GABA modulates development of cerebellar Purkinje cell dendrites under control of endocannabinoid signaling

Purkinje cells (PCs) are the sole projection neurons in the cerebellar cortex with highly arborized dendrites, on which they receive glutamatergic and GABAergic inputs. Whereas influences of glutamatergic inputs on dendritic development of PCs have been well studied, those of GABA remain elusive. Here we examined effects of GABAergic signaling on dendritogenesis of PCs in dissociated cerebellar cultures. Treatment with GABA(A) agonists such as muscimol altered Purkinje dendrites to longer and less branched morphology, while GABA(A) antagonists resulted in shorter dendrites. In contrast, neither a GABA(B) agonist nor antagonist had major effects on dendritic morphology. Simultaneous addition of a glutamatergic antagonist cocktail or the Trk receptor antagonist K252a did not block muscimol. Furthermore, blockade of endocannabinoid signaling by either AM251 or tetrahydrolipstatin resulted in longer and less branched dendrites similar to those treated with GABA(A) agonists suggesting upstream regulation by endocannabinoids. Notably, whereas Purkinje dendrites extended in random directions in the presence of muscimol, they oriented to coexisting GABAergic interneurons when treated with AM251. Taken together, our results postulate the hypothesis that GABA released from the cerebellar interneurons modulates dendritogenesis of PCs in an endocannabinoid-dependent manner in the developing cerebellar cortex.