Direct assessment of presynaptic modulation of cortico-striatal glutamate release in a Huntington’s disease mouse model

Glutamate is the main excitatory neurotransmitter in the brain, and impairments in its signaling are associated with many neurological disorders, including Huntington’s disease (HD). Previous studies in HD mouse models demonstrate altered glutamate receptor distribution and signaling at cortico-striatal synapses, and some studies suggest that glutamate release is altered; however, traditional methods to study synaptic glutamate release are indirect or have poor temporal resolution. Here we utilize iGluSnFR, a modified green fluorescent protein reporter for real-time imaging of glutamate transmission, to study presynaptic modulation of cortical glutamate release in the striatum of the YAC128 HD mouse model. We determined that iGluSnFR can be used to accurately measure short- and long-term changes in glutamate release caused by modulation of extracellular Ca2+ levels, activation of presynaptic receptors, and high-frequency stimulation (HFS) protocols. We also confirmed a difference in the expression of HFS-induced long-term depression in YAC128. Together, this research demonstrates the utility of iGluSnFR in studying presynaptic modulation of glutamate release in healthy mice and disease models that display impairments in glutamate signaling. NEW & NOTEWORTHY We use iGluSnFR to directly assess presynaptic modulation of cortico-striatal glutamate release in brain slice and compare changes in glutamate release between wild type and a Huntington’s disease mouse model, YAC128. We observed reductions in glutamate release after low extracellular Ca2+ and activation of various presynaptic receptors. We also demonstrate a presynaptic mechanism of reduced glutamate release in high-frequency stimulation-induced long-term depression and show this to be altered in YAC128.

Presynaptic modulation by somatostatin in the rat neostriatum is altered in a model of parkinsonism

Somatostatin (SST) is a peptide synthesized and released by a class of neostriatal local GABAergic interneurons, which, to some extent, are in charge of the feedforward inhibitory circuit. Spiny projection neurons (SPNs) make synapses with each other via their local axon collaterals, shaping the feedback inhibitory circuit. Both inhibitory circuits, feedforward and feedback, are related through SST, which, being released by interneurons, presynaptically inhibits connections among SPNs. Here, we studied SST presynaptic modulation of synapses among SPNs in the 6-hydroxydopamine (6-OHDA) rodent model of parkinsonism. We performed antidromic field stimulation from the external globus pallidus and whole cell voltage-clamp recordings of antidromically evoked inhibitory postsynaptic currents (IPSCs) among SPNs. SST presynaptically reduced IPSCs by ∼34% in all control synapses tested. However, after striatal dopamine deprivation, three changes became evident. First, it was harder to evoke feedback inhibition. Second, presynaptic inhibition of some SPNs connections was larger than in controls: 57% reduction in ∼53% of evoked IPSCs. Presynaptic inhibition was recorded from direct pathway neurons (direct SPNs). Finally, SST also induced presynaptic facilitation in some SPNs connections, with 82% enhancement in ∼43% of evoked IPSCs. Presynaptic facilitation was recorded from indirect pathway neurons (indirect SPNs). Both inhibition and facilitation were accompanied by corresponding changes in the paired pulse ratio. It was demonstrated that after dopamine deprivation, SST modulation is altered in surviving feedback inhibitory synapses. It may underlie a homeostatic mechanism trying to compensate for the excitability imbalance between direct and indirect basal ganglia pathways found during parkinsonism.