Glutamatergic Innervation onto Striatal Neurons Potentiates GABAergic Synaptic Output

Abstract

Striatal output pathways are known to play a crucial role in the control of movement. One possible component for shaping the synaptic output of striatal neuron is the glutamatergic input that originates from cortex and thalamus. Although reports focusing on quantifying glutamatergic-induced morphological changes in striatum exist, the role of glutamatergic input in regulating striatal function remains poorly understood. Using primary neurons from newborn mice of either sex in a reduced two-neuron microcircuit culture system, we examined whether glutamatergic input modulates the output of striatal neurons. We found that glutamatergic input enhanced striatal inhibition in vitro. With a glutamatergic partner from either cortex or thalamus, we attributed this potentiation to an increase in the size of quantal IPSC, suggesting a strengthening of the postsynaptic response to GABAergic signaling. Additionally, a differential effect of cortical and thalamic innervation onto striatal GABAergic neurons output was revealed. We observed that cortical, but not thalamic input, enhanced the number of releasable GABAergic synaptic vesicles and morphological synapses. Importantly, these alterations were reverted by blockade of neuronal activity and glutamate receptors, as well as disruption of BDNF-TrkB signaling. Together, our data indicate, for first time, that GABAergic synapse formation in corticostriatal pairs depends on two parallel, but potentially intersecting, signaling pathways that involve glutamate receptor activation in striatal neurons, as well as BDNF signaling. Understanding how cortical and thalamic inputs refine striatal output will pave the way toward dissecting basal ganglia activity in both physiological and pathological conditions. Significance StatementStriatal GABAergic microcircuits are critical for motor function. However, the mechanisms controlling striatal output, particularly at the level of synaptic strength, are unclear. Using two-neuron culture system, we quantified the synaptic output of individual striatal GABAergic neurons paired with a glutamatergic partner and studied the influence of the excitatory connections that are known to be interregionally formed in vivo. We found that glutamatergic input potentiated striatal inhibitory output, potentially involving an increased feedback and/or feedforward inhibition. Moreover, distinct components of glutamatergic innervation, such as firing activity or release of neurotrophic factors were shown to be required for the glutamatergic-induced phenotype. Investigation, therefore, of two-neuron in vitro microcircuits could be a powerful tool to explore synaptic mechanisms or disease pathophysiology.

Nitric Oxide Signaling Strengthens Inhibitory Synapses of Cerebellar Molecular Layer Interneurons through a GABARAP-Dependent Mechanism

“…In agreement with this, we have previously shown that reactive oxygen species enhance recruitment of postsynaptic a6but not a1-containing GABA A Rs in mouse granule cells (Accardi et al, 2015), whereas others have shown a presynaptic action of NO on GABA release from rat Golgi cells (Mapelli et al, 2016). Differential regulation of input-specific GABAergic synapses onto the same neuron has recently been described in the cerebral cortex (Chiu et al, 2018) and striatum (Paraskevopoulou et al, 2019), consequently, it is possible that a similar arrangement is found in both inhibitory synapses of MLIs and granule cells of the cerebellum. An important caveat to both presynaptic and postsynaptic roles of NO in granule cells, however, is that nNOS expression in the presynaptic terminals of Golgi cells is high in the rat but almost completely absent from the mouse, particularly mice with the C57BL/6 background used in this study (Kaplan et al, 2013).…”

Autaptic Cultures: Methods and Applications

“…Other work has explored the competition between glutamatergic and GABAergic neurons when grown as mixed or homotypic pairs (Rao et al, 2000;Chang et al, 2014;Wierda and Sørensen, 2014), or between wildtype and mutant neurons that lack presynaptic proteins involved in transmitter release (Tarsa and Goda, 2002;García-Pérez et al, 2015). Finally, two-cell microislands with different combinations of striatal, cortical and thalamic neurons have been used to examine the effect of glutamatergic input on refining striatal output (Paraskevopoulou et al, 2019).…”

Network-centered homeostasis through inhibition maintains hippocampal spatial map and cortical circuit function

“…Inhibitory output has also been shown to be modulated by activity, through modulation of rate limiting enzymes of GABA synthesis (Lau & Murthy 2012) or GABA transporters (De Gois et al 2005). Such plasticity mechanisms have also recently been reported in the chandelier cells (Pan-Vazquez et al 2020) and striatial inhibitory neurons (Paraskevopoulou et al 2019) during development. Altogether, these studies indicate that our model of tonic inhibition modulated as a function of synaptic input to the inhibitory neurons is a biologically plausible mechanism.…”