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Structural homeostasis: compensatory adjustments of dendritic arbor geometry in response to variations of synaptic input.

Tripodi M, Evers JF, Mauss A, Bate M, Landgraf M - PLoS Biol. (2008)

Bottom Line: Conversely, an increase in the density of presynaptic release sites induces a reduction in the extent of the dendritic arbor.These findings suggest that the dendritic arbor, at least during early stages of connectivity, behaves as a homeostatic device that adjusts its size and geometry to the level and the distribution of input received.The growing arbor thus counterbalances naturally occurring variations in synaptic density and activity so as to ensure that an appropriate level of input is achieved.

View Article: PubMed Central - PubMed

Affiliation: Department of Zoology, University of Cambridge, Cambridge, United Kingdom. ml10006@cam.ac.uk

ABSTRACT
As the nervous system develops, there is an inherent variability in the connections formed between differentiating neurons. Despite this variability, neural circuits form that are functional and remarkably robust. One way in which neurons deal with variability in their inputs is through compensatory, homeostatic changes in their electrical properties. Here, we show that neurons also make compensatory adjustments to their structure. We analysed the development of dendrites on an identified central neuron (aCC) in the late Drosophila embryo at the stage when it receives its first connections and first becomes electrically active. At the same time, we charted the distribution of presynaptic sites on the developing postsynaptic arbor. Genetic manipulations of the presynaptic partners demonstrate that the postsynaptic dendritic arbor adjusts its growth to compensate for changes in the activity and density of synaptic sites. Blocking the synthesis or evoked release of presynaptic neurotransmitter results in greater dendritic extension. Conversely, an increase in the density of presynaptic release sites induces a reduction in the extent of the dendritic arbor. These growth adjustments occur locally in the arbor and are the result of the promotion or inhibition of growth of neurites in the proximity of presynaptic sites. We provide evidence that suggest a role for the postsynaptic activity state of protein kinase A in mediating this structural adjustment, which modifies dendritic growth in response to synaptic activity. These findings suggest that the dendritic arbor, at least during early stages of connectivity, behaves as a homeostatic device that adjusts its size and geometry to the level and the distribution of input received. The growing arbor thus counterbalances naturally occurring variations in synaptic density and activity so as to ensure that an appropriate level of input is achieved.

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An Increase in Presynaptic Density, but Not Efficacy, Induces a Decrease of Postsynaptic Dendritic Arbor Extension(A) Reconstruction of a representative aCC arbor at 18 h AEL from a specimen in which faf was overexpressed in the presynaptic cholinergic neurons. Presynaptic sites on the arbor are indicated by coloration, with the colour code representing relative intensities of colocalised fluorescence signals. Scale bar indicates 5 μm.(B) Quantification of the synaptic density (dendritic surface occupied by synapses divided by total dendritic length) on the aCC arbor in control (red), Cha::faf (cyan), and Ace mutant animals (magenta). The synaptic density on the postsynaptic dendritic arbor is increased when faf is overexpressed presynaptically but not in Ace mutants (controls: 0.22 ± 0.03, n = 12; Cha::faf : 0.54 ± 0.07, n = 10; Ace mutants: 0.18 ± 0.01, n = 8).(C) Reconstruction of a representative aCC arbor of an Ace mutant animal. aCC arbors and the density of presynaptic cholinergic sites on these are comparable to controls. Scale bar indicates 5 μm.(D) Quantification of total dendritic tree length in control (red), Cha::faf (cyan), and Ace mutant animals (magenta). Presynaptic overexpression of faf induces reduced growth of the arbor (94 ± 4 μm, n = 10) as compared to controls (115 ± 7 μm, n = 13; p = 0.02). aCC arbors in Ace mutants are not significantly different from control animals (124 μm ± 14 μm, n = 8; p > 0.05).Box-plots show the median of the distribution (middle line), the 75th percentile (upper limit of box), and 25th percentile (lower limit of box). Whiskers indicate the highest and lowest value of each experimental group. Significance was assessed by unpaired, two-tailed t-test. A single asterisk (*) indicates p < 0.05; NS indicates p > 0.05.
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pbio-0060260-g005: An Increase in Presynaptic Density, but Not Efficacy, Induces a Decrease of Postsynaptic Dendritic Arbor Extension(A) Reconstruction of a representative aCC arbor at 18 h AEL from a specimen in which faf was overexpressed in the presynaptic cholinergic neurons. Presynaptic sites on the arbor are indicated by coloration, with the colour code representing relative intensities of colocalised fluorescence signals. Scale bar indicates 5 μm.(B) Quantification of the synaptic density (dendritic surface occupied by synapses divided by total dendritic length) on the aCC arbor in control (red), Cha::faf (cyan), and Ace mutant animals (magenta). The synaptic density on the postsynaptic dendritic arbor is increased when faf is overexpressed presynaptically but not in Ace mutants (controls: 0.22 ± 0.03, n = 12; Cha::faf : 0.54 ± 0.07, n = 10; Ace mutants: 0.18 ± 0.01, n = 8).(C) Reconstruction of a representative aCC arbor of an Ace mutant animal. aCC arbors and the density of presynaptic cholinergic sites on these are comparable to controls. Scale bar indicates 5 μm.(D) Quantification of total dendritic tree length in control (red), Cha::faf (cyan), and Ace mutant animals (magenta). Presynaptic overexpression of faf induces reduced growth of the arbor (94 ± 4 μm, n = 10) as compared to controls (115 ± 7 μm, n = 13; p = 0.02). aCC arbors in Ace mutants are not significantly different from control animals (124 μm ± 14 μm, n = 8; p > 0.05).Box-plots show the median of the distribution (middle line), the 75th percentile (upper limit of box), and 25th percentile (lower limit of box). Whiskers indicate the highest and lowest value of each experimental group. Significance was assessed by unpaired, two-tailed t-test. A single asterisk (*) indicates p < 0.05; NS indicates p > 0.05.

