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Activity-dependent modulation of neural circuit synaptic connectivity.

Tessier CR, Broadie K - Front Mol Neurosci (2009)

Bottom Line: This conclusion has been challenged recently through the use of new transgenic tools employed in the powerful Drosophila system, which have allowed unprecedented temporal control and single neuron imaging resolution.Such mechanisms of circuit refinement may be key to understanding a number of human neurological diseases, including developmental disorders such as Fragile X syndrome (FXS) and autism, which are hypothesized to result from defects in synaptic connectivity and activity-dependent circuit function.The particular emphasis of this review is on the expanding array of new genetically-encoded tools that are allowing cellular events and molecular players to be dissected with ever greater precision and detail.

View Article: PubMed Central - PubMed

Affiliation: Department of Biological Sciences, Vanderbilt University Nashville, TN, USA.

ABSTRACT
In many nervous systems, the establishment of neural circuits is known to proceed via a two-stage process; (1) early, activity-independent wiring to produce a rough map characterized by excessive synaptic connections, and (2) subsequent, use-dependent pruning to eliminate inappropriate connections and reinforce maintained synapses. In invertebrates, however, evidence of the activity-dependent phase of synaptic refinement has been elusive, and the dogma has long been that invertebrate circuits are "hard-wired" in a purely activity-independent manner. This conclusion has been challenged recently through the use of new transgenic tools employed in the powerful Drosophila system, which have allowed unprecedented temporal control and single neuron imaging resolution. These recent studies reveal that activity-dependent mechanisms are indeed required to refine circuit maps in Drosophila during precise, restricted windows of late-phase development. Such mechanisms of circuit refinement may be key to understanding a number of human neurological diseases, including developmental disorders such as Fragile X syndrome (FXS) and autism, which are hypothesized to result from defects in synaptic connectivity and activity-dependent circuit function. This review focuses on our current understanding of activity-dependent synaptic connectivity in Drosophila, primarily through analyzing the role of the fragile X mental retardation protein (FMRP) in the Drosophila FXS disease model. The particular emphasis of this review is on the expanding array of new genetically-encoded tools that are allowing cellular events and molecular players to be dissected with ever greater precision and detail.

No MeSH data available.


Related in: MedlinePlus

Use of transgenic calcium reporter gCAMP to visualize synaptic activity. (A) OK107-GAL4 driving UAS-gCAMP in primary neuron culture before and after depolarization. (B) OK107-GAL4 driving UAS-gCAMP in whole brain Mushroom Body axonal lobes (α, β, γ). Depolarization causes fluorescence increases throughout the Mushroom Body.
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Figure 5: Use of transgenic calcium reporter gCAMP to visualize synaptic activity. (A) OK107-GAL4 driving UAS-gCAMP in primary neuron culture before and after depolarization. (B) OK107-GAL4 driving UAS-gCAMP in whole brain Mushroom Body axonal lobes (α, β, γ). Depolarization causes fluorescence increases throughout the Mushroom Body.

Mentions: In addition to electrophysiological approaches, recent advances in Drosophila calcium imaging permit monitoring cellular responses to neuronal activation. Several GFP reporters have been generated which alter their fluorescence properties in the presence of calcium, thus allowing the visual monitoring of calcium influx and buffering dynamics (Reiff et al., 2005). Reporters including the camgaroos and gCAMPs are GFP fusion proteins coupled to calmodulin Ca2+ binding domains (Pologruto et al., 2004; Yu et al., 2003). Upon binding with calcium, the GFP reporter undergoes a conformational change to enhance fluorescence intensity (Figure 5). In Drosophila, these reporters can be used either in primary neuronal cultures of identified neuronal subtypes (Figure 5A) or in the intact brain (Figure 5B). In addition, the commonly utilized cameleon reporters are a fusion of the calmodulin binding domain situated between CFP and YFP (Miyawaki et al., 1997). The cameleon reporter relies on a FRET based mechanism to generate fluorescence changes in response to calcium binding. With this reporter, Ca2+ binding is monitored by a concomitant decrease in CFP emission and an increase in YFP emission (Fiala and Spall, 2003). Similarly, reporters based on the calcium-binding troponin C protein have been optimized by mutageneisis (TN-XXL) to produce high affinity calcium binding and reliable responses to stimulation (Mank et al., 2008). TN-XXL is sensitive over a range of stimulations and functions in both flies and mice as a stable monitor of calcium dynamics. Each transgenic reporter has distinct advantages and disadvantages, most notably in the respective signal to noise ratios, but they are continually being modified to provide the best physiological responses to neuronal activation.


