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Protocadherin-dependent dendritic self-avoidance regulates neural connectivity and circuit function.

Kostadinov D, Sanes JR - Elife (2015)

Bottom Line: The functional roles of these processes remain unknown.These alterations degrade the direction selectivity of DSGCs.Thus, self-avoidance, self/non-self discrimination, and synapse elimination are essential for proper function of a circuit that computes directional motion.

View Article: PubMed Central - PubMed

Affiliation: Center for Brain Science, Department of Molecular and Cellular Biology, Harvard University, Cambridge, United States.

ABSTRACT
Dendritic and axonal arbors of many neuronal types exhibit self-avoidance, in which branches repel each other. In some cases, these neurites interact with those of neighboring neurons, a phenomenon called self/non-self discrimination. The functional roles of these processes remain unknown. In this study, we used retinal starburst amacrine cells (SACs), critical components of a direction-selective circuit, to address this issue. In SACs, both processes are mediated by the gamma-protocadherins (Pcdhgs), a family of 22 recognition molecules. We manipulated Pcdhg expression in SACs and recorded from them and their targets, direction-selective ganglion cells (DSGCs). SACs form autapses when self-avoidance is disrupted and fail to form connections with other SACs when self/non-self discrimination is perturbed. Pcdhgs are also required to prune connections between closely spaced SACs. These alterations degrade the direction selectivity of DSGCs. Thus, self-avoidance, self/non-self discrimination, and synapse elimination are essential for proper function of a circuit that computes directional motion.

No MeSH data available.


Related in: MedlinePlus

Decreased SAC–SAC connections in Pcdhg1 retina.(A) Replacement of all 22 Pcdhgs in SACs with a single Pcdhg isoform (top) rescues self-avoidance in individual SACs (bottom). (B) Plexus of all SAC dendrites (stained with anti-ChAT) in Pcdhg22 (left), Pcdhg0 (middle), and Pcdhg1 (right) retinas. (C) Presynaptic voltage steps from Vh = −70 to +20 mV (top) and examples of currents recorded from both pre- and postsynaptic pairs of SACs that were connected (middle) and not connected (bottom) in juvenile Pcdhg1 retinas. (D–E) Scatter plots of intercellular distance vs peak current size in juvenile (D) and adult (E) Pcdhg1 retinas. (F) Percent of P15-24 recorded SAC pairs that were connected, irrespective of intercellular distance. Number of connections tested = 34, 37, and 19 in Pcdhg22, Pcdhg0, and Pcdhg1 retinas, respectively. (G) Same as F for adult retinas. Number of connections tested = 35, 39, and 13 in Pcdhg22, Pcdhg0, and Pcdhg1 retinas, respectively. (H) Average peak current in connected SAC pairs at all ages. Number of recorded connections = 30, 43, and 3 in Pcdhg22, Pcdhg0, and Pcdhg1 retinas, respectively. Scale bar = 50 μm in A and 25 μm in B. Data are shown as mean ± S.E.M. Statistics: **p < 0.01.DOI:http://dx.doi.org/10.7554/eLife.08964.011
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fig4: Decreased SAC–SAC connections in Pcdhg1 retina.(A) Replacement of all 22 Pcdhgs in SACs with a single Pcdhg isoform (top) rescues self-avoidance in individual SACs (bottom). (B) Plexus of all SAC dendrites (stained with anti-ChAT) in Pcdhg22 (left), Pcdhg0 (middle), and Pcdhg1 (right) retinas. (C) Presynaptic voltage steps from Vh = −70 to +20 mV (top) and examples of currents recorded from both pre- and postsynaptic pairs of SACs that were connected (middle) and not connected (bottom) in juvenile Pcdhg1 retinas. (D–E) Scatter plots of intercellular distance vs peak current size in juvenile (D) and adult (E) Pcdhg1 retinas. (F) Percent of P15-24 recorded SAC pairs that were connected, irrespective of intercellular distance. Number of connections tested = 34, 37, and 19 in Pcdhg22, Pcdhg0, and Pcdhg1 retinas, respectively. (G) Same as F for adult retinas. Number of connections tested = 35, 39, and 13 in Pcdhg22, Pcdhg0, and Pcdhg1 retinas, respectively. (H) Average peak current in connected SAC pairs at all ages. Number of recorded connections = 30, 43, and 3 in Pcdhg22, Pcdhg0, and Pcdhg1 retinas, respectively. Scale bar = 50 μm in A and 25 μm in B. Data are shown as mean ± S.E.M. Statistics: **p < 0.01.DOI:http://dx.doi.org/10.7554/eLife.08964.011

