Role of pre- and postsynaptic activity in thalamocortical axon branching

Yamada, Akito; Uesaka, Naofumi; Hayano, Yasufumi; Tabata, Toshihide; Kano, Masanobu; Yamamoto, Naoya

doi:10.1073/pnas.0900613107

Cited by 49 publications

(69 citation statements)

References 52 publications

(61 reference statements)

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“…However, axonal branching seems to be more sensitive to intrinsic excitability rather than neurotransmitter release; the development of the olfactory sensory map is more severely disrupted by expression of Kir2.1 than by the expression of TTLC (Yu et al, 2004). In addition, suppression of postsynaptic intrinsic excitability also affects axonal branching of presynaptic neurons (Yamada et al, 2010). We found that inhibition of intrinsic excitability, and not neurotransmitter release, affects spine development.…”

Section: Discussionmentioning

confidence: 71%

“…Axonal development in the olfactory system, the thalamocortical path and the retina are all sensitive to synaptic transmission, because overexpression of Kir2.1 or TTLC alters axonal branching and connectivity (Yu et al, 2004;Yamada et al, 2010;Morgan et al, 2011). However, axonal branching seems to be more sensitive to intrinsic excitability rather than neurotransmitter release; the development of the olfactory sensory map is more severely disrupted by expression of Kir2.1 than by the expression of TTLC (Yu et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

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Excitability governs neural development in a hippocampal region specific manner

et al. 2015

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Neuronal activity, including intrinsic neuronal excitability and synaptic transmission, is an essential regulator of brain development. However, how the intrinsic neuronal excitability of distinct neurons affects their integration into developing circuits remains poorly understood. To investigate this problem, we created several transgenic mouse lines in which intrinsic excitability is suppressed, and the neurons are effectively silenced, in different excitatory neuronal populations of the hippocampus. Here we show that CA1, CA3 and dentate gyrus neurons each have unique responses to suppressed intrinsic excitability during circuit development. Silenced CA1 pyramidal neurons show altered spine development and synaptic transmission after postnatal day 15. By contrast, silenced CA3 pyramidal neurons seem to develop normally. Silenced dentate granule cells develop with input-specific decreases in spine density starting at postnatal day 11; however, a compensatory enhancement of neurotransmitter release onto these neurons maintains normal levels of synaptic activity. The synaptic changes in CA1 and dentate granule neurons are not observed when synaptic transmission, rather than intrinsic excitability, is blocked in these neurons. Thus, our results demonstrate a crucial role for intrinsic neuronal excitability in establishing hippocampal connectivity and reveal that neuronal development in each hippocampal region is distinctly regulated by excitability.

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Section: Discussionmentioning

confidence: 71%

Section: Discussionmentioning

confidence: 99%

Excitability governs neural development in a hippocampal region specific manner

et al. 2015

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“…Because we have shown previously that spontaneous activity promotes TC axon branching in cocultures of the thalamus and cortex (27,28), we attempted to identify gene(s) whose expression is down-regulated in corticalslice cultures by blocking firing and synaptic activity. Based on prior molecular screening and gene-expression analyses in the developing cortex, cadherin-6 (cdh6), ephrin-A5 (efna5), netrin-4 (ntn4), semaphorin7a (sema7a) and kit ligand (kitlg) were selected as candidate genes that are expressed in and around the TC recipient layer and may directly affect axon behavior (29)(30)(31)(32)(33).…”

Section: Identification Of a Target-derived Molecule Whose Expression Ismentioning

confidence: 99%

Netrin-4 regulates thalamocortical axon branching in an activity-dependent fashion

Hayano

Sasaki

Ohmura

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Axon branching is remodeled by sensory-evoked and spontaneous neuronal activity. However, the underlying molecular mechanism is largely unknown. Here, we demonstrate that the netrin family member netrin-4 (NTN4) contributes to activity-dependent thalamocortical (TC) axon branching. In the postnatal developmental stages of rodents, ntn4 expression was abundant in and around the TC recipient layers of sensory cortices. Neuronal activity dramatically altered the ntn4 expression level in the cortex in vitro and in vivo. TC axon branching was promoted by exogenous NTN4 and suppressed by depletion of the endogenous protein. Moreover,, which strongly bound to NTN4, was expressed in the sensory thalamus, and knockdown of Unc5B in thalamic cells markedly reduced TC axon branching. These results suggest that NTN4 acts as a positive regulator for TC axon branching through activity-dependent expression.A xon branching is an essential process to determine the final pattern of neuronal connections. Previous studies have demonstrated that axon branching is controlled not only by axon guidance-related molecules (1-6) but also by neuronal activity, such as firing and synaptic activity (7-10). However, how neuronal activity is converted into the molecular signals that underlie axon branching is still largely unknown.The thalamocortical (TC) projection is a well-characterized system in which to address this issue. TC axons originating from sensory thalamic nuclei form elaborate arbors, primarily in layer 4 of the neocortex (11). Lamina-specific axon branching occurs from the onset of development and is universal in the mammalian cortex (12-17), indicating that a rigid developmental program is predominant for laminar specificity. TC axon branching is also known to be modified by neuronal activity. In the visual system, geniculocortical axon arbors can be remodeled drastically by manipulating visual experience and cortical-cell activity (18)(19)(20)(21)(22). A similar feature has been demonstrated in the somatosensory system. In mutant mice in which synaptic transmission or downstream signaling mechanisms are disrupted, TC axon arbors are affected primarily along the tangential axis whereas their laminar pattern is not obviously influenced (23-26). We have also shown in vitro that the loss of firing and synaptic activities substantially suppresses TC axon branching in the target layer (27). All of these findings imply the existence of a target-derived, branch-promoting molecule whose expression is regulated by neuronal activity. In this study, we attempted to identify this hypothetical molecule and to reveal the molecular mechanism of its action. Results Identification of a Target-Derived Molecule Whose Expression IsRegulated by Neural Activity. Because we have shown previously that spontaneous activity promotes TC axon branching in cocultures of the thalamus and cortex (27, 28), we attempted to identify gene(s) whose expression is down-regulated in corticalslice cultures by blocking firing and synaptic activity. Based on prior mole...