Activity-dependent modulation of neural circuit synaptic connectivity.

Tessier CR, Broadie K - Front Mol Neurosci (2009)

Use of transgenic calcium reporter gCAMP to visualize synaptic activity. (A) OK107-GAL4 driving UAS-gCAMP in primary neuron culture before and after depolarization. (B) OK107-GAL4 driving UAS-gCAMP in whole brain Mushroom Body axonal lobes (α, β, γ). Depolarization causes fluorescence increases throughout the Mushroom Body.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2724028&req=5

Figure 5: Use of transgenic calcium reporter gCAMP to visualize synaptic activity. (A) OK107-GAL4 driving UAS-gCAMP in primary neuron culture before and after depolarization. (B) OK107-GAL4 driving UAS-gCAMP in whole brain Mushroom Body axonal lobes (α, β, γ). Depolarization causes fluorescence increases throughout the Mushroom Body.
Mentions: In addition to electrophysiological approaches, recent advances in Drosophila calcium imaging permit monitoring cellular responses to neuronal activation. Several GFP reporters have been generated which alter their fluorescence properties in the presence of calcium, thus allowing the visual monitoring of calcium influx and buffering dynamics (Reiff et al., 2005). Reporters including the camgaroos and gCAMPs are GFP fusion proteins coupled to calmodulin Ca2+ binding domains (Pologruto et al., 2004; Yu et al., 2003). Upon binding with calcium, the GFP reporter undergoes a conformational change to enhance fluorescence intensity (Figure 5). In Drosophila, these reporters can be used either in primary neuronal cultures of identified neuronal subtypes (Figure 5A) or in the intact brain (Figure 5B). In addition, the commonly utilized cameleon reporters are a fusion of the calmodulin binding domain situated between CFP and YFP (Miyawaki et al., 1997). The cameleon reporter relies on a FRET based mechanism to generate fluorescence changes in response to calcium binding. With this reporter, Ca2+ binding is monitored by a concomitant decrease in CFP emission and an increase in YFP emission (Fiala and Spall, 2003). Similarly, reporters based on the calcium-binding troponin C protein have been optimized by mutageneisis (TN-XXL) to produce high affinity calcium binding and reliable responses to stimulation (Mank et al., 2008). TN-XXL is sensitive over a range of stimulations and functions in both flies and mice as a stable monitor of calcium dynamics. Each transgenic reporter has distinct advantages and disadvantages, most notably in the respective signal to noise ratios, but they are continually being modified to provide the best physiological responses to neuronal activation.

Bottom Line: This conclusion has been challenged recently through the use of new transgenic tools employed in the powerful Drosophila system, which have allowed unprecedented temporal control and single neuron imaging resolution.Such mechanisms of circuit refinement may be key to understanding a number of human neurological diseases, including developmental disorders such as Fragile X syndrome (FXS) and autism, which are hypothesized to result from defects in synaptic connectivity and activity-dependent circuit function.The particular emphasis of this review is on the expanding array of new genetically-encoded tools that are allowing cellular events and molecular players to be dissected with ever greater precision and detail.

View Article: PubMed Central - PubMed

Affiliation: Department of Biological Sciences, Vanderbilt University Nashville, TN, USA.

ABSTRACT
In many nervous systems, the establishment of neural circuits is known to proceed via a two-stage process; (1) early, activity-independent wiring to produce a rough map characterized by excessive synaptic connections, and (2) subsequent, use-dependent pruning to eliminate inappropriate connections and reinforce maintained synapses. In invertebrates, however, evidence of the activity-dependent phase of synaptic refinement has been elusive, and the dogma has long been that invertebrate circuits are "hard-wired" in a purely activity-independent manner. This conclusion has been challenged recently through the use of new transgenic tools employed in the powerful Drosophila system, which have allowed unprecedented temporal control and single neuron imaging resolution. These recent studies reveal that activity-dependent mechanisms are indeed required to refine circuit maps in Drosophila during precise, restricted windows of late-phase development. Such mechanisms of circuit refinement may be key to understanding a number of human neurological diseases, including developmental disorders such as Fragile X syndrome (FXS) and autism, which are hypothesized to result from defects in synaptic connectivity and activity-dependent circuit function. This review focuses on our current understanding of activity-dependent synaptic connectivity in Drosophila, primarily through analyzing the role of the fragile X mental retardation protein (FMRP) in the Drosophila FXS disease model. The particular emphasis of this review is on the expanding array of new genetically-encoded tools that are allowing cellular events and molecular players to be dissected with ever greater precision and detail.

No MeSH data available.


Related in: MedlinePlus