Cryo-correlative light and electron tomography of dopaminergic axonal varicosities reveals non-synaptic modulation of cortico-striatal synapses

Dopamine is an essential neuromodulator in the brain, involved in reward and motor control. Dopaminergic (DA) neurons project to most brain areas, with particularly dense innervation in the striatum. DA varicosities bind to target striatal synapses, forming dopamine hub synapses (DHS). However, the basic features of dopamine release sites are still largely unknown. Here we studied the ultrastructure of fluorescent DA and glutamatergic (GLU) synaptosomes isolated from the striatum of adult mice with cryo-correlative light and electron microscopy and cryo-electron tomography. We observed that DA synaptosomes display ~10 times fewer vesicles than GLU ones. DA vesicles are bigger and less round. The nanoscale organization of vesicles indicates that most GLU synaptosomes have tethered and primed vesicles, indicative of a readily releasable pool, while only 37% of DA synaptosomes have tethered vesicles, which appear not to be primed. In addition, GLU terminals contacted by DA terminals in DHS have more primed vesicles than others. While DA varicosities do not form genuine synapses, their adhesion to cortico-striatal synapses may convey a local regulation of synaptic release properties.