Abstract
The spatiotemporal distribution of mitochondria is crucial for precise ATP provision and calcium buffering required to support neuronal signaling. Fast-spiking GABAergic interneurons expressing parvalbumin (PV+) have a high mitochondrial content reflecting their large energy utilization. The importance for correct trafficking and precise mitochondrial positioning remains poorly elucidated in inhibitory neurons. Miro1 is a Ca²+-sensing adaptor protein that links mitochondria to the trafficking apparatus, for their microtubule-dependent transport along axons and dendrites, in order to meet the metabolic and Ca2+-buffering requirements of the cell. Here, we explore the role of Miro1 in PV+ interneurons and how changes in mitochondrial trafficking could alter network activity in the mouse brain. By employing live and fixed imaging, we found that the impairments in Miro1-directed trafficking in PV+ interneurons altered their mitochondrial distribution and axonal arborization, while PV+ interneuron-mediated inhibition remained intact. These changes were accompanied by an increase in the ex vivo hippocampal γ-oscillation (30-80 Hz) frequency and promoted anxiolysis. Our findings show that precise regulation of mitochondrial dynamics in PV+ interneurons is crucial for proper neuronal signaling and network synchronization.
Highlights
Parvalbumin (PV+) interneurons constitute a small proportion of the total neuronal population, yet they possess crucial roles in shaping neuronal network activity (Freund and Buzsaki, 1996; Jonas et al, 2004; Pelkey et al, 2017)
Using two-photon live-imaging of ex vivo organotypic brain slices, we demonstrated a reduction in mitochondrial trafficking in the absence of Miro1 in PV+ interneurons in the hippocampus
To examine the role of mitochondrial transport in PV+ interneurons, we disrupted the mitochondrial adaptor protein Miro1 by crossing the PvalbCre mouse line (Hippenmeyer et al, 2005) with the Rhot1flox/flox mouse (Lopez-Domenech et al, 2016), generating a model where Miro1 was selectively knocked-out in PV+ interneurons (Figure 1—figure supplement 1A)
Summary
Parvalbumin (PV+) interneurons constitute a small proportion of the total neuronal population (less than 2% in the hippocampus), yet they possess crucial roles in shaping neuronal network activity (Freund and Buzsaki, 1996; Jonas et al, 2004; Pelkey et al, 2017). Network oscillations at g-band frequency are believed to facilitate information transmission through circuit synchronization and local gain control that may be instrumental in multiple cognitive processes such as attention, learning, and memory (Akam and Kullmann, 2010; Fries, 2015; Howard et al, 2003; Montgomery and Buzsaki, 2007; Sohal, 2016) These oscillations are thought to be metabolically very costly, and it has been postulated that PV+ interneurons require substantial amounts of energy via ATP hydrolysis to sustain the high firing rate and dissipate ion gradients during neuronal transmission (Attwell and Laughlin, 2001; Kann, 2011; Kann, 2016; Kann and Kovacs, 2007; Kann et al, 2014). We show that Miro1-dependent mitochondrial positioning is essential for correct PV+ interneuron function, network activity, and anxiolytic animal behavior
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