Parvalbumin Role in Epilepsy and Psychiatric Comorbidities: From Mechanism to Intervention.

Lívea Dornela Godoy,José Luiz Liberato,Tamiris Prizon,João Pereira Leite,Matheus Teixeira Rossignoli

doi:10.3389/fnint.2022.765324

Abstract

Parvalbumin is a calcium-binding protein present in inhibitory interneurons that play an essential role in regulating many physiological processes, such as intracellular signaling and synaptic transmission. Changes in parvalbumin expression are deeply related to epilepsy, which is considered one of the most disabling neuropathologies. Epilepsy is a complex multi-factor group of disorders characterized by periods of hypersynchronous activity and hyperexcitability within brain networks. In this scenario, inhibitory neurotransmission dysfunction in modulating excitatory transmission related to the loss of subsets of parvalbumin-expressing inhibitory interneuron may have a prominent role in disrupted excitability. Some studies also reported that parvalbumin-positive interneurons altered function might contribute to psychiatric comorbidities associated with epilepsy, such as depression, anxiety, and psychosis. Understanding the epileptogenic process and comorbidities associated with epilepsy have significantly advanced through preclinical and clinical investigation. In this review, evidence from parvalbumin altered function in epilepsy and associated psychiatric comorbidities were explored with a translational perspective. Some advances in potential therapeutic interventions are highlighted, from current antiepileptic and neuroprotective drugs to cutting edge modulation of parvalbumin subpopulations using optogenetics, designer receptors exclusively activated by designer drugs (DREADD) techniques, transcranial magnetic stimulation, genome engineering, and cell grafting. Creating new perspectives on mechanisms and therapeutic strategies is valuable for understanding the pathophysiology of epilepsy and its psychiatric comorbidities and improving efficiency in clinical intervention.

Highlights

Epilepsy is one of the most disabling chronic neurologic disorders, significantly impacting patients’ quality of life (Devinsky et al, 2018)
The protein is organized in three domains: a 12 amino acid loop surrounded by two 8– 9 amino acid alpha-helices, referred to as A, B, C, D, E, and F, according to its position to the N-terminus of the protein [Figure 1A(I); parvalbumin protein representation was adapted from https://www.uniprot.org/uniprot/P20472]
There is probably morphological plasticity in which increases in the initial axon segments and/or reductions or abnormal dendritic and somatic innervations contribute to excitability and synchronization

Summary

Introduction

Epilepsy is one of the most disabling chronic neurologic disorders, significantly impacting patients’ quality of life (Devinsky et al, 2018). The reduction of GABAergic and parvalbumin staining of the axo-somatic plexus in the hippocampal granule cell layer has been observed in clinical studies, further confirmed in experimental epilepsy models [Sloviter, 1991; Zhu et al, 1997; Kobayashi and Buckmaster, 2003; Arellano et al, 2004; Van Vliet et al, 2004; Figures 1C(III,IV)].

Results

Conclusion