Profiling parvalbumin interneurons using iPSC: challenges and perspectives for Autism Spectrum Disorder (ASD)

Abstract

Autism spectrum disorders (ASD) are persistent conditions resulting from disrupted/altered neurodevelopment. ASD multifactorial etiology-and its numerous comorbid conditions-heightens the difficulty in identifying its underlying causes, thus obstructing the development of effective therapies. Increasing evidence from both animal and human studies suggests an altered functioning of the parvalbumin (PV)-expressing inhibitory interneurons as a common and possibly unifying pathway for some forms of ASD. PV-expressing interneurons (short: PVALB neurons) are critically implicated in the regulation of cortical networks' activity. Their particular connectivity patterns, i.e., their preferential targeting of perisomatic regions and axon initial segments of pyramidal cells, as well as their reciprocal connections, enable PVALB neurons to exert a fine-tuned control of, e.g., spike timing, resulting in the generation and modulation of rhythms in the gamma range, which are important for sensory perception and attention. New methodologies such as induced pluripotent stem cells (iPSC) and genome-editing techniques (CRISPR/Cas9) have proven to be valuable tools to get mechanistic insight in neurodevelopmental and/or neurodegenerative and neuropsychiatric diseases. Such technological advances have enabled the generation of PVALB neurons from iPSC. Tagging of these neurons would allow following their fate during the development, from precursor cells to differentiated (and functional) PVALB neurons. Also, it would enable a better understanding of PVALB neuron function, using either iPSC from healthy donors or ASD patients with known mutations in ASD risk genes. In this concept paper, the strategies hopefully leading to a better understanding of PVALB neuron function(s) are briefly discussed. We envision that such an iPSC-based approach combined with emerging (genetic) technologies may offer the opportunity to investigate in detail the role of PVALB neurons and PV during "neurodevelopment ex vivo."

Comprehensive Analysis of RNA-Seq Gene Expression Profiling of Brain Transcriptomes Reveals Novel Genes, Regulators, and Pathways in Autism Spectrum Disorder

“…Parvalbumin (PV) is a calcium-binding protein expressed in a subset of GABAergic interneurons in the brain. Recently, this population of inhibitory (GABAergic) interneurons, expressing the calcium-binding protein PV (here indicated as Pvalb neurons), has attracted much attention with regard to ASD [ 34 ]. Indeed, Pvalb neurons control the coordination of neuronal networks and studies on ASD animal models have shown a reduced number of PV-immunoreactive (PV+) cells.…”

Cadherin-13 is a critical regulator of GABAergic modulation in human stem cell derived neuronal networks

“…Since the first postulation of an increased E/I ratio in ASD 67 , an increasing amount of studies has shown that altered E/I balance contributes to many NDDs 1 . Interestingly, evidence from both animal models and human studies suggest that altered function of PV + GABAergic neurons is a common unifying pathway for common forms of NDDs 4,30,43 . Although several efforts have been made to generate PV + GABAergic neurons from hiPSCs, their generation has been proven challenging 43 .…”

“…Interestingly, evidence from both animal models and human studies suggest that altered function of PV + GABAergic neurons is a common unifying pathway for common forms of NDDs 4,30,43 . Although several efforts have been made to generate PV + GABAergic neurons from hiPSCs, their generation has been proven challenging 43 . Here we show that Ascl1 overexpression and FSK supplementation resulted in approximately 30% SST + GABAergic neurons.…”

“…Moreover, specific classes of GABAergic neurons, such as SST + and PV + neurons have been found to have a particularly strong influence on the E/I balance [30][31][32] . Although recent advances in differentiating human induced pluripotent stem cells (hiPSCs) into GABAergic neurons [33][34][35][36][37][38][39][40][41][42] , protocols that enable the generation of SST + and PV + human neurons are still challenging due to the long functional maturation of these cells 43 . Investigating E/I balance in human in vitro models for brain disorders ideally requires a model system that consists of a) neuronal networks In this study, we investigated the role of CDH13 in maintaining E/I balance in a human neuronal model.…”

Generation of cerebral cortical GABAergic interneurons from pluripotent stem cells

“…With the capacity to generate hCIn‐like cells, there has been tremendous interest in particular CIn subclasses, again with some emphasis on the FS, PV‐expressing subclass that has been implicated in neuropsychiatric disease 94 . With regard to other hCIn populations, several studies have reported methods to direct Foxg1 + progenitors into CGE‐derived cell types, such as the vertically oriented, bipolar, calretinin‐expressing interneurons, by treating cultures with Activin, 82 or FGF19 48 …”