripts coexist in cells of the VP and other nuclei but not in the posterior or intralaminar nuclei. We show that the two isoforms are completely segregated at VP synapses, despite their widespread expression throughout the dorsal and ventral thalamus. We present immunocytochemical, ultrastructural, gene expression, and connectional evidence that VGluT1 in the VP is only found at corticothalamic synapses, whereas VGluT2 is only found at terminals made by axons originating in the spinal cord and brainstem. By contrast, the two VGluT isoforms are co-localized in thalamocortical axon terminals targeting layer IV, but not in those targeting layer I, suggesting the presence of two distinct projection systems related to the core/matrix pattern of organization of thalamocortical connectivity described in other mammals.

GAP-43 is critical for normal targeting of thalamocortical and corticothalamic, but not trigeminothalamic axons in the whisker barrel system

Mice lacking the growth-associated protein GAP-43 (KO) show disrupted cortical topography and no barrels. Whisker-related patterns of cells are normal in the KO brainstem trigeminal complex (BSTC), while the pattern in KO ventrobasal thalamus (VB) is somewhat compromised. To better understand the basis for VB and cortical abnormalities, we used small placements of DiI to trace axonal projections between BSTC, VB, and barrel cortex in wildtype (WT) and GAP-43 KO mice. The trigeminothalamic (TT) pathway consists of axons from cells in the Nucleus Prinicipalis that project to the contralateral VB thalamus. DiI-labeled KO TT axons crossed the midline from BSTC and projected to contralateral VB normally, consistent with normal BSTC cytoarchitecture. By contrast, the KO thalamocortical axons (TCA) projection was highly abnormal. KO TCAs showed delays of 1–2 days in initial ingrowth to cortex. Postnatally, KO TCAs showed multiple pathfinding errors near intermediate targets, and were abnormally fasciculated within the internal capsule (IC). Interestingly, most individually labeled KO TCAs terminated in deep layers instead of in layer IV as in WT. This misprojection is consistent with birthdating analysis in KO mice, which revealed that neurons normally destined for layer IV remain in deep cortical layers. Early outgrowth of KO corticofugal (CF) axons was similar for both genotypes. However, at P7 KO CF fibers remained bundled as they entered the IC, and exhibited few terminal branches in VB. Thus, the establishment of axonal projections between thalamus and cortex are disrupted in GAP-43 KO mice.

Cell-type specific circuit analysis using a digital brain atlas which integrates anatomical and physiological data

Event Abstract Back to Event Cell-type specific circuit analysis using a digital brain atlas which integrates anatomical and physiological data Patrik Krieger1*, Bert Sakmann2, Alexander Groh2, Hanno Meyer2 and Nathaniel Heintz3 1 Karolinska Institutet, Sweden 2 Max Planck Institute for Medical Research, Germany 3 The Rockefeller University, United States In BAC (Bacterial artificial chromosome) transgenic mice we investigated the anatomical and functional properties of two populations of layer 5 pyramids in somatosensory and visual cortex. The two populations were selectively labelled by EGFP expressed under the control of cell-type specific promoters. The genotypic profile discriminated between thick-tufted corticopontine and slender-tufted corticostriatal layer 5 pyramids. The projection target specificity of the two populations was determined by retrograde tracer injections and visualization of EGFP-labelled axons in the target area. Using the fluorescent labelling we could target our investigation to a specific cell-type in layer 5 and perform (i) electrophysiological recordings to investigate cell-type specific intrinsic membrane properties and connectivity (ii) a quantification of the dendrite morphology and (iii) an analysis of the spatial distribution profiles of somata from the two populations and (iv) an investigation of the overlap of thalamocortical axons and dendrites from the two populations of corticofugal layer 5 pyramids. We show that targeting cell types using BAC-transgenic mice could be a valuable approach to generate atlases consisting of both detailed anatomical data, including both cell-type specific output and input, and physiological data relevant for functional circuit analysis. Conference: Neuroinformatics 2008, Stockholm, Sweden, 7 Sep - 9 Sep, 2008. Presentation Type: Poster Presentation Topic: General Neuroinformatics Citation: Krieger P, Sakmann B, Groh A, Meyer H and Heintz N (2008). Cell-type specific circuit analysis using a digital brain atlas which integrates anatomical and physiological data. Front. Neuroinform. Conference Abstract: Neuroinformatics 2008. doi: 10.3389/conf.neuro.11.2008.01.007 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 28 Jul 2008; Published Online: 28 Jul 2008. * Correspondence: Patrik Krieger, Karolinska Institutet, Stockholm, Sweden, patrik.krieger@rub.de Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Patrik Krieger Bert Sakmann Alexander Groh Hanno Meyer Nathaniel Heintz Google Patrik Krieger Bert Sakmann Alexander Groh Hanno Meyer Nathaniel Heintz Google Scholar Patrik Krieger Bert Sakmann Alexander Groh Hanno Meyer Nathaniel Heintz PubMed Patrik Krieger Bert Sakmann Alexander Groh Hanno Meyer Nathaniel Heintz Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Close Homolog of L1 and Neuropilin 1 Mediate Guidance of Thalamocortical Axons at the Ventral Telencephalon

