Dendritic BDNF Synthesis Is Required for Late-Phase Spine Maturation and Recovery of Cortical Responses Following Sensory Deprivation

W.M. Keck Foundation Center for Integrative Neuroscience and Department of Physiology, University of California San Francisco, San Francisco, California 94143, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 04/2012; 32(14):4790-802. DOI: 10.1523/JNEUROSCI.4462-11.2012
Source: PubMed


Sensory experience in early postnatal life shapes neuronal connections in the brain. Here we report that the local synthesis of brain-derived neurotrophic factor (BDNF) in dendrites plays an important role in this process. We found that dendritic spines of layer 2/3 pyramidal neurons of the visual cortex in mutant mice lacking dendritic Bdnf mRNA and thus local BDNF synthesis were normal at 3 weeks of age, but thinner, longer, and more closely spaced (morphological features of immaturity) at 4 months of age than in wild-type (WT) littermates. Layer 2/3 of the visual cortex in these mutant animals also had fewer GABAergic presynaptic terminals at both ages. The overall size and shape of dendritic arbors were, however, similar in mutant and WT mice at both ages. By using optical imaging of intrinsic signals and single-unit recordings, we found that mutant animals failed to recover cortical responsiveness following monocular deprivation (MD) during the critical period, although they displayed normally the competitive loss of responsiveness to an eye briefly deprived of vision. Furthermore, MD still induced a loss of responsiveness to the closed eye in adult mutant mice, but not in adult WT mice. These results indicate that dendritic BDNF synthesis is required for spine pruning, late-phase spine maturation, and recovery of cortical responsiveness following sensory deprivation. They also suggest that maturation of dendritic spines is required for the maintenance of cortical responsiveness following sensory deprivation in adulthood.

