On the role of parvalbumin interneurons in neuronal network activity in the prefrontal cortex

The prefrontal cortex (PFC) is an area important for executive functions, the initiation and temporal organization of goal-directed behavior, as well as social behaviors. Inhibitory interneurons expressing parvalbumin (PV) have a vital role in modulating PFC circuit plasticity and output, as inhibition by PV interneurons on excitatory pyramidal neurons regulates the excitability of the network. Thus, dysfunctions of prefrontal PV interneurons are implicated in the pathophysiology of a range of PFC-dependent neuropsychiatric disorders characterized by excitation and inhibition (E/I) imbalance and impaired gamma oscillations.

In particular, the hypofunction of receptors important for neurotransmission and regulating cellular functions, such as the N-methyl-D-aspartate receptors (NMDARs) and the tyrosine receptor kinase B (trkB), has been implicated in PV dysfunction. Notably, this hypofunction is known to impair the normal development of PV interneurons. However, it can also affect adult brain activity. The effects of altered receptors on PV interneurons are multiple, from impaired morphological connectivity to disruption of intrinsic activity, but have not yet been fully characterized. Moreover, the effects of deficits of PV neuron-mediated inhibition on neuronal network activity are complex, involved with compensatory mechanisms, and not fully understood either. For instance, the E/I imbalance due to PV inhibition has been suggested to functionally disrupt the cortex, which can be observed through an abnormal increase in broadband gamma activity. But as the synchronous activity of cortical PV interneurons is necessary for the generation of cortical gamma oscillations, it is paradoxical that deficient PV inhibition is associated with increased broadband gamma power.

This thesis aims to examine the role of PV interneurons in shaping neuronal network activity in the mouse PFC by investigating the microscopic to macroscopic functional effects of disrupting receptors necessary for the proper activity of PV interneurons. In paper I, we observed that the increase of broadband gamma power due to NMDAR hypofunction in PV neurons is associated with asynchronies of network activity, confirming that dysfunction of neuronal inhibition can cause desynchronization at multiple time scales (affecting entrainment of spikes by the LFP, as well as cross-frequency coupling and brain states fragmentation). In Paper II, we prompted and analyzed the rippling effect of PV dysfunction in the adult PFC by expressing a dominant-negative trkB receptor specifically in PV interneurons. Despite avoiding interfering with the development of the brain, we found pronounced morphological and functional alterations in the targeted PV interneurons. These changes were associated with unusual aggressive behavior coupled with gamma-band alterations and a decreased modulation of prefrontal excitatory neuronal populations by PV interneurons.

Thus, the work presented in this thesis furthers our understanding of the role of PV function in PFC circuitry, particularly of two receptors that are central to the role of PV interneurons in coordinating local circuit activity. A better understanding of the potential mechanisms that could explain the neuronal changes seen in individuals with neuropsychiatric dysfunctions could lead to using gamma oscillations or BDNF-trkB levels as biomarkers in psychiatric disorders. It also presents possibilities for potential treatments designed around reestablishing E/I balance by modifying receptor levels in particular cell types.

List of scientific papers

I. Network asynchrony underlying increased broadband gamma power. Nicolas Guyon, Leonardo Rakauskas Zacharias, Eliezyer Fermino de Oliveira, Hoseok Kim, João Pereira Leite, Cleiton Lopes-Aguiar, Marie Carlén. The Journal of Neuroscience. 2021 Mar 31;41(13):2944-2963.
https://doi.org/10.1523/JNEUROSCI.2250-20.2021

II. Adult trkB signaling in parvalbumin interneurons is essential to prefrontal network dynamics. Nicolas Guyon, Leonardo Rakauskas Zacharias, Josina Anna van Lunteren, Jana Immenschuh, Janos Fuzik, Antje Märtin, Yang Xuan, Misha Zilberter, Hoseok Kim, Konstantinos Meletis, Cleiton Lopes-Aguiar, Marie Carlén. The Journal of Neuroscience. 2021 Apr 7;41(14):3120-3141.
https://doi.org/10.1523/JNEUROSCI.1848-20.2021