We report a cooperation between the neural adhesion molecule close homolog of L1 (CHL1) and the semaphorin 3A (Sema3A) receptor, neuropilin 1 (Npn1), important for establishment of area-specific thalamocortical projections. CHL1 deletion in mice selectively disrupted the projection of somatosensory thalamic axons from the ventrobasal (VB) nuclei, causing them to shift caudally and target the visual cortex. At the ventral telencephalon, an intermediate target with graded Sema3A expression, VB axons were caudally shifted in CHL1- embryos and in Npn1(Sema-/-) mutants, in which axons are nonresponsive to Sema3A. CHL1 colocalized with Npn1 on thalamic axons, and associated with Npn1 through a sequence in the CHL1 Ig1 domain that was required for Sema3A-induced growth cone collapse. These results identify a novel function for CHL1 in thalamic axon responsiveness to ventral telencephalic cues, and demonstrate a role for CHL1 and Npn1 in establishment of proper targeting of specific thalamocortical projections.

Cooperative activity of multiple upper layer proteins for thalamocortical axon growth

During development, sensory thalamocortical (TC) axons grow into the neocortex and terminate primarily in layer 4. To study the molecular mechanism that underlies lamina-specific TC axon termination, we investigated the responsiveness of TC axons to ephrin-A5, semaphorin-7A (Sema7A) and kit ligand (KL), which are expressed in the upper layers of the developing cortex. Dissociated cells of the dorsal thalamus from embryonic rat brain were cultured on dishes that were coated with preclustered Fc-tagged extracellular domains of these molecules. Each protein was found to promote TC axon growth in a dose-dependent fashion of a bell-shaped curve. Any combination of the three proteins showed a cooperative effect in lower concentrations but not in higher concentrations, suggesting that their growth-promoting activities act in a common pathway. The effect of spatial distributions of these proteins was further tested on a filter membrane, in which these proteins were printed at a size that recapitulates the scale of laminar thickness in vivo, using a novel protein-printing technique, Simple-To-mAke Micropore Protein-Printing (STAMP2) method. The results demonstrated that TC axons grew massively on the laminin-coated region but were prevented from invading the adjacent ephrin-A5-printed region, suggesting that TC axons detect relative differences in the growth effect between these regions. Moreover, the inhibitory action of ephrin-A5 was enhanced by copresence with KL and Sema7A. Together, these results suggest that the lamina-specific TC axon targeting mechanism involves growth-inhibitory activity by multiple molecules in the upper layers and detection in the molecular environments between the upper and deep layers.

Transiently increased colocalization of vesicular glutamate transporters 1 and 2 at single axon terminals during postnatal development of mouse neocortex: a quantitative analysis with correlation coefficient

Vesicular glutamate transporter 1 (VGLUT1) and VGLUT2 show complementary distribution in neocortex; VGLUT1 is expressed mainly in axon terminals of neocortical neurons, whereas VGLUT2 is located chiefly in thalamocortical axon terminals. However, we recently reported a frequent colocalization of VGLUT1 and VGLUT2 at a subset of axon terminals in postnatal developing neocortex. We here quantified the frequency of colocalization between VGLUT1 and VGLUT2 immunoreactivities at single axon terminals by using the correlation coefficient (CC) as an indicator in order to determine the time course and spatial extent of the colocalization during postnatal development of mouse neocortex. The colocalization was more frequent in the primary somatosensory (S1) area than in both the primary visual (V1) and the motor areas; of area S1 cortical layers, colocalization was most evident in layer IV barrels at postnatal day (P) 7 and in adulthood. CC in layer IV showed a peak at P7 in area S1, and at P10 in area V1 though the latter peak was much smaller than the former. These results suggest that thalamocortical axon terminals contained not only VGLUT2 but also VGLUT1, especially at P7-10. Double fluorescence in situ hybridization confirmed coexpression of VGLUT1 and VGLUT2 mRNAs at P7 in the somatosensory thalamic nuclei and later in the thalamic dorsal lateral geniculate nucleus. As VGLUT1 is often used in axon terminals that show synaptic plasticity in adult brain, the present findings suggest that VGLUT1 is used in thalamocortical axons transiently during the postnatal period when plasticity is required.