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“…Second, the relative patterns of activity between individual axons projecting to the same targets can determine competitive interactions between them, ultimately affecting wiring patterns, as has been well documented in the visual system (Casagrande and Condo 1988;Penn et al 1998;Huberman et al 2006;Fredj et al 2010;Furman et al 2013). Finally, manipulation of the activity of either pre-or postsynaptic neurons can also affect axonal wiring patterns (Zhang et al 1998;Yamada et al 2010). Such is the case in the development of interhemispheric connections, where the targeting of callosal axons is impaired when activity is disrupted in either the cell bodies of projecting axons, or in their contralateral targets (Mizuno et al 2007;Mizuno et al 2010).…”

Section: Introductionmentioning

confidence: 99%

“…Formation of these callosal projections occurs at postnatal stages in rodents and is prevented by unilateral disruptions of sensory input (Innocenti and Frost 1979;Olavarria et al 1987;Koralek and Killackey 1990) or excitability of cortical neurons via overexpression of Kir2.1, a hyperpolarizing inward-rectifying potassium channel (Mizuno et al 2007;Mizuno et al 2010). It has previously been shown that both sensory deprivation of the whisker pad ) and overexpression of Kir2.1 in cortical neurons (Yamada et al 2010) affect the electrical activity of the cortex, which suggests that their effect on the development of callosal projections are due to altered cortical activity. However, exactly how activity affects interhemispheric targeting is not known.…”

Section: Introductionmentioning

confidence: 99%

Contralateral targeting of the corpus callosum

Fenlon¹

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During development, the brain establishes billions of precise connections in order to perform its myriad functions. The largest of these connections in placental mammals is the corpus callosum, which is a large bundle of axons linking the two cortical hemispheres of the brain. Absence or gross malformation of this structure is a relatively common developmental disorder in humans, producing symptoms ranging from severe to mild cognitive, emotional and motor deficits. However, recent evidence suggests that the corpus callosum can also display subtle malformations that are not visible with traditional magnetic resonance imaging methods, and that these may be involved in neurodevelopmental disorders such as autism and schizophrenia. The possibility of callosal misconnectivity arising independently of the widely-studied process of midline crossing highlights the need to investigate other less well-understood stages of callosal development. One such process that may be disrupted after normal midline crossing of the corpus callosum is contralateral targeting, where axons must locate, innervate and stabilize in their appropriate contralateral cortical targets.This thesis focuses on understanding the normal process of contralateral targeting, as well as the nature of its dependence on neuronal activity and the molecular mechanisms that regulate it. To investigate these topics, diverse approaches including in utero electroporation, stereotaxic brain injection, sensory deprivation paradigms, tissuespecific RNA extraction and RNA sequencing were used in the mouse somatosensory cortex model system of callosal connectivity. Novel patterns and processes of normal contralateral targeting were identified, as well as distinct periods of region-specific activitydependent and -independent axonal exuberance. Contralateral callosal targeting was also shown to be not just dependent on neuronal activity, but rather a balance of spatially symmetric activity between the two cortical hemispheres. The molecular mechanisms underlying activity-dependent and -independent stages of contralateral callosal targeting were also investigated, and a novel technique to extract RNA from an electroporated population of cell bodies and/or their callosal axons was developed to facilitate this study in the future.These results constitute fundamental insights into the process of contralateral callosal targeting, as well as some of the mechanisms that may lead to its disruption. This work provides solid foundations for future studies to build upon, and may ultimately help us to better understand subtle human disorders of neuronal connectivity.3

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Role of pre- and postsynaptic activity in thalamocortical axon branching

Cited by 49 publications

References 52 publications

Excitability governs neural development in a hippocampal region specific manner

Excitability governs neural development in a hippocampal region specific manner

Netrin-4 regulates thalamocortical axon branching in an activity-dependent fashion

Contralateral targeting of the corpus callosum

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