Periodic unitary synaptic currents in the mouse globus pallidus during spontaneous firing in slices

Abstract

Neurons in the external globus pallidus (GPe) are autonomous pacemakers, but their spontaneous firing is continually perturbed by synaptic input. Because GPe neurons fire rhythmically in slices, spontaneous inhibitory synaptic currents (IPSCs) should be evident there. We identified periodic series of IPSCs in slices, each corresponding to unitary synaptic currents from one presynaptic cell. Optogenetic stimulation of the striatal indirect pathway axons caused a pause and temporal resetting of the periodic input, confirming that it arose from local neurons subject to striatal inhibition. We determined the firing statistics of the presynaptic neurons from the unitary IPSC statistics and estimated their frequencies, peak amplitudes, and reliabilities. To determine what types of GPe neurons received the spontaneous inhibition, we recorded from genetically labeled parvalbumin (PV) and Npas1 expressing neurons. Both cell types received periodic spontaneous IPSCs with similar frequencies. Optogenetic inhibition of PV neurons reduced the spontaneous IPSC rate in almost all neurons with active unitary inputs, whereas inhibition of Npas1 neurons rarely affected the spontaneous IPSC rate in any neurons. These results suggest that PV neurons provided most of the active unitary inputs to both cell types. Optogenetic pulse stimulation of PV neurons at light levels that can activate cut axons yielded an estimate of connectivity in the fully connected network. The local network is a powerful source of inhibition to both PV and Npas1 neurons, that contributes to irregular firing and may influence the responses to external synaptic inputs.

Distinct mechanisms of CB1 and GABABreceptor presynaptic modulation of striatal indirect pathway projections to mouse Globus Pallidus

“…A detailed analysis of the striato-pallidal and pallido-pallidal circuitry has proposed that iSPN-GPe projections are the densest in the GPe and primarily target prototypic over arkypallidal GPe neurons (Cui et al, 2021; Ketzef & Silberberg, 2021). PV+ neurons represent the primary source of collateral inhibition in the GPe (Cui et al, 2021; Higgs et al, 2021; Ketzef & Silberberg, 2021). Presynaptic inhibition of iSPN-GPe projections might therefore produce primarily a disinhibition of the output of GPe prototypic neurons to the SNr, Subthalamic Nucleus and Parafascicular Thalamus (Lilasharoen et al, 2020; Pamukcu et al, 2020) in addition to disinhibiting local collaterals.…”

“…A detailed analysis of the striato-pallidal and pallido-pallidal circuitry has proposed that iSPN-GPe projections are the densest in the GPe and primarily target prototypic over arkypallidal GPe neurons (Cui et al, 2021;Ketzef & Silberberg, 2021). PV+ neurons represent the primary source of collateral inhibition in the GPe (Cui et al, 2021;Higgs et al, 2021;Ketzef & Silberberg, 2021). Presynaptic inhibition of iSPN-GPe projections might therefore produce primarily a disinhibition of the output of GPe prototypic neurons to the SNr, Subthalamic Nucleus and Parafascicular Thalamus (Lilasharoen et al, 2020;Pamukcu et al, 2020)…”

“…CB1 receptors control GABA release in the GPe (Engler et al, 2006) but it is unknown what set of GABAergic synapses mediates this effect. Sources of extra-striatal GABAergic inputs in the GPe include local collaterals (Ketzef et al, 2021; Higgs et al, 2021) and GPi inputs (Weglage et al, 2022). GABA B receptors are expressed on striatopallidal projections (Chen et al, 2004).…”

Distinct mechanisms of CB1 and GABAB receptor presynaptic modulation of striatal indirect pathway projections to mouse globus pallidus

“…A detailed analysis of the striato‐pallidal and pallido‐pallidal circuitry has proposed that iSPN‐GPe projections are the densest in the GPe and primarily target prototypical over arkypallidal GPe neurons (Cui et al., 2021 ; Ketzef & Silberberg, 2021 ). Parvalbumin expressing neurons represent the primary source of collateral inhibition in the GPe (Cui et al., 2021 ; Higgs et al., 2021 ; Ketzef & Silberberg, 2021 ). Presynaptic inhibition of iSPN‐GPe projections might therefore produce primarily a disinhibition of the output of GPe prototypic neurons to the SNr, subthalamic nucleus and parafascicular thalamus (Lilascharoen et al., 2021 ; Pamukcu et al., 2020 ) in addition to disinhibiting local collaterals.…”

“…CB1 receptors control GABA release in the GPe (Engler et al, 2006) but it is unknown what set of GABAergic synapses mediates this effect. Sources of extra-striatal GABAergic inputs in the GPe include local collaterals (Higgs et al, 2021;Ketzef & Silberberg, 2021) and GPi inputs (Weglage et al, 2022). GABA B receptors are expressed on striatopallidal projections (Chen et al, 2004).…”