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

Abstract

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 versus indirect pathway neurons, mGluR4 immunostaining was combined with D1 receptor immunoreactivity. These data showed that around 30% mGluR4-imunoreactive glutamatergic terminals target D1 receptor-positive spines (i.e. direct pathway neurons), while almost 70% formed synapses with D1 receptor-negative spines. Thus, these immuno-electron microscopic studies indicate 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 the “indirect” pathway striatal projection neurons in mice.

An mGlu4‐Positive Allosteric Modulator Alleviates Parkinsonism in Primates

“…In macaques, PET imaging was performed using [ 11 C]‐PXT012253, a radioligand that binds to the same allosteric site of mGlu4 as PXT002331 . Competition studies revealed that binding of the radioactive tracer was reduced in the presence of PXT002331 in brain areas where mGlu4 expression has been described (caudate, putamen, cortex, thalamus, and globus pallidus) (Fig. B), thus confirming that peripherally administered PXT002331 was able to gain access to the brain of primates.…”

“…Therefore, acting at key relays that will normalize the pathological activity of the basal ganglia motor circuit, be it at corticostriatal, striatopallidal, and/or subthalamopallidal synapses, represents a tantalizing approach. In that respect, metabotropic glutamate receptor 4 (mGlu4) has received much interest as a therapeutic target for a l ‐dopa‐sparing strategy in PD, given that it is presynaptically expressed in these key relays . At the striatopallidal and subthalamopallidal synapses, mGlu4 activation reduces gamma‐aminobutyric acid (GABA) and glutamate release in both pallidal segments and is predicted to restrain the overall activity of the overactive indirect pathway in PD .…”

Facilitating mGluR4 activity reverses the long-term deleterious consequences of chronic morphine exposure

“…Finally, morphine-exposed mice displayed significant locomotor sensitization to morphine after prolonged abstinence, consistent with previous findings (14,77), which was dampened by VU055041. Morphine-induced sensitization involves D1 receptor activation in striatal D1-MSNs (77)(78)(79), whose activity may be impacted by mGluR4 either directly in D1-MSNs (80,81) or through corticostriatal terminals forming synapses at D1-MSNs (82). However, an effect of VU0155041 at D2-MSNs cannot be ruled out, as they also contribute to drug-induced sensitization (83,84).…”

The Modulation of Pain by Metabotropic Glutamate Receptors 7 and 8 in the Dorsal Striatum

“…2). In the corticostriatal glutamatergic terminals, mGluR4 stimulation decreases glutamate release [86][87][88][89] and the excitatory transmission from the cortex [86][87][88]. In particular, mGluR4 is predominantly localized on the glutamatergic corticostriatal terminals, targeting the indirect pathway [90], whose hyperactivity in Parkinson's disease has been widely reported [91][92][93][94].…”