mGluR5 Tunes NGF/TrkA Signaling to Orient Spiny Stellate Neuron Dendrites Toward Thalamocortical Axons During Whisker-Barrel Map Formation

Abstract

Neurons receive and integrate synaptic inputs at their dendrites, thus dendritic patterning shapes neural connectivity and behavior. Aberrant dendritogenesis is present in neurodevelopmental disorders such as Down’s syndrome and autism. Abnormal glutamatergic signaling has been observed in these diseases, as has dysfunction of the metabotropic glutamate receptor 5 (mGluR5). Deleting mGluR5 in cortical glutamatergic neurons disrupted their coordinated dendritic outgrowth toward thalamocortical axons and perturbed somatosensory circuits. Here we show that mGluR5 loss-of-function disrupts dendritogenesis of cortical neurons by increasing mRNA levels of nerve growth factor (NGF) and fibroblast growth factor 10 (FGF10), in part through calcium-permeable AMPA receptors (CP-AMPARs), as the whisker-barrel map is forming. Postnatal NGF and FGF10 expression in cortical layer IV spiny stellate neurons differentially impacted dendritic patterns. Remarkably, NGF-expressing neurons exhibited dendritic patterns resembling mGluR5 knockout neurons: increased total dendritic length/complexity and reduced polarity. Furthermore, suppressing the kinase activity of TrkA, a major NGF receptor, prevents aberrant dendritic patterning in barrel cortex of mGluR5 knockout neurons. These results reveal novel roles for NGF-TrkA signaling and CP-AMPARs for proper dendritic development of cortical neurons. This is the first in vivo demonstration that cortical neuronal NGF expression modulates dendritic patterning during postnatal brain development.