Plasticity in the development of neocortical areas.

Heterotopic transplantation analysis suggests that individual areas of the developing neocortex have the capacity to differentiate many of the architectural and connectional features normally characteristic of other neocortical areas. Many studies indicate a pivotal role for thalamocortical afferents in the differentiation of the area-specific features that distinguish neocortical areas. Both activity-dependent and activity-independent mechanisms contribute to the patterning of thalamocortical afferent terminations. The available evidence suggests that positional information is established in the cortical subplate and that this information controls the precise targeting of developing thalamocortical axons. In this way appropriate thalamocortical relationships can be established that allow these afferents to promote the differentiation of the functionally specialized and anatomically distinct areas of the adult neocortex.

OL-protocadherin is essential for growth of striatal axons and thalamocortical projections

The ventral telencephalon in the embryonic brain is thought to provide guidance cues for navigation of thalamocortical axons, but the mechanisms involved remain largely elusive. OL-protocadherin (OL-pc), a member of the cadherin superfamily, is highly expressed by striatal neurons in the developing ventral telencephalon. Here we show that OL-pc-deficient (Pcdh10(-/-)) mice have defects in axon pathways through the ventral telencephalon; for example, thalamocortical and corticothalamic projections cannot cross the ventral telencephalon. In the ventral telencephalon, striatal axons fail to grow out, and, concomitantly, the caudal portion of the globus pallidus and the associated 'corridor' thought to be important for thalamocortical fiber navigation do not form. The inability of the striatum to extend axons is also observed in vitro. These results show that OL-pc is essential for both elongation of striatal axons and patterning of the putative guidance cues for thalamocortical projections.

Nicotinic control of axon excitability regulates thalamocortical transmission

The thalamocortical pathway, a bundle of myelinated axons that arises from thalamic relay neurons, carries sensory information to the neocortex. Because axon excitation is an obligatory step in the relay of information from the thalamus to the cortex, it represents a potential point of control. We now show that, in adult mice, the activation of nicotinic acetylcholine receptors (nAChRs) in the initial portion of the auditory thalamocortical pathway modulates thalamocortical transmission of information by regulating axon excitability. Exogenous nicotine enhanced the probability and synchrony of evoked action potential discharges along thalamocortical axons in vitro, but had little effect on synaptic release mechanisms. In vivo, the blockade of nAChRs in the thalamocortical pathway reduced sound-evoked cortical responses, especially those evoked by sounds near the acoustic threshold. These data indicate that endogenous acetylcholine activates nAChRs in the thalamocortical pathway to lower the threshold for thalamocortical transmission and to increase the magnitude of sensory-evoked cortical responses. Our results show that a neurotransmitter can modulate sensory processing by regulating conduction along myelinated thalamocortical axons.

Defects in reciprocal projections between the thalamus and cerebral cortex in the early development of Fezl‐deficient mice

Fez-like (Fezl), the forebrain embryonic zinc finger-like protein, is a transcriptional repressor selectively expressed in the deep layers of the developing cortex. We examined the thalamocortical and corticofugal pathways in Fezl-deficient fetal mice by using immunohistochemistry and by axonal labeling with the lipophilic dyes DiI and DiA, with special attention to the spatiotemporal relation between thalamocortical and corticofugal axons. In normal mice, thalamic and cortical axons meet in the internal capsule between embryonic day (E) 13.5 and E14.5 and fasciculate with each other as they extend to their targets, the cortex and thalamus, respectively. In Fezl-deficient mice, most of the thalamic and cortical axons stop in the internal capsule and at the pallial-subpallial boundary at E14.5, respectively. This abnormality is transient, and the thalamic and cortical axons reach their targets at E15.5, although the number of thalamic axons is remarkably reduced in the cortical anlage. Double labeling with DiI and DiA demonstrated close apposition of the thalamic and cortical axons in the subpallium and pallium as well as in the external capsule of this mutant after E15.5. Because the expression of genes that define the pallial-subpallial boundary and guidance molecules of thalamocortical axons did not show remarkable changes in Fezl-deficient mice, abnormal formation of thalamocortical pathway in this mutant may be caused by the defect of axons of cortical efferent neurons that express Fezl.