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    • "Cortical dendritic spines, including those in V1, follow a stereotypic maturation timeline (Irwin et al., 2001). Long, highly motile filopodia-type protrusions abundant in early development give way to short, stable, wide-headed mushroom spines in the mature brain (Figure 5—figure supplement 1A) (Kaneko et al., 2012). The spine maturation timeline coincides to a large extent with the expression of hevin protein, which reaches its highest levels at P25 (Figure 1A,B). "
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    ABSTRACT: During cortical synaptic development, thalamic axons must establish synaptic connections despite the presence of the more abundant intracortical projections. How thalamocortical synapses are formed and maintained in this competitive environment is unknown. Here, we show that astrocyte-secreted protein hevin is required for normal thalamocortical synaptic connectivity in the mouse cortex. Absence of hevin results in a profound, long-lasting reduction in thalamocortical synapses accompanied by a transient increase in intracortical excitatory connections. Three-dimensional reconstructions of cortical neurons from serial section electron microscopy (ssEM) revealed that, during early postnatal development, dendritic spines often receive multiple excitatory inputs. Immuno-EM and confocal analyses revealed that majority of the spines with multiple excitatory contacts (SMECs) receive simultaneous thalamic and cortical inputs. Proportion of SMECs diminishes as the brain develops, but SMECs remain abundant in Hevin-null mice. These findings reveal that, through secretion of hevin, astrocytes control an important developmental synaptic refinement process at dendritic spines. DOI:
    Full-text · Article · Dec 2014 · eLife Sciences
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    • "The deficits in granule cell maturation seen in g2 þ/À mice are reminiscent of similar deficits seen in multiple mouse lines with genetically induced defects in BDNF/TrkB signaling (Sairanen et al., 2005; Kaneko et al., 2012; Waterhouse et al., 2012). This is consistent with substantial evidence that neurotrophic mechanisms of BDNF/TrkB are intrinsically intertwined with mechanisms of GABAergic transmission. "
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    ABSTRACT: Mice that were rendered heterozygous for the γ2 subunit of GABAA receptors (γ2(+/-) mice) have been characterized extensively as a model for major depressive disorder. The phenotype of these mice includes behavior indicative of heightened anxiety, despair, and anhedonia, as well as defects in hippocampus-dependent pattern separation, HPA axis hyperactivity and increased responsiveness to antidepressant drugs. The γ2(+/-) model thereby provides strong support for the GABAergic deficit hypothesis of major depressive disorder. Here we show that γ2(+/-) mice additionally exhibit specific defects in late stage survival of adult-born hippocampal granule cells, including reduced complexity of dendritic arbors and impaired maturation of synaptic spines. Moreover, cortical γ2(+/-) neurons cultured in vitro show marked deficits in GABAergic innervation selectively when grown under competitive conditions that may mimic the environment of adult-born hippocampal granule cells. Finally, brain extracts of γ2(+/-) mice show a numerical but insignificant trend (p = 0.06) for transiently reduced expression of brain derived neurotrophic factor (BDNF) at three weeks of age, which might contribute to the previously reported developmental origin of the behavioral phenotype of γ2(+/-) mice. The data indicate increasing congruence of the GABAergic, glutamatergic, stress-based and neurotrophic deficit hypotheses of major depressive disorder.
    Full-text · Article · Aug 2014 · Neuropharmacology
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    • "In excitatory neurons, BDNF-TrkB signaling regulates dendritic growth (Xu et al., 2000), spine maturation, stabilization (Gorski et al., 2003; Wirth et al., 2003; Chakravarthy et al., 2006; Tanaka et al., 2008; Kaneko et al., 2012), and long-term potentiation (LTP; Kang and Schuman, 1995; Figurov et al., 1996; Patterson et al., 1996; Tanaka et al., 1997; Frerking et al., 1998; Gottschalk et al., 1998; Huber et al., 1998). BDNF-TrkB signaling also plays a critical role in the development of synapses by regulating the transport of the membrane associated guanylate kinase the post-synaptic density protein PSD-95. "
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    ABSTRACT: BDNF and its receptor TrkB regulate synaptic plasticity. TrkB triggers three downstream signaling pathways; Phosphatidylinositol 3-kinase (PI3K), Phospholipase Cγ (PLC γ) and Mitogen activated protein kinases/ Extracellular signal-regulated kinases (MAPK/ERK). We previously showed two distinct mechanisms whereby BDNF-TrkB pathway controls trafficking of PSD-95, which is the major scaffold at excitatory synapses and is critical for synapse maturation. BDNF activates the PI3K-Akt pathway and regulates synaptic delivery of PSD-95 via vesicular transport (Yoshii et al. 2007). BDNF-TrkB signaling also triggers PSD-95 palmitoylation and its transport to synapses through the phosphorylation of the palmitoylation enzyme ZDHHC8 by a Protein kinase C (PKC) (Yoshii et al. 2011). The second study used PKC inhibitors chelerythrine as well as a synthetic zeta inhibitory peptide (ZIP) which was originally designed to block the brain-specific PKC isoform protein kinase Mζ (PKMζ). However, recent studies raise concerns about specificity of ZIP. Here, we assessed the contribution of TrkB and its three downstream pathways to the synaptic distribution of endogenous PSD-95 in cultured neurons using chemical and genetic interventions. We confirmed that TrkB, PLC and PI3K were critical for the postsynaptic distribution of PSD-95. Furthermore, suppression of MAPK/ERK also disrupted PSD-95 expression. Next, we examined the contribution of PKC. While both chelerythrine and ZIP suppressed the postsynaptic localization of PSD-95, RNA interference for PKMζ did not have a significant effect. This result suggests that the ZIP peptide, widely used as the “specific” PKMζ antagonist by many investigators may block a PKC variant other than PKMζ such as PKCλ/ι. Our results indicate that TrkB regulates postsynaptic localization of PSD-95 through all three downstream pathways, but also recommend further work to identify other PKC variants that regulate palmitoylation and synaptic localization of PSD-95.
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