The Role of Parvalbumin-positive Interneurons in Auditory Steady-State Response Deficits in Schizophrenia

Abstract

Despite an increasing body of evidence demonstrating subcellular alterations in parvalbumin-positive (PV + ) interneurons in schizophrenia, their functional consequences remain elusive. Since PV + interneurons are involved in the generation of fast cortical rhythms, these changes have been hypothesized to contribute to well-established alterations of beta and gamma range oscillations in patients suffering from schizophrenia. However, the precise role of these alterations and the role of different subtypes of PV + interneurons is still unclear. Here we used a computational model of auditory steady-state response (ASSR) deficits in schizophrenia. We investigated the differential effects of decelerated synaptic dynamics, caused by subcellular alterations at two subtypes of PV + interneurons: basket cells and chandelier cells. Our simulations suggest that subcellular alterations at basket cell synapses rather than chandelier cell synapses are the main contributor to these deficits Particularly, basket cells might serve as target for innovative therapeutic interventions aiming at reversing the oscillatory deficits.

Single-cell dissection of schizophrenia reveals neurodevelopmental-synaptic axis and transcriptional resilience

“…The Ex-SZTR cell state is predominantly associated with superficial-layer excitatory neurons (layers II/III), whereas cortico-cortical excitatory neurons are enriched for layer V. The observed layer-specificity of perturbations is consistent with the enrichment of schizophrenia genetic variants proximal to genes preferentially expressed in layer II and layer V 59 . Among inhibitory neurons, we detected the strongest association between schizophrenia DEGs and genomic variants in In-PV-Basket cells, consistent with the known dysregulation of PV-expressing GABAergic neurons in schizophrenia hypothesized to contribute to the disruption of synchronous neural activity in schizophrenia 60,61 . Unlike neuronal populations, we did not observe any significant association between patterns of differential expression and genetic association in either glial or endothelial cells, suggesting non-neuronal cell types do not play a primary role in schizophrenia pathologies mediated by transcriptional dysregulation.…”

Taxonomy of neural oscillation events in primate auditory cortex

“…Biophysical modeling could further allow us to develop a revised taxonomy of the different oscillations, by predicting which circuit components each oscillation arises from [48,[59][60][61]. This type of modeling can be taken a step further by delineating how circuit features contribute to oscillation event dynamics that support particular aspects of auditory processing, such as speech tracking [62][63][64] or auditory steady-state responses [65][66][67]. A clearer understanding of the mechanisms creating oscillations will also pave the way to improving neuropathologies associated with disrupted brain rhythms, via pharmacology or targeted neuromodulation that normalizes rhythmic activity in a principled manner [68].…”

The beta component of gamma-band auditory steady-state responses in patients with schizophrenia

“…We used a simple computational model consisting of an excitatory population, representing pyramidal cells, and an inhibitory population, representing PV + inhibitory interneurons. While most of the experimental evidence for a reduction in GAT1, which in turn would lead to an increase in IPSC decay times, points towards chandelier cells [25], we have previously shown that at realistically low ratios of chandelier cells to basket cells in a microcircuit, gamma and beta range ASSR changes as seen in SCZ patients, are most likely due to an increase of IPSC decay times at basket cell synapses [32]. Our simplified model does not incorporate other types of inhibitory interneurons such as somatostatin-positive (SST + ) or vasoactive intestinal peptide-positive (VIP + ), although they have been shown to play important functional roles in cortical microcircuits [5].…”

“…The model proposed here is based on a recent reimplementation [28] of the simple model presented by Vierling-Claassen et al [44], which has been used in previous studies of ASSR deficits [32], and which is integrated in the ASSRUnit model database, a framework for automated testing of ASSR models against observations from empirical studies [30].…”

“…To evaluate the oscillatory entrainment we calculate simulated EEG/MEG signals by summing all excitatory synaptic variables over all pyramidal cells (as in [44, 28, 32]). As the main measures for entrainment we perform a Fourier transform on these ‘EEG/MEG’ signals and extract the power at 40 Hz and at 20 Hz.…”