mGluR4-containing corticostriatal terminals: synaptic interactions with direct and indirect pathway neurons in mice

Glutamatergic afferents from the cerebral cortex are the main excitatory drive of striatal projection neurons. The metabotropic glutamate receptor 4 (mGluR4) presynaptically modulates transmission at corticostriatal synapses, and is considered as a potent drug target for Parkinson’s disease and other brain disorders. To better characterize the anatomical substrate that underlies the functional effects of mGluR4 in the striatum, we undertook electron microscopic localization studies of mGluR4 expression in the mouse striatum. Our data demonstrate that more than 80 % mGluR4-immunoreactive structures are accounted for by unmyelinated axons and axon terminals, and that almost 50 % putative glutamatergic terminals (i.e. forming asymmetric synapses) express mGluR4 in the mouse striatum. Using vGluT1 as a presynaptic marker of glutamatergic corticostriatal boutons, our findings indicate: (1) all striatal mGluR4-positive terminals co-express vGluT1 immunoreactivity, (2) 44.3 % total striatal glutamatergic terminals co-express vGluT1 and mGluR4, and (3) mGluR4 is expressed in 73.4 % of total striatal vGluT1-positive terminals. To determine if mGluR4 terminals target preferentially direct vs. indirect pathway neurons, mGluR4 immunostaining was combined with D1 receptor immunoreactivity. These data showed that around 30 % mGluR4-immunoreactive glutamatergic terminals target D1 receptor-positive spines (i.e. direct pathway neurons), while almost 70 % formed synapses with D1 receptor-negative spines (i.e. putative indirect pathway neurons). Thus, these immuno-electron microscopic studies suggest that pre-synaptic mGluR4 in striatal glutamatergic terminals is expressed almost exclusively in cortical boutons to subserve regulatory influences upon a large contingent of corticostriatal terminals that preferentially target putative “indirect” pathway striatal projection neurons in mice. These observations provide a rationale for the use of mGluR4 allosteric potentiator as a potential therapy in Parkinson’s disease.