Spontaneous Activity of the Local GABAergic Synaptic Network Causes Irregular Neuronal Firing in the External Globus Pallidus

Abstract

Autonomously firing GABAergic neurons in the external globus pallidus (GPe) form a local synaptic network. In slices, most GPe neurons receive a continuous inhibitory synaptic barrage from 1-2 presynaptic GPe neurons. We measured the barrage's effect on the firing rate and regularity of GPe neurons in male and female mice using perforated patch recordings. Silencing the firing of parvalbumin-positive (PV+) GPe neurons by activating genetically expressed Archaerhodopsin current increased the firing rate and regularity of PV- neurons. In contrast, silencing Npas1+ GPe neurons with Archaerhodopsin had insignificant effects on Npas1- neuron firing. Blocking spontaneous GABAergic synaptic input with gabazine reproduced the effects of silencing PV+ neuron firing on the firing rate and regularity of Npas1+ neurons and had similar effects on PV+ neuron firing. To simulate the barrage, we constructed conductance waveforms for dynamic clamp based on experimentally measured inhibitory postsynaptic conductance trains from 1-2 unitary local connections. The resulting inhibition replicated the effect on firing seen in the intact active network in the slice. We then increased the number of unitary inputs to match estimates of local network connectivityin vivo. As few as 5 unitary inputs produced large increases in firing irregularity. The firing rate was also reduced initially, but PV+ neurons exhibited a slow spike frequency adaptation that partially restored the rate despite sustained inhibition. We conclude that the irregular firing pattern of GPe neuronsin vivois largely due the ongoing local inhibitory synaptic barrage produced by the spontaneous firing of other GPe neurons.SIGNIFICANCE:Functional roles of local axon collaterals in the external globus pallidus (GPe) have remained elusive due to difficulty in isolating local inhibition from other GABAergic inputsin vivo, and in preserving the autonomous firing of GPe neurons and detecting their spontaneous local inputs in slices. We used perforated patch recordings to detect spontaneous local inputs during rhythmic firing. We found that the autonomous firing of single presynaptic GPe neurons produces inhibitory synaptic barrages that significantly alter the firing regularity of other GPe neurons. Our findings suggest that although GPe neurons receive input from only a few other GPe neurons, each local connection has a large impact on their firing.

Phase delays between mouse globus pallidus neurons entrained by common oscillatory drive arise from their intrinsic properties, not their coupling

“…The GPe neural network was simulated as described in Olivares et al (2022 One thousand model neurons were connected using a small-world architecture; each neuron was connected in a ring-like organization to its ten closest neighbors, and then 1% of the synapses were randomly rewired. The degree of connectivity is consistent with experimental data (Sadek et al, 2007; Bugaysen et al, 2013; Higgs et al, 2021, Jones et al, 2023). Neurons in the network were heterogeneous with respect to their iPRCs and intrinsic firing rates; both neuron properties were drawn from distributions that qualitatively represent experimental data from GPe neurons.…”

“…Out of these, 10 were PV-Cre, 2 were Npas1-Cre-tdTomato mice, and 2 were wildtype C57BL/6 mice without any genetic modifications. In total, 16 GPe neurons were examined, all classified as prototypic cells using the electrophysiological criterion of Jones et al (2023) [56]. Eleven of these were confirmed as parvalbumin-positive (PV+) either through fluorescence or via a distinct light-induced Archaerhodopsin-3 (Arch) hyperpolarization.…”

Phase Delays between Mouse Globus Pallidus Neurons Entrained by Common Oscillatory Drive Arise from Their Intrinsic Properties, Not Their Coupling

“…One thousand model neurons were connected using a small-world architecture; each neuron was connected in a ring-like organization to its 10 closest neighbors, and then 1% of the synapses were randomly rewired. The degree of connectivity is consistent with experimental data ( Sadek et al, 2007 ; Bugaysen et al, 2013 ; Higgs et al, 2021 ; Jones et al, 2023 ). Neurons in the network were heterogeneous with respect to their iPRCs and intrinsic firing rates; both neuron properties were drawn from distributions that qualitatively represent experimental data from GPe neurons.…”

“…The study involved 14 mice of either sex aged between 74 and 193 d. Out of these, 10 were parvalbumin-Cre (PV-Cre), 2 were Npas1-Cre-tdTomato mice, and 2 were wild-type C57BL/6 mice without any genetic modifications. In total, 16 GPe neurons were examined, all classified as prototypic cells using the electrophysiological criterion of Jones et al (2023) . Eleven of these were confirmed as parvalbumin-positive (PV+) either through fluorescence or via a distinct light-induced Archaerhodopsin-3 (Arch) hyperpolarization.…”

“…Out of these, 10 were PV-Cre, 2 were Npas1-Cre-tdTomato mice, and 2 were wildtype C57BL/6 mice without any genetic modifications. In total, 16 GPe neurons were examined, all classified as prototypic cells using the electrophysiological criterion of Jones et al (2023).…”