Mentions: The overall morphology, number, and spacing of SACs, as well as overall retinal structure, were normal in Pcdhg1 mice (Figure 4A and Figure 2—figure supplements 3, 4), and SAC dendrites formed a fine plexus within which, despite a decrease in overlap between pairs of neurons (Lefebvre et al., 2012), they had ample opportunity to come into close proximity to each other (Figure 4B). We made paired recordings from SACs in Pcdhg1 mice at P15-24 using methods described in Figure 2 (Figure 4C,D). The frequency of SAC–SAC connections in Pcdhg1 mice was ∼20% of that in Pcdhg22 or Pcdhg0 mice (Figure 4F). Similarly, current sizes in connected pairs in Pcdhg1 mice were on average ∼40% of those recorded in Pcdhg22 or Pcdhg0 mice (Figure 4H). Thus, forcing expression of the same Pcdhg isoform in all SACs decreased their connection strength to <10% (0.2 × 0.4) of controls. A similar decrease was observed in adult Pcdhg1 retinas (Figure 4E,G,H). We conclude that Pcdhg diversity is required for functional connectivity between neighboring SACs.10.7554/eLife.08964.011Figure 4.Decreased SAC–SAC connections in Pcdhg1 retina.


Protocadherin-dependent dendritic self-avoidance regulates neural connectivity and circuit function.

Kostadinov D, Sanes JR - Elife (2015)

Decreased SAC–SAC connections in Pcdhg1 retina.(A) Replacement of all 22 Pcdhgs in SACs with a single Pcdhg isoform (top) rescues self-avoidance in individual SACs (bottom). (B) Plexus of all SAC dendrites (stained with anti-ChAT) in Pcdhg22 (left), Pcdhg0 (middle), and Pcdhg1 (right) retinas. (C) Presynaptic voltage steps from Vh = −70 to +20 mV (top) and examples of currents recorded from both pre- and postsynaptic pairs of SACs that were connected (middle) and not connected (bottom) in juvenile Pcdhg1 retinas. (D–E) Scatter plots of intercellular distance vs peak current size in juvenile (D) and adult (E) Pcdhg1 retinas. (F) Percent of P15-24 recorded SAC pairs that were connected, irrespective of intercellular distance. Number of connections tested = 34, 37, and 19 in Pcdhg22, Pcdhg0, and Pcdhg1 retinas, respectively. (G) Same as F for adult retinas. Number of connections tested = 35, 39, and 13 in Pcdhg22, Pcdhg0, and Pcdhg1 retinas, respectively. (H) Average peak current in connected SAC pairs at all ages. Number of recorded connections = 30, 43, and 3 in Pcdhg22, Pcdhg0, and Pcdhg1 retinas, respectively. Scale bar = 50 μm in A and 25 μm in B. Data are shown as mean ± S.E.M. Statistics: **p < 0.01.DOI:http://dx.doi.org/10.7554/eLife.08964.011
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4548410&req=5

