This Week in The Journal

doi:10.1523/JNEUROSCI.twij.43.8.2023

Local Circuits in the Globus Pallidus Produce Irregular Firing

James A. Jones, Matthew H. Higgs, Erick Olivares, Jacob Peña, and Charles J. Wilson

The external globus pallidus (GPe), a part of the basal ganglia, plays a key role in the planning and execution of movement and has been indicated in the neuropathology of Huntington’s, Parkinson’s, and other movement-related diseases. This largely GABAergic region—and its local inhibitory circuits in particular—has proved especially difficult to study due to its complex connectivity and its neurons’ heterogenous firing rates and irregular firing patterns. Now Jones et al. use perforated patch-clamp recordings in combination with optogenetics, dynamic clamp, and phase model simulations to tease apart the outsized influence of GABAergic circuits contained within the GPe. About half of GPe neurons express parvalbumin (PV) and participate in the so-called indirect pathway, which includes a variety of basal ganglia regions. Another third of GPe neurons express Npas1 and project to either the striatum or to the cortex and thalamus. Most input to the GPe is striatal, but a small number of GPe neurons form basket-like connections on local cell bodies and dendrites, which the authors suspected might be the source driving the irregularity of GPe neurons’ firing. In coronal slices of GPe from mice, which left only local GABAergic circuitry intact, PV⁺ neurons were selectively engineered to express the light-sensitive ion pump archaerhodopsin (Arch), the activation of which results in neuronal inhibition. Using the perforated patch technique, the authors recorded from PV^– neurons while silencing PV⁺ neurons, which led to a decrease in IPSPs in some of the PV^– neurons, and individual neurons slightly increased their rate and regularity when PV⁺ neurons were silenced. Silencing Npas1⁺ neurons had no effect on the firing activity of Npas1^– neurons. The GABA_A receptor antagonist gabazine (but not a GABA_B receptor antagonist) blocked IPSPs and increased the firing rate and regularity of GPe neurons. The inhibitory influence of PV⁺ neurons proved powerful; the spontaneous firing of a single PV⁺ neuron alone silenced an active Npas1⁺ neuron. Simulation of input from PV⁺ neurons elicited similar inhibition. The authors conclude that, in vivo, the PV⁺ network strongly deregularizes the firing of GPe neurons. Irregular firing has the potential to carry highly rich information, and this study identifying the origin of that irregularity as local PV⁺ inputs in the GPe will lend new clues to how this highly complex brain region operates.

A sagittal section of the GPe shows a PV⁺ Arch-expressing neuron labeled with GFP at 40×.

Autophagy Emerges as Key Process in Alzheimer’s Pathophysiology

Hua Zhang, Caitlynn Knight, S.R. Wayne Chen, and Ilya Bezprozvanny

(see pages 1441–1454)

Alzheimer's disease (AD) is a neurodegenerative disorder with pathophysiology characterized by the accumulation of plaques formed of amyloid protein in the hippocampus and cortex. Despite intense investigation, no disease-modifying treatments exist, and efforts to target plaques have been unsuccessful. This week, Zhang et al. examine a potential role for autophagy, a cellular process from the Greek for “self-devouring,” by which cells degrade and recycle dysfunctional cellular components, including long-lived protein aggregates. Specifically, the authors probed the role of ryanodine receptors (RyanRs), which control the release of calcium from intracellular stores. Although blocking RyanRs has previously shown beneficial effects in cellular and animal models of AD, these are the first authors to test autophagy as an underlying mechanism. For the current study, the researchers used a genetically modified mouse called EQ in which RyanR2 activity is diminished due to a shortened channel open time, enabling them to observe reduced endogenous RyanR2 in hippocampal neuronal cells. Autophagic flux was higher and basal intracellular Ca²⁺ levels were reduced in EQ mice and in EQ mice crossed with the AD mouse model APPKI (EQ;APPKI) than in wild type (WT). When RyanR activity was pharmacologically inhibited, autophagic flux was decreased in neurons from WT and APPKI mice but not EQ or EQ;APPKI mice, supporting a role for RyanRs. Inhibition of calcineurin (CaN) dramatically enhanced autophagy in neurons from all mice, indicating a crucial role for CaN in control of autophagy. Biochemical experiments further suggested that basal Ca²⁺ released via RyanRs modulated autophagy via the AMP-activated protein kinase (AMPK) and the Unc-51-like autophagy-activating kinase (ULK1) pathway. Together, the results suggested that reduced RyanR activity in EQ neurons led to stimulation of autophagy. In hippocampal slices from APPKI mice and another, more aggressive model of AD, APPPS1, the EQ mutation led to increased autophagy, rescued the deficits seen in the autophagy–lysosomal pathways in AD-affected neurons, and decreased levels of amyloid protein. Most importantly, the EQ mutation also reduced plaque load in APPPS1 mice in vivo and rescued deficits in synaptic signaling in both mouse models. The work identifies a link between calcium dysregulation and autophagy as a key process in AD pathophysiology and pinpoints specific molecular targets that could potentially be exploited as AD interventions.