Cell-type-specific regulation of neuronal intrinsic excitability by macroautophagy

Abstract

The basal ganglia are a group of subcortical nuclei that contribute to action selection and reinforcement learning. The principal neurons of the striatum, spiny projection neurons of the direct (dSPN) and indirect (iSPN) pathways, maintain low intrinsic excitability, requiring convergent excitatory inputs to fire. Here, we examined the role of autophagy in mouse SPN physiology and animal behavior by generating conditional knockouts of Atg7 in either dSPNs or iSPNs. Loss of autophagy in either SPN population led to changes in motor learning but distinct effects on cellular physiology. dSPNs, but not iSPNs, required autophagy for normal dendritic structure and synaptic input. In contrast, iSPNs, but not dSPNs, were intrinsically hyperexcitable due to reduced function of the inwardly rectifying potassium channel, Kir2. These findings define a novel mechanism by which autophagy regulates neuronal activity: control of intrinsic excitability via the regulation of potassium channel function.

mTOR Suppresses Macroautophagy During Striatal Postnatal Development and Is Hyperactive in Mouse Models of Autism Spectrum Disorders

“…Moreover, environmental and genetic animal models of ASD have contributed to conclusively demonstrate a causal relationship between striatal functions and pathophysiological alterations ASD-like (Arndt et al, 2005;Centonze et al, 2008;Shafritz et al, 2008;Shmelkov et al, 2010;Peça et al, 2011;Peñagarikano et al, 2011;Dölen et al, 2013;Santini et al, 2013). Interestingly, we have recently discovered that autophagy is differentially involved in the control of the synaptic functions and excitability of the two subtypes of SPNs (i.e., direct and indirect SPNs; Lieberman et al, 2020). Moreover, mice with specific genetic deletion of atg7, a protein required for autophagy, either in direct or indirect SPNs display hyperactivity, stereotypes and behavioral abnormalities consistent with ASD (Lieberman et al, 2020).…”

“…Interestingly, we have recently discovered that autophagy is differentially involved in the control of the synaptic functions and excitability of the two subtypes of SPNs (i.e., direct and indirect SPNs; Lieberman et al, 2020). Moreover, mice with specific genetic deletion of atg7, a protein required for autophagy, either in direct or indirect SPNs display hyperactivity, stereotypes and behavioral abnormalities consistent with ASD (Lieberman et al, 2020). Given the dynamic regulations of autophagy occurring in the SPNs during postnatal development and the ASD-like phenotypes displayed by mice with genetic ablation of autophagy in SPNs, the regulation of autophagy during early postnatal development of SPNs may be one of the cellular process disrupted in ASD.…”

Natural Compounds and Autophagy: Allies Against Neurodegeneration

“…Recently, Tomoda et al (2019) outlined a novel essential role of autophagy, at synaptic level, regulating information processing, memory, mood, and cognitive functions in mouse models. Moreover, Lieberman et al (2020) discovered another essential function of autophagy in the regulation of potassium channels in neurons in the striatum of mice, necessary for excitability and motor learning. However, autophagy is not only a peculiarity of neurons but also present in astrocytes, oligodendrocytes and microglia in aging and neurodegenerative disorders ( Kim et al, 2017 ; Plaza-Zabala et al, 2017 ; Belgrad et al, 2020 ; Wang and Xu, 2020 ).…”

Long-term synaptic depression triggers local biogenesis of autophagic vesicles in dendrites and requires autophagic degradation

“…Though initially considered as a process in bulk, it is increasingly appreciated that autophagy can also serve specific functions, such as the regulation of food intake in hypothalamic neurons (Aveleira et al, 2015;Kaushik et al, 2011;Oh et al, 2016;Xiao et al, 2017). In line with this notion, the contribution of autophagy to higher brain functions and to the underlying mechanisms of synaptic plasticity is beginning to be addressed (Glatigny et al, 2019;Liang, 2019;Lieberman et al, 2020;Nikoletopoulou and Tavernarakis, 2018). For example, autophagy was recently shown to participate in memory erasure by synaptic destabilization (Shehata et al, 2018).…”