Miro1-dependent mitochondrial dynamics in parvalbumin interneurons

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 parvalbumin 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.

A Nanobody-Based Toolset to Monitor and Modify the Mitochondrial GTPase Miro1

“…The emerging role of Miro1 in the development and progression of diseases, particularly neurological disorders, underscores the need for new methods and tools to study this protein in detail at the molecular level (Fatiga et al, 2021;Kassab et al, 2021;Kontou et al, 2021;López-Doménech et al, 2021;Nguyen et al, 2021).…”

“…The emerging role of Miro1 in the development and progression of diseases, particularly neurological disorders, underscores the need for new methods and tools to study this protein in detail at the molecular level ( Fatiga et al, 2021 ; Kassab et al, 2021 ; Kontou et al, 2021 ; López‐Doménech et al, 2021 ; Nguyen et al, 2021 ). Currently, most studies rely on ectopic expression of genetically modified (tagged) Miro1 ( Kanfer et al, 2015 ; Castro et al, 2018 ; Nemani et al, 2018 ; Fatiga et al, 2021 ) which previously has been shown to affect mitochondrial morphology and transport in living cells ( Fransson et al, 2006 ).…”

Parvalbumin basket cell myelination accumulates axonal mitochondria to internodes

“…3 ) is in keeping with previous studies in axons of other cell types and different models of demyelination 7 , 8 , 11 , suggesting its toxicity does not play a role in the present analysis. To determine the features of motility, Ca 2+ buffering, anatomical properties of size and shape as well as the distribution of the mitochondria in PV + interneurons we used two-photon and confocal microscopy together with 3D EM data, which have been used previously to study mitochondria 7 , 9 , 35 , 50 , 77 . Confocal imaging has the advantage of allowing the mapping of mitochondria in large parts of single cells from multiple animals and distinct genetically modified mice but with the tradeoff of a lower spatial resolution.…”

“…If in PV + interneurons newly formed myelin sheaths attract mitochondria this could represent a glial mechanism to strengthen axonal pathways and promote specific circuits of inhibitory transmission. Both myelination and mitochondrial distribution in PV + interneurons are known to be important for gamma oscillations, indicating they may represent converging pathways that shape PV + interneuron inhibitory functions 22 , 35 . More research will be necessary to test this hypothesis, by for instance using longitudinal mitochondrial imaging during myelin development or activity-induced myelination.…”

“…With a low threshold of action potential generation, sustained high firing frequencies and synchronization with fast gamma oscillations, PV + interneurons use large amounts of energy to fuel the sodium/potassium ATPase to maintain the balance of ionic gradients 31 , 32 . In line with their high energy usage, PV + interneurons have a relatively high mitochondrial content and cytochrome c oxidase levels 33 , 34 while deficits in the spatial distribution of mitochondria in PV + axons are associated with impairments of gamma oscillations 35 . One leading hypothesis is that myelination provides trophic support to mitochondria in PV + axons to maintain their levels of high-frequency spike generation and activity during gamma oscillations 21 , 36 , 37 .…”