Interplay between Laminar Specificity and Activity-Dependent Mechanisms of Thalamocortical Axon Branching

Target and activity-dependent mechanisms of axonal branching were studied in the thalamocortical (TC) projection using organotypic cocultures of the thalamus and cortex. TC axons were labeled with enhanced yellow fluorescent protein (EYFP) by a single-cell electroporation method and observed over time by confocal microscopy. Changes in the firing activity of cocultures grown on multielectrode dishes were also monitored over time. EYFP-labeled TC axons exhibited more branch formation in and around layer 4 of the cortical explant during the second week in vitro, when spontaneous firing activity increased in both thalamic and cortical cells. Time-lapse imaging further demonstrated that branching patterns were generated dynamically by addition and elimination with a bias toward branch accumulation in the target layer. To examine the relationship between neural activity and TC branch formation, the dynamics of axonal branching was analyzed under various pharmacological treatments. Chronic blockade of firing or synaptic activity reduced the remodeling process, in particular, branch addition in the target layer. However, extension of branches was not affected by this treatment. Together, these findings suggest that neural activity can modify the molecular mechanisms that regulate lamina-specific TC axon branching.

The Neuregulin-1 Receptor ErbB4 Controls Glutamatergic Synapse Maturation and Plasticity

Neuregulin-1 (NRG1) signaling participates in numerous neurodevelopmental processes. Through linkage analysis, nrg1 has been associated with schizophrenia, although its pathophysiological role is not understood. The prevailing models of schizophrenia invoke hypofunction of the glutamatergic synapse and defects in early development of hippocampal-cortical circuitry. Here, we show that the erbB4 receptor, as a postsynaptic target of NRG1, plays a key role in activity-dependent maturation and plasticity of excitatory synaptic structure and function. Synaptic activity leads to the activation and recruitment of erbB4 into the synapse. Overexpressed erbB4 selectively enhances AMPA synaptic currents and increases dendritic spine size. Preventing NRG1/erbB4 signaling destabilizes synaptic AMPA receptors and leads to loss of synaptic NMDA currents and spines. Our results indicate that normal activity-driven glutamatergic synapse development is impaired by genetic deficits in NRG1/erbB4 signaling leading to glutamatergic hypofunction. These findings link proposed effectors in schizophrenia: NRG1/erbB4 signaling perturbation, neurodevelopmental deficit, and glutamatergic hypofunction.

Serotonin’s Axon Guidance Switch

Alterations in signaling by the neurotransmitter serotonin (also called 5-hydroxytryptamine or 5-HT) are associated with psychiatric illnesses, including anxiety disorders and depression. Such effects may reflect abnormal signaling at synapses in adult brain or changes in brain development, during which serotonin is also present and influences pathfinding by thalamocortical neurons. Bonnin et al . provide mechanistic insight into how changes in serotonin signals can disrupt axon migration. In cultured explants from the dorsal thalamus of mice, axons are normally attracted to HEK-293 cells in the same culture that are engineered to express the axon guidance protein netrin-1. But when the authors treated the explants with serotonin, the axons reversed their response to netrin-1 and were repelled from the cells producing the netrin-1. This response was caused by decreased synthesis of the second messenger cAMP (adenosine 3′,5′-monophosphate) in the serotonin-stimulated dorsal thalamus neurons. Pharmacological inhibition of the cAMP-dependent protein kinase could reproduce the effect of serotonin, and activation of the kinase blocked the serotonin effect. To show the importance of this effect in vivo, the authors used targeted electroporation of the developing brain in mouse embryos in the mother’s uterus, thereby causing the cells of the dorsal thalamus to express more serotonin receptors (to enhance signaling) or to express small interfering RNA to the receptors (to limit serotonin signaling). At the same time, the authors introduced a plasmid encoding a fluorescent marker protein that allowed them to trace the growth of the transfected axons. Increasing and decreasing serotonin signaling produced opposite effects, and both caused abnormal migration trajectories of the thalamus axons. Thus the authors propose that developmental abnormalities in serotonin signaling--either too much or too little--may alter the circuitry of thalamocortical axons and thus alter brain functions that later contribute to mental health disorders. A. Bonnin, M. Torii, L. Wang, P. Rakic, P. Levitt, Serotonin modulates the response of embryonic thalamocortical axons to netrin-1. Nat. Neurosci. 10 , 588-597 (2007). [PubMed]