Mentions: Our findings show that the absence of synaptic input (e.g., in Cha mutant or Cha::TNT-G animals) induces an increase in dendritic arbor extension. This indicates that evoked neurotransmitter release acts as a stop-growing signal. This finding further suggests that the additional dendritic growth, which is induced by the absence of evoked neurotransmitter release, might be exploratory and represent a homeostatic mechanism that balances the growth of the dendritic arbor with the state of its connectivity. If this were the case, one would expect that increasing the density of synaptic sites (from which the stop-growing signal[s] originate) should induce the opposite effect, namely a reduction of dendritic arbor extension. To test this idea, we generated embryos in which the number of presynaptic sites on aCC was increased. At the Drosophila larval neuromuscular junction, the number of presynaptic release sites formed by the motor neuron on the postsynaptic target muscle can be increased considerably by neuronal (presynaptic) overexpression of the deubiquitination enzyme fat-facets (Faf) [30]. When we overexpressed faf in the cholinergic neurons (Cha::faf), we found that this manipulation caused an increase in the density of synapses formed on the aCC motor neuron. In order to obtain a quantitative readout of synaptic density, we measured the surface of cholinergic synapses on the aCC dendritic arbor and normalized this for arbor length (μm2 of synaptic surface divided by μm of dendritic length). Overexpressing faf in cholinergic neurons does indeed significantly increase the density of presynaptic sites on the aCC dendritic arbor at 18 h AEL (in control animals, the synaptic density is 0.22 ± 0.03 μm, n = 12; in Cha::faf, 0.54 ± 0.07 μm, n = 10; p = 0.003) (Figure 5B).


Structural homeostasis: compensatory adjustments of dendritic arbor geometry in response to variations of synaptic input.

Tripodi M, Evers JF, Mauss A, Bate M, Landgraf M - PLoS Biol. (2008)

An Increase in Presynaptic Density, but Not Efficacy, Induces a Decrease of Postsynaptic Dendritic Arbor Extension(A) Reconstruction of a representative aCC arbor at 18 h AEL from a specimen in which faf was overexpressed in the presynaptic cholinergic neurons. Presynaptic sites on the arbor are indicated by coloration, with the colour code representing relative intensities of colocalised fluorescence signals. Scale bar indicates 5 μm.(B) Quantification of the synaptic density (dendritic surface occupied by synapses divided by total dendritic length) on the aCC arbor in control (red), Cha::faf (cyan), and Ace mutant animals (magenta). The synaptic density on the postsynaptic dendritic arbor is increased when faf is overexpressed presynaptically but not in Ace mutants (controls: 0.22 ± 0.03, n = 12; Cha::faf : 0.54 ± 0.07, n = 10; Ace mutants: 0.18 ± 0.01, n = 8).(C) Reconstruction of a representative aCC arbor of an Ace mutant animal. aCC arbors and the density of presynaptic cholinergic sites on these are comparable to controls. Scale bar indicates 5 μm.(D) Quantification of total dendritic tree length in control (red), Cha::faf (cyan), and Ace mutant animals (magenta). Presynaptic overexpression of faf induces reduced growth of the arbor (94 ± 4 μm, n = 10) as compared to controls (115 ± 7 μm, n = 13; p = 0.02). aCC arbors in Ace mutants are not significantly different from control animals (124 μm ± 14 μm, n = 8; p > 0.05).Box-plots show the median of the distribution (middle line), the 75th percentile (upper limit of box), and 25th percentile (lower limit of box). Whiskers indicate the highest and lowest value of each experimental group. Significance was assessed by unpaired, two-tailed t-test. A single asterisk (*) indicates p < 0.05; NS indicates p > 0.05.
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Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC2573934&req=5

