Abstract
BackgroundThe development of functional neural circuits requires the precise formation of synaptic connections between diverse neuronal populations. The molecular pathways that allow GABAergic interneuron subtypes in the mammalian brain to initially recognize their postsynaptic partners remain largely unknown. The transmembrane glycoprotein Dystroglycan is localized to inhibitory synapses in pyramidal neurons, where it is required for the proper function of CCK+ interneurons. However, the precise temporal requirement for Dystroglycan during inhibitory synapse development has not been examined.MethodsIn this study, we use NEXCre or Camk2aCreERT2 to conditionally delete Dystroglycan from newly-born or adult pyramidal neurons, respectively. We then analyze forebrain development from postnatal day 3 through adulthood, with a particular focus on CCK+ interneurons.ResultsIn the absence of postsynaptic Dystroglycan in developing pyramidal neurons, presynaptic CCK+ interneurons fail to elaborate their axons and largely disappear from the cortex, hippocampus, amygdala, and olfactory bulb during the first two postnatal weeks. Other interneuron subtypes are unaffected, indicating that CCK+ interneurons are unique in their requirement for postsynaptic Dystroglycan. Dystroglycan does not appear to be required in adult pyramidal neurons to maintain CCK+ interneurons. Bax deletion did not rescue CCK+ interneurons in Dystroglycan mutants during development, suggesting that they are not eliminated by canonical apoptosis. Rather, we observed increased innervation of the striatum, suggesting that the few remaining CCK+ interneurons re-directed their axons to neighboring areas where Dystroglycan expression remained intact.ConclusionTogether these findings show that Dystroglycan functions as part of a synaptic partner recognition complex that is required early for CCK+ interneuron development in the forebrain.
Highlights
The development of functional neural circuits requires the precise formation of synaptic connections between diverse neuronal populations
CCK+ interneurons are largely absent in mice lacking Dystroglycan from pyramidal neurons To investigate the role of neuronal Dystroglycan in forebrain development, we used a conditional genetic approach to delete Dystroglycan selectively from pyramidal neurons (PyNs)
Cannabinoid receptor 1 (CB1R)+ cell bodies could be seen in the cortex near the striatal boundary, with their axon terminals projecting into the striatum (Fig. 9H). These results suggest that some CCK+ interneuron (CCK+ IN) in the cortex of Dag1cKO mice may redirect their axons into the Discussion Dystroglycan plays a critical role in maintaining the integrity of the neuroepithelial scaffold during early stages of brain development, which has made it difficult to assess its function within neurons at subsequent stages
Summary
The development of functional neural circuits requires the precise formation of synaptic connections between diverse neuronal populations. The transmembrane glycoprotein Dystroglycan is localized to inhibitory synapses in pyramidal neurons, where it is required for the proper function of CCK+ interneurons. Proper function of neural circuits requires precise connections between specific populations of excitatory pyramidal and inhibitory neurons. The proper integration of inhibitory interneurons into neural circuits during development relies on multiple processes such as proliferation, migration, axon guidance, cell death, synaptic target selection, synapse formation (synaptogenesis) and synaptic maintenance. Many families of cell adhesion molecules have been implicated in controlling synapse development, they are often involved in multiple aspects of neural circuit development, making it difficult to determine their precise role in mediating synaptic specificity
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