Serotonin modulates the response of embryonic thalamocortical axons to netrin-1

Modifying serotonin (5-HT) abundance in the embryonic mouse brain disrupts the precision of sensory maps formed by thalamocortical axons (TCAs), suggesting that 5-HT influences their growth. We investigated the mechanism by which 5-HT influences TCAs during development. 5-HT(1B) and 5-HT(1D) receptor expression in the fetal forebrain overlaps with that of the axon guidance receptors DCC and Unc5c. In coculture assays, axons originating from anterior and posterior halves of the embryonic day 14.5 dorsal thalamus responded differently to netrin-1, reflecting the patterns of DCC and Unc5c expression. 5-HT converts the attraction exerted by netrin-1 on posterior TCAs to repulsion. Pharmacological manipulation of 5-HT(1B/1D) receptors and intracellular cAMP showed the signaling cascade through which this modulation occurs. An in vivo correlate of altered TCA pathfinding was obtained by transient manipulation of 5-HT(1B/1D) receptor expression abundance in the dorsal thalamus by in utero electroporation. These data demonstrate that serotonergic signaling has a previously unrecognized role in the modulation of axonal responsiveness to a classic guidance cue.

Rac1 Controls the Formation of Midline Commissures and the Competency of Tangential Migration in Ventral Telencephalic Neurons

Previous studies using dominant-mutant constructs have implicated Rac1 GTPase in neuritogenesis and neuronal migration. However, overexpression of dominant mutants generally blocks Rho-GTPase activity; thus, it may not reveal the specific or physiological functions of Rac1. To address this issue, we have applied a conditional gene-targeting strategy, using Foxg1-Cre mice to delete Rac1 in the ventricular zone (VZ) of telencephalon and Dlx5/6-Cre-IRES (internal ribosomal entry site)-EGFP (enhanced green fluorescent protein) (Dlx5/6-CIE) in the subventricular zone (SVZ) of ventral telencephalon, respectively. Surprisingly, the deletion of Rac1 in VZ progenitors did not prevent axonal outgrowth of telencephalic neurons. However, the anterior commissure was absent, and the corpus callosal as well as hippocampal commissural axons failed to cross the midline in Rac1/Foxg1-Cre knock-out embryos. The thalamocortical and corticothalamic axons also showed defasciculation or projection defects. These results suggest that Rac1 controls axon guidance rather than neuritogenesis. In addition, although Rac1/Foxg1-Cre knock-out embryos showed delayed radial migration of cortical projection neurons and severe impairment of tangential migration by the ventral telencephalon-derived interneurons, deletion of Rac1 in the SVZ by Dlx5/6-CIE mice produced no discernible defects in tangential migration. These contrasting effects of Rac1 deletion on tangential migration suggest that Rac1 is dispensable for cellular motility per se during neuronal migration. Together, these results underscore the challenge of deciphering the biological functions of Rac1, and Rho-GTPases in general, during mammalian brain development. Moreover, they indicate that Rac1 has a critical role in axon guidance and in acquisition of migratory competency during differentiation of the progenitors for the ventral telencephalon-derived interneurons.

Development of Cortical Maps: Perspectives From the Barrel Cortex

One approach to examining how higher sensory, motor, and cognitive faculties emerge in the neocortex is to elucidate the underlying wiring principles of the brain during development. The mammalian neocortex is a layered structure generated from a sheet of proliferating ventricular cells that progressively divide to form specific functional areas, such as the primary somatosensory (S1) and motor (M1) cortices. The basic wiring pattern in each of these functional areas is based on a similar framework, but is distinct in detail. Functional specialization in each area derives from a combination of molecular cues within the cortex and neuronal activity-dependent cues provided by innervating axons from the thalamus. One salient feature of neocortical development is the establishment of topographic maps in which neighboring neurons receive input relayed from neighboring sensory afferents. Barrels, which are prominent sensory units in the somatosensory cortex of rodents, have been examined in detail, and data suggest that the initial, gross formation of the barrel map relies on molecular cues, but the refinement of this topography depends on neuronal activity. Several excellent reviews have been published on the patterning and plasticity of the barrel cortex and the precise targeting of ventrobasal thalamic axons. In this review, the authors will focus on the formation and functional maturation of synapses between thalamocortical axons and cortical neurons, an event that coincides with the formation of the barrel map. They will briefly review cortical patterning and the initial targeting of thalamic axons, with an emphasis on recent findings. The rest of the review will be devoted to summarizing their understanding of the cellular and molecular mechanisms underlying thalamocortical synapse maturation and its role in barrel map formation.