Neural cell adhesion molecule-mediated Fyn activation promotes GABAergic synapse maturation in postnatal mouse cortex

TY - JOUR

T1 - Neural cell adhesion molecule-mediated Fyn activation promotes GABAergic synapse maturation in postnatal mouse cortex

AU - Chattopadhyaya, Bidisha

AU - Baho, Elie

AU - Huang, Z Josh

AU - Schachner, Melitta

AU - Di Cristo, Graziella

PY - 2013/4/3

Y1 - 2013/4/3

N2 - GABAergic basket interneurons form perisomatic synapses, which are essential for regulating neural networks, and their alterations are linked to various cognitive dysfunction. Maturation of basket synapses in postnatal cortex is activity dependent. In particular, activity-dependent downregulation of polysialiac acid carried by the neural cell adhesion molecule (NCAM) regulates the timing of their maturation. Whether and how NCAM per se affects GABAergic synapse development is unknown. Using single-cell genetics to knock out NCAM in individual basket interneurons in mouse cortical slice cultures, at specific developmental time periods, we found that NCAM loss during perisomatic synapse formation impairs the process of basket cell axonal branching and bouton formation. However, loss of NCAM once the synapses are already formed did not show any effect. We further show that NCAM120 and NCAM140, but not the NCAM180 isoform, rescue the phenotype. Finally, we demonstrate that a dominant-negative form of Fyn kinase mimics, whereas a constitutively active form of Fyn kinase rescues, the effects of NCAM knockdown. Altogether, our data suggest that NCAM120/NCAM140-mediated Fyn activation promotes GABAergic synapse maturation in postnatal cortex.

AB - GABAergic basket interneurons form perisomatic synapses, which are essential for regulating neural networks, and their alterations are linked to various cognitive dysfunction. Maturation of basket synapses in postnatal cortex is activity dependent. In particular, activity-dependent downregulation of polysialiac acid carried by the neural cell adhesion molecule (NCAM) regulates the timing of their maturation. Whether and how NCAM per se affects GABAergic synapse development is unknown. Using single-cell genetics to knock out NCAM in individual basket interneurons in mouse cortical slice cultures, at specific developmental time periods, we found that NCAM loss during perisomatic synapse formation impairs the process of basket cell axonal branching and bouton formation. However, loss of NCAM once the synapses are already formed did not show any effect. We further show that NCAM120 and NCAM140, but not the NCAM180 isoform, rescue the phenotype. Finally, we demonstrate that a dominant-negative form of Fyn kinase mimics, whereas a constitutively active form of Fyn kinase rescues, the effects of NCAM knockdown. Altogether, our data suggest that NCAM120/NCAM140-mediated Fyn activation promotes GABAergic synapse maturation in postnatal cortex.

KW - Analysis of Variance

KW - Animals

KW - Animals, Newborn

KW - Cerebral Cortex

KW - Female

KW - Gene Expression Regulation, Developmental

KW - Green Fluorescent Proteins

KW - Interneurons

KW - Male

KW - Mice

KW - Mice, Transgenic

KW - Neural Cell Adhesion Molecules

KW - Neural Inhibition

KW - Organ Culture Techniques

KW - Phosphopyruvate Hydratase

KW - Protein Isoforms

KW - Proto-Oncogene Proteins c-fyn

KW - Statistics, Nonparametric

KW - Synapses

KW - gamma-Aminobutyric Acid

U2 - 10.1523/JNEUROSCI.1306-12.2013

DO - 10.1523/JNEUROSCI.1306-12.2013

M3 - SCORING: Journal article

C2 - 23554477

VL - 33

SP - 5957

EP - 5968

JO - J NEUROSCI

JF - J NEUROSCI

SN - 0270-6474

IS - 14

ER -