Myelination of parvalbumin interneurons: a new crucial mechanism underlying cortical activity and experience-dependent plasticity.

In the neocortex, inhibitory GABAergic parvalbumin expressing (PV+) interneurons (INs) are involved in circuits responsible for important functions like sensory perception and higher cognitive functions. PV+ INs exert their inhibitory function by acting on excitatory pyramidal neurons via feedback or feedforward inhibition. Given their tight control on excitatory neurons, PV+ INs are of paramount importance because they contribute to the processing and integration of sensory information, such as tactile and visual inputs, by the establishment and maintenance of cortical excitation/inhibition (E/I) balance. Recent studies revealed that the axons of PV+ INs are myelinated, but the functional significance of myelin deposition on their function in the regulation of cortical circuits is still largely unexplored. In this thesis, I will review very recent evidence describing the importance of myelination of this major subclass of cortical INs. First, I will focus on the experiments run by Benamer et al. (2020) showing that, by genetically disrupting the interaction of PV+ INs and oligodendrocytes precursor cells in mice, both the myelination and function of PV+ INs are severely disrupted, including a reduction of these cells ability to control excitatory neurons activation. As a result, the circuits of the somatosensory cortex show a robust E/I imbalance that correlates with impaired processing of whisker-mediated tactile stimuli. Furthermore, I will present data showing that myelination changes in PV+ INs are essential for experience-dependent maturation and plasticity of cortical circuits as indicated by findings obtained on the primary visual cortex (V1) by Yang et al. (2020). Indeed, until recently, whether PV+ INs plasticity in V1 depends on myelination remodelling was completely unknown. In this work, Yang et al., used monocular deprivation (MD) to promote experience–dependent plasticity in V1 and investigated whether it modified PV+ INs myelination profiles. These authors revealed that PV+ INs, more than excitatory neurons, undergo extensive myelin reconfiguration upon MD. Indeed, MD elicits an increase in myelin sheath dynamics specifically on PV+ INs as shown by an increase in the displacement rate of nodes of Ranvier. These data indicate that the adaptive rearrangement of myelin configuration is driven by visual experience and participates in PV+ INs-mediated cortical circuits plasticity. Finally, it is established that PV+ INs are heavily involved in higher cognitive functions, such as working memory and attentional flexibility. Importantly, impairments in PV+ INs number and/or activity are associated with the emergence of complex neuropsychiatric disorders, including schizophrenia (SZ). Nevertheless, no data is available on the role of PV+ INs myelination on SZ-dependent cognitive impairments. By using a SZ rat model generated by a combination of genetic and environmental factors, I will present data from Maas et al. (2020) showing that SZ cognitive deficits are paralleled by PV+ INs hypomyelination during prefrontal cortex development. Intriguingly, environmental enrichment applied during adolescence corrected PV+ INs hypomyelination as well as cognitive deficits suggesting a possible future therapy for SZ. In conclusion, the data described in my thesis support myelination of PV+ INs as a previously underestimated crucial mechanism in cortical activity and experience-dependent plasticity underlying important cognitive functions.