The development of neuronal circuits is controlled by guidance molecules that are hypothesized to interact with the cholesterol-enriched domains of the plasma membrane termed lipid rafts. Whether such domains enable local intracellular signalling at the submicrometre scale in developing neurons and are required for shaping the nervous system connectivity in vivo remains controversial. Here, we report a role for lipid rafts in generating domains of local cAMP signalling in axonal growth cones downstream of ephrin-A repulsive guidance cues. Ephrin-A-dependent retraction of retinal ganglion cell axons involves cAMP signalling restricted to the vicinity of lipid rafts and is independent of cAMP modulation outside of this microdomain. cAMP modulation near lipid rafts controls the pruning of ectopic axonal branches of retinal ganglion cells in vivo, a process requiring intact ephrin-A signalling. Together, our findings indicate that lipid rafts structure the subcellular organization of intracellular cAMP signalling shaping axonal arbors during the nervous system development.

Highlights d Cocaine seeking is potentiated by stimulating GABAergic ventral pallidum neurons d Cocaine seeking is reduced by stimulating glutamatergic ventral pallidal neurons d Glutamate and enkephalin neurons are differentially innervated by accumbens neurons d Calcium is increased during seeking in GABA and during extinction in glutamate neurons

Background: Microdeletions of the MEF2C gene are linked to a syndromic form of autism termed MEF2C Haploinsufficiency Syndrome (MCHS). MEF2C hypofunction in neurons is presumed to underlie most of the MCHS symptoms. However, it is unclear in which cell populations MEF2C functions to regulate neurotypical development.Methods: Multiple biochemical, molecular, electrophysiological, behavioral and transgenic mouse approaches were used to characterize MCHS-relevant synaptic, behavioral and gene expression changes in mouse models of MCHS. Results:We show here that MCHS-associated missense mutations cluster in the conserved DNA binding domain and disrupt MEF2C DNA binding. DNA binding-deficient global Mef2c heterozygous mice (Mef2c-Het) display numerous MCHS-related behaviors, including autism-*

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