pbio-0060260-g005: An Increase in Presynaptic Density, but Not Efficacy, Induces a Decrease of Postsynaptic Dendritic Arbor Extension(A) Reconstruction of a representative aCC arbor at 18 h AEL from a specimen in which faf was overexpressed in the presynaptic cholinergic neurons. Presynaptic sites on the arbor are indicated by coloration, with the colour code representing relative intensities of colocalised fluorescence signals. Scale bar indicates 5 μm.(B) Quantification of the synaptic density (dendritic surface occupied by synapses divided by total dendritic length) on the aCC arbor in control (red), Cha::faf (cyan), and Ace mutant animals (magenta). The synaptic density on the postsynaptic dendritic arbor is increased when faf is overexpressed presynaptically but not in Ace mutants (controls: 0.22 ± 0.03, n = 12; Cha::faf : 0.54 ± 0.07, n = 10; Ace mutants: 0.18 ± 0.01, n = 8).(C) Reconstruction of a representative aCC arbor of an Ace mutant animal. aCC arbors and the density of presynaptic cholinergic sites on these are comparable to controls. Scale bar indicates 5 μm.(D) Quantification of total dendritic tree length in control (red), Cha::faf (cyan), and Ace mutant animals (magenta). Presynaptic overexpression of faf induces reduced growth of the arbor (94 ± 4 μm, n = 10) as compared to controls (115 ± 7 μm, n = 13; p = 0.02). aCC arbors in Ace mutants are not significantly different from control animals (124 μm ± 14 μm, n = 8; p > 0.05).Box-plots show the median of the distribution (middle line), the 75th percentile (upper limit of box), and 25th percentile (lower limit of box). Whiskers indicate the highest and lowest value of each experimental group. Significance was assessed by unpaired, two-tailed t-test. A single asterisk (*) indicates p < 0.05; NS indicates p > 0.05.
Mentions: Our findings show that the absence of synaptic input (e.g., in Cha mutant or Cha::TNT-G animals) induces an increase in dendritic arbor extension. This indicates that evoked neurotransmitter release acts as a stop-growing signal. This finding further suggests that the additional dendritic growth, which is induced by the absence of evoked neurotransmitter release, might be exploratory and represent a homeostatic mechanism that balances the growth of the dendritic arbor with the state of its connectivity. If this were the case, one would expect that increasing the density of synaptic sites (from which the stop-growing signal[s] originate) should induce the opposite effect, namely a reduction of dendritic arbor extension. To test this idea, we generated embryos in which the number of presynaptic sites on aCC was increased. At the Drosophila larval neuromuscular junction, the number of presynaptic release sites formed by the motor neuron on the postsynaptic target muscle can be increased considerably by neuronal (presynaptic) overexpression of the deubiquitination enzyme fat-facets (Faf) [30]. When we overexpressed faf in the cholinergic neurons (Cha::faf), we found that this manipulation caused an increase in the density of synapses formed on the aCC motor neuron. In order to obtain a quantitative readout of synaptic density, we measured the surface of cholinergic synapses on the aCC dendritic arbor and normalized this for arbor length (μm2 of synaptic surface divided by μm of dendritic length). Overexpressing faf in cholinergic neurons does indeed significantly increase the density of presynaptic sites on the aCC dendritic arbor at 18 h AEL (in control animals, the synaptic density is 0.22 ± 0.03 μm, n = 12; in Cha::faf, 0.54 ± 0.07 μm, n = 10; p = 0.003) (Figure 5B).

Bottom Line: Conversely, an increase in the density of presynaptic release sites induces a reduction in the extent of the dendritic arbor.These findings suggest that the dendritic arbor, at least during early stages of connectivity, behaves as a homeostatic device that adjusts its size and geometry to the level and the distribution of input received.The growing arbor thus counterbalances naturally occurring variations in synaptic density and activity so as to ensure that an appropriate level of input is achieved.

View Article: PubMed Central - PubMed

Affiliation: Department of Zoology, University of Cambridge, Cambridge, United Kingdom. ml10006@cam.ac.uk

ABSTRACT
As the nervous system develops, there is an inherent variability in the connections formed between differentiating neurons. Despite this variability, neural circuits form that are functional and remarkably robust. One way in which neurons deal with variability in their inputs is through compensatory, homeostatic changes in their electrical properties. Here, we show that neurons also make compensatory adjustments to their structure. We analysed the development of dendrites on an identified central neuron (aCC) in the late Drosophila embryo at the stage when it receives its first connections and first becomes electrically active. At the same time, we charted the distribution of presynaptic sites on the developing postsynaptic arbor. Genetic manipulations of the presynaptic partners demonstrate that the postsynaptic dendritic arbor adjusts its growth to compensate for changes in the activity and density of synaptic sites. Blocking the synthesis or evoked release of presynaptic neurotransmitter results in greater dendritic extension. Conversely, an increase in the density of presynaptic release sites induces a reduction in the extent of the dendritic arbor. These growth adjustments occur locally in the arbor and are the result of the promotion or inhibition of growth of neurites in the proximity of presynaptic sites. We provide evidence that suggest a role for the postsynaptic activity state of protein kinase A in mediating this structural adjustment, which modifies dendritic growth in response to synaptic activity. These findings suggest that the dendritic arbor, at least during early stages of connectivity, behaves as a homeostatic device that adjusts its size and geometry to the level and the distribution of input received. The growing arbor thus counterbalances naturally occurring variations in synaptic density and activity so as to ensure that an appropriate level of input is achieved.

Show MeSH
Related in: MedlinePlus