Autophagy regulates PVALB (parvalbumin) interneuron excitability and memory

Macroautophagy/autophagy was previously shown to play a critical role in the hippocampus for memory formation, with age-related autophagy deficits being further linked to cognitive decline. However, the neuronal subtypes where autophagy is required to form new memories remain unknown. Given the well-established role of PVALB (parvalbumin) interneurons in hippocampus-dependent memory formation and consolidation, we examined whether autophagy in these cells is required for such complex behaviors. We show that contrary to other neuronal subtypes, the vast majority of PVALB neurons, with the exception of cerebellar Purkinje cells, survive and are maintained long-term independently of autophagy. However, autophagy controls the homeostasis of mitochondria, endoplasmic reticulum, and synaptic proteins within PVALB interneurons, ultimately regulating their synaptic excitation, neuronal excitability and excitation-inhibition balance in the hippocampus. Consequently, mice with conditional impairment of autophagy in PVALB-expressing neurons exhibit impaired inhibitory neurotransmission and deficits in hippocampus-dependent memory. Taken together, these findings identify PVALB interneurons as key cellular substrates of autophagy in the context of learning and memory.<b>Abbreviation</b>: ATG5: autophagy related 5; BNIP3: BCL2/adenovirus E1B interacting protein 3; BNIP3L: BCL2/adenovirus E1B interacting protein 3-like; CA1: cornu ammonis 1; CALCOCO1: calcium binding and coiled coil domain 1; ER: endoplasmic reticulum; GABA: gamma-aminobutyric acid; GRIA/AMPAR: glutamate receptor, ionotropic, AMPA; GRIN2A/NR2A/GluN2A: glutamate receptor, ionotropic, NMDA2A (epsilon 1); PRKN: parkin RBR E3 ubiquitin protein ligase; PC: pyramidal cells; PJ: Purkinje; PVALB: parvalbumin; RTN3: reticulon 3; SQSTM1/p62: sequestosome 1.