fig4: Decreased SAC–SAC connections in Pcdhg1 retina.(A) Replacement of all 22 Pcdhgs in SACs with a single Pcdhg isoform (top) rescues self-avoidance in individual SACs (bottom). (B) Plexus of all SAC dendrites (stained with anti-ChAT) in Pcdhg22 (left), Pcdhg0 (middle), and Pcdhg1 (right) retinas. (C) Presynaptic voltage steps from Vh = −70 to +20 mV (top) and examples of currents recorded from both pre- and postsynaptic pairs of SACs that were connected (middle) and not connected (bottom) in juvenile Pcdhg1 retinas. (D–E) Scatter plots of intercellular distance vs peak current size in juvenile (D) and adult (E) Pcdhg1 retinas. (F) Percent of P15-24 recorded SAC pairs that were connected, irrespective of intercellular distance. Number of connections tested = 34, 37, and 19 in Pcdhg22, Pcdhg0, and Pcdhg1 retinas, respectively. (G) Same as F for adult retinas. Number of connections tested = 35, 39, and 13 in Pcdhg22, Pcdhg0, and Pcdhg1 retinas, respectively. (H) Average peak current in connected SAC pairs at all ages. Number of recorded connections = 30, 43, and 3 in Pcdhg22, Pcdhg0, and Pcdhg1 retinas, respectively. Scale bar = 50 μm in A and 25 μm in B. Data are shown as mean ± S.E.M. Statistics: **p < 0.01.DOI:http://dx.doi.org/10.7554/eLife.08964.011
Mentions: The overall morphology, number, and spacing of SACs, as well as overall retinal structure, were normal in Pcdhg1 mice (Figure 4A and Figure 2—figure supplements 3, 4), and SAC dendrites formed a fine plexus within which, despite a decrease in overlap between pairs of neurons (Lefebvre et al., 2012), they had ample opportunity to come into close proximity to each other (Figure 4B). We made paired recordings from SACs in Pcdhg1 mice at P15-24 using methods described in Figure 2 (Figure 4C,D). The frequency of SAC–SAC connections in Pcdhg1 mice was ∼20% of that in Pcdhg22 or Pcdhg0 mice (Figure 4F). Similarly, current sizes in connected pairs in Pcdhg1 mice were on average ∼40% of those recorded in Pcdhg22 or Pcdhg0 mice (Figure 4H). Thus, forcing expression of the same Pcdhg isoform in all SACs decreased their connection strength to <10% (0.2 × 0.4) of controls. A similar decrease was observed in adult Pcdhg1 retinas (Figure 4E,G,H). We conclude that Pcdhg diversity is required for functional connectivity between neighboring SACs.10.7554/eLife.08964.011Figure 4.Decreased SAC–SAC connections in Pcdhg1 retina.

Bottom Line: The functional roles of these processes remain unknown.These alterations degrade the direction selectivity of DSGCs.Thus, self-avoidance, self/non-self discrimination, and synapse elimination are essential for proper function of a circuit that computes directional motion.

View Article: PubMed Central - PubMed

Affiliation: Center for Brain Science, Department of Molecular and Cellular Biology, Harvard University, Cambridge, United States.

ABSTRACT
Dendritic and axonal arbors of many neuronal types exhibit self-avoidance, in which branches repel each other. In some cases, these neurites interact with those of neighboring neurons, a phenomenon called self/non-self discrimination. The functional roles of these processes remain unknown. In this study, we used retinal starburst amacrine cells (SACs), critical components of a direction-selective circuit, to address this issue. In SACs, both processes are mediated by the gamma-protocadherins (Pcdhgs), a family of 22 recognition molecules. We manipulated Pcdhg expression in SACs and recorded from them and their targets, direction-selective ganglion cells (DSGCs). SACs form autapses when self-avoidance is disrupted and fail to form connections with other SACs when self/non-self discrimination is perturbed. Pcdhgs are also required to prune connections between closely spaced SACs. These alterations degrade the direction selectivity of DSGCs. Thus, self-avoidance, self/non-self discrimination, and synapse elimination are essential for proper function of a circuit that computes directional motion.

No MeSH data available.


Related in: MedlinePlus