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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: 6.75). 04/2012; 32(14):4790-802. DOI: 10.1523/JNEUROSCI.4462-11.2012
Source: PubMed

ABSTRACT 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: eLife digest The central nervous system—which is made up of the brain and spinal cord—processes information from all over the body. The information travels through cells called neurons, which connect to each other at junctions called synapses. A single neuron can receive information from many different places because it is covered with protrusions known as dendritic spines that enable it to form synapses with a variety of other neurons. In recent years, it has become apparent that brain cells other than neurons can influence synapse formation. The most abundant cells in the central nervous system are star-shaped cells known as astrocytes, which secrete molecules that control the timing and extent of synapse formation. Many previous studies on synapses have used a type of neuron found in the eye—called retinal ganglion cells—because these cells can be purified and grown in the laboratory in the absence of astrocytes. Under these conditions, they form very few synapses. However, in the presence of astrocytes the retinal ganglion cells form many more synapses, which is thought to be due to a protein called hevin and several other proteins that are secreted by the astrocytes. Risher et al. studied a region of the brain called the cerebral cortex in mice that were missing hevin. In the cortex of normal mice, the neurons generally form synapses with other neurons within the cortex, or with neurons from other parts of the brain that send long-distance projections into the cortex. The experiments revealed that fewer of these long-distance synapses formed in the cortex of the mice missing hevin compared to normal mice. When hevin was injected directly into the brains of the mice, more long-distance synapses were formed. Using a technique called three-dimensional electron microscopy, Risher et al. examined the structure of the synapses. In mice missing hevin, the synapses were much smaller and the dendritic spines were thin and long, indicating that they were not fully grown. The images also show that in normal mice, the dendritic spines often have multiple synapses when the animal is young, but many are lost as the brain matures so that only a single synapse remains in each dendritic spine. However, multiple synapses persist in the dendritic spines of mice lacking hevin, which could lead to competition between short and long distance synapses and may contribute to neurological diseases. These results indicate that astrocytes are crucial for controlling the formation of synapses in dendritic spines. In humans, defects in hevin have been implicated in autism, schizophrenia and other neurological conditions. Future studies will seek to determine the precise role of astrocytes in these conditions, which may help us to develop new therapies. DOI: http://dx.doi.org/10.7554/eLife.04047.002
    eLife Sciences 12/2014; 3. DOI:10.7554/eLife.04047 · 8.52 Impact Factor
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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.
    Neuropharmacology 08/2014; 88. DOI:10.1016/j.neuropharm.2014.07.019 · 4.82 Impact Factor
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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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    Frontiers in Synaptic Neuroscience 03/2014; 6:6. DOI:10.3389/fnsyn.2014.00006
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