Parvalbumin-positive (PV+) γ-aminobutyric acid (GABA) interneurons are critically involved in producing rapid network oscillations and cortical microcircuit computations, but the significance of PV+ axon myelination to the temporal features of inhibition remains elusive. Here, using toxic and genetic mouse models of demyelination and dysmyelination, respectively, we find that loss of compact myelin reduces PV+ interneuron presynaptic terminals and increases failures, and the weak phasic inhibition of pyramidal neurons abolishes optogenetically driven gamma oscillations in vivo. Strikingly, during behaviors of quiet wakefulness selectively theta rhythms are amplified and accompanied by highly synchronized interictal epileptic discharges. In support of a causal role of impaired PV-mediated inhibition, optogenetic activation of myelin-deficient PV+ interneurons attenuated the power of slow theta rhythms and limited interictal spike occurrence. Thus, myelination of PV axons is required to consolidate fast inhibition of pyramidal neurons and enable behavioral state-dependent modulation of local circuit synchronization.
Keywords: demyelination; mouse; neocortex; neuroscience; parvalbumin interneuron.
The brain contains billions of neurons that connect with each other via cable-like structures called axons. Axons transmit electrical impulses and are often wrapped in a fatty substance called myelin. This insulation increases the speed of nerve impulses and reduces the energy lost over long distances. Loss or damage of the myelin layer – as is the case for multiple sclerosis, a chronic neuroinflammatory and neurodegenerative disease of the central nervous system – can cause serious disability. However, a fast-firing neuron within the brain, called PV+ interneuron, has short, sparsely myelinated axons. Even so, PV+ interneurons are powerful inhibitors that regulate important cognitive processes in gray matter areas, including the outermost parts, in the cortex. Yet it remains unclear how the unusual, patchy myelination affects their function. To examine these questions, Dubey et al. used genetically engineered mice either lacking or losing myelin and studied the impact on PV+ interneurons and slow brain waves. As mice progressively lost myelin, the speed of inhibitory signals from PV+ interneurons did not change but their signal strength decreased. As a result, the power of slow brain waves, no longer inhibited by PV+ interneurons, increased. These waves also triggered spikes of epileptic-like brain activity when the mice were inactive and quiet. Restoring the activity of myelin-deficient PV+ interneurons helped to reverse these deficits. This suggests that myelination, however patchy on PV+ interneurons, is required to reach their full inhibitory potential. Moreover, the findings shed light on how myelin loss might underpin aberrant brain activity, which have been observed in people with multiple sclerosis. More research could help determine whether these epilepsy-like spikes could be a biomarker of multiple sclerosis and/or a target for developing new therapeutic strategies to limit cognitive impairments.
© 2022, Dubey et al.