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

© The Author(s) 2019. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.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.Peer reviewe

On the interaction of gamma-rhythmic neuronal populations

Local gamma-band (~30-100Hz) oscillations in the brain, produced by feedback inhibition on a characteristic timescale, appear in multiple areas of the brain and are associated with a wide range of cognitive functions. Some regions producing gamma also receive gamma-rhythmic input, and the interaction and coordination of these rhythms has been hypothesized to serve various functional roles. This thesis consists of three stand-alone chapters, each of which considers the response of a gamma-rhythmic neuronal circuit to input in an analytical framework. In the first, we demonstrate that several related models of a gamma-generating circuit under periodic forcing are asymptotically drawn onto an attracting invariant torus due to the convergence of inhibition trajectories at spikes and the convergence of voltage trajectories during sustained inhibition, and therefore display a restricted range of dynamics. In the second, we show that a model of a gamma-generating circuit under forcing by square pulses cannot maintain multiple stably phase-locked solutions. In the third, we show that a separation of time scales of membrane potential dynamics and synaptic decay causes the gamma model to phase align its spiking such that periodic forcing pulses arrive under minimal inhibition. When two of these models are mutually coupled, the same effect causes excitatory pulses from the faster oscillator to arrive at the slower under minimal inhibition, while pulses from the slower to the faster arrive under maximal inhibition. We also show that such a time scale separation allows the model to respond sensitively to input pulse coherence to an extent that is not possible for a simple one-dimensional oscillator. We draw on a wide range of mathematical tools and structures including return maps, saltation matrices, contraction methods, phase response formalism, and singular perturbation theory in order to show that the neuronal mechanism of gamma oscillations is uniquely suited to reliably phase lock across brain regions and facilitate the selective transmission of information