Dopamine and gamma band synchrony in schizophrenia – insights from computational and empirical studies

Abstract

Dopamine modulates cortical circuit activity, in part, through its actions on GABAergic interneurons, including increasing the excitability of fast-spiking interneurons. Though such effects have been demonstrated in single cells, there are no studies that examine how such mechanisms may lead to the effects of dopamine at a neural network level. With this motivation, we investigated the effects of dopamine on synchronization in a simulated neural network, composed of excitatory and fast-spiking inhibitory Wang-Buzsaki neurons. The effects of dopamine were implemented through varying leak K+ conductance of the fast-spiking interneurons and the network synchronization within gamma band (~40 Hz) was analyzed. Parametrically varying the leak K+ conductance revealed an inverted-U shaped relationship, with low gamma band power at both low and high conductance levels, and optimal synchronization at intermediate conductance levels. We also examined the effects of modulating excitability of the inhibitory neurons more generically using an idealized model with theta neurons, with similar findings. Moreover, such relationship holds both when the external input is tonic vs. periodic. Our computational results mirror our empirical study of dopamine modulation in schizophrenia and healthy controls, which showed that amphetamine administration increased gamma power in patients but decreased it in controls. Together, our computational and empirical investigations indicate that dopamine can modulate cortical gamma band synchrony in an inverted-U fashion, and that the physiologic effects of dopamine on single fast-spiking interneurons can give rise to such non-monotonic effects at the network level.

Brain Rhythms Connect Impaired Inhibition to Altered Cognition in Schizophrenia

“…In a recent empirical and modeling study, amphetamine administration induced gamma decreases and increases in healthy and patient participants, respectively [80], changes replicated in a PFC model [80]. In a hippocampal network model [81], dopamine had the opposite effect, reducing stimulus-induced gamma activity in “putatively schizophrenic” parameter regimes and increasing it in others.…”

Alterations in Cortical Network Oscillations and Parvalbumin Neurons in Schizophrenia

“…A MEG study of mental arithmetic found lower induced left frontal gamma activity at low frequency sub-bands (30–45 Hz), but higher right frontal and fronto-temporal activity at higher frequency sub-bands (46–71 Hz) (46), suggesting disturbances of specific sub-bands of the gamma range. Although not probing prefrontal circuits specifically, ASSR paradigms provide convergent support for such frequency specificity, consistently identifying 40 Hz deficits in schizophrenia (27;29;30;47;48), including a study that sampled sub-bands from the gamma range, and found deficits in the 30–45 Hz range for phase-locking factor and total power in patients (30). Another study combined transcranial magnetic stimulation (TMS) with EEG to probe for gamma deficits in schizophrenia; relative to healthy controls the natural frequency responses in the frontal regions of the schizophrenia subjects were lower in the gamma range (31).…”

“…For example, computational studies have highlighted the important role of PV cell excitability in modulating network gamma oscillations (29;68;135), including demonstrations of cell type-specific effects (135). In addition, the development of novel experimental methods in the form of optogenetics (19) and DREADD (Designer Receptors Exclusively Activated by Designer Drugs) approaches (136) have provided the basis for explicit cell type-specific empirical investigations of the effects of excitatory-inhibitory balance shifts on gamma oscillations.…”

Dopamine-NMDA interactions and relevance to gamma band synchrony in schizophrenia

“…However, the exact mechanism through which DA leads to such non-monotonic modulation of network activity needs further investigation. Our recent work suggests that DA's modulation of potassium currents in the fast-spiking interneurons could be a potential mechanism underlying this inverted-U relationship [2]. Here we propose that another potential mechanism could contribute in the form of interactions between DA D1 receptors and NMDA conductance in the cortex.…”