Autophagy in parvalbumin interneurons is required for inhibitory transmission and memory via regulation of synaptic proteostasis

Abstract

With the emerging role of the autophagic machinery in healthy brain development and aging, there is a pressing need to better characterize its functions in different neuronal populations, providing cellular insight into autophagy-related brain diseases. Here, we generated and characterized mice with conditional ablation of atg5 in GABAergic neurons expressing parvalbumin (PV-atg5KO), mostly comprising fast-spiking interneurons, as well as Purkinje cells in the cerebellum. Using light-sheet microscopy to image PV neurons throughout the brain, we reveal that autophagy is required for the sustenance of Purkinje cells but not of PV-interneurons. Yet, proteomic analysis showed that autophagy deficiency in cortical and hippocampal PV-interneurons alters the proteostasis of key synaptic proteins, as well as the surface expression of glutamate receptor subunits. Consistently, hippocampal autophagy-deficient PV-interneurons exhibit reduced inhibitory neurotransmission and PV-atg5KO mice display excitation-inhibition imbalance in the hippocampus and memory deficits. Our findings demonstrate a neuronal type-specific vulnerability to autophagy deficiency, while also identifying PV-interneurons as cellular substrates where autophagy is required for memory.

Native-state proteomics of Parvalbumin interneurons identifies novel molecular signatures and metabolic vulnerabilities to early Alzheimer’s disease pathology

“…Interestingly, all PV-IN (WT or 5xFAD) systematically showed higher levels of LC3-II as compared to bulk brain samples (Fig 7M). These patterns suggest that PV-INs, as a cell type, exhibit higher levels of autophagy as compared to the rest of the brain 5 , and this phenotype is exaggerated in early AD pathology.…”

“…Functional information is nonetheless limited in these transcriptomic studies, due to substantial discordance between mRNA and protein levels, especially in neurons [2][3][4] . More direct proteomic studies relying on physical isolation of individual neuron types are also inadequate, as physical isolation of individual neurons is poorly tolerated, and of those that do survive, the vast majority of their functional surface area (i.e., dendrites and axons) is lost 5,6 . To overcome these limitations, we recently developed an in vivo strategy called cell type-specific in vivo biotinylation of proteins (CIBOP).…”