Dataset Information

Dopaminergic contributions to hippocampal pathophysiology in schizophrenia: a computational study.

ABSTRACT: Since the original formulation of the dopamine hypothesis, a number of other cellular-level abnormalities--eg, NMDA receptor hypofunction, GABA system dysfunction, neural connectivity disturbances--have been identified in schizophrenia, but the manner in which these potentially interact with hyperdopaminergia to lead to schizophrenic symptomatology remains uncertain. Previously, we created a neuroanatomically detailed, biophysically realistic computational model of hippocampus in the control (unaffected) and schizophrenic conditions, implemented on a 72-processor supercomputer platform. In the current study, we apply the effects of dopamine (DA), dose-dependently, to both models on the basis of an exhaustive review of the neurophysiologic literature on DA's ion channel and synaptic level effects. To index schizophrenic behavior, we use the specific inability of the model to attune to the 40 Hz (gamma band) frequency, a finding that has been well replicated in the clinical electroencephalography (EEG) and magnetoencephalography literature. In trials using 20 'simulated patients', we find that DA applied to the control model produces modest increases in 40 Hz activity, similar to experimental studies. However, in the schizophrenic model, increasing DA induces a decrement in 40 Hz resonance. This modeling work is significant in that it suggests that DA's effects may vary based on the neural substrate on which it acts, and--via simulated EEG recordings-points to the neurophysiologic mechanisms by which this may occur. We also feel that it makes a methodological contribution, as it exhibits a process by which a large amount of neurobiological data can be integrated to run pharmacologically relevant in silico experiments, using a systems biology approach.

SUBMITTER: Siekmeier PJ

PROVIDER: S-EPMC4023145 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Dopaminergic contributions to hippocampal pathophysiology in schizophrenia: a computational study.

Siekmeier Peter J PJ vanMaanen David P DP

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20140128 7

Since the original formulation of the dopamine hypothesis, a number of other cellular-level abnormalities--eg, NMDA receptor hypofunction, GABA system dysfunction, neural connectivity disturbances--have been identified in schizophrenia, but the manner in which these potentially interact with hyperdopaminergia to lead to schizophrenic symptomatology remains uncertain. Previously, we created a neuroanatomically detailed, biophysically realistic computational model of hippocampus in the control (un ...[more]

PMID: 24469592

Similar Datasets

Project description:According to the tripartite synapse model, astrocytes have a modulatory effect on neuronal signal transmission. More recently, astrocyte malfunction has been associated with psychiatric diseases such as schizophrenia. Several hypotheses have been proposed on the pathological mechanisms of astrocytes in schizophrenia. For example, post-mortem examinations have revealed a reduced astrocytic density in patients with schizophrenia. Another hypothesis suggests that disease symptoms are linked to an abnormality of glutamate transmission, which is also regulated by astrocytes (glutamate hypothesis of schizophrenia). Electrophysiological findings indicate a dispute over whether the disorder causes an increase or a decrease in neuronal and astrocytic activity. Moreover, there is no consensus as to which molecular pathways and network mechanisms are altered in schizophrenia. Computational models can aid the process in finding the underlying pathological malfunctions. The effect of astrocytes on the activity of neuron-astrocyte networks has been analysed with computational models. These can reproduce experimentally observed phenomena, such as astrocytic modulation of spike and burst signalling in neuron-astrocyte networks. Using an established computational neuron-astrocyte network model, we simulate experimental data of healthy and pathological networks by using different neuronal and astrocytic parameter configurations. In our simulations, the reduction of neuronal or astrocytic cell densities yields decreased glutamate levels and a statistically significant reduction in the network activity. Amplifications of the astrocytic ATP release toward postsynaptic terminals also reduced the network activity and resulted in temporarily increased glutamate levels. In contrast, reducing either the glutamate release or re-uptake in astrocytes resulted in higher network activities. Similarly, an increase in synaptic weights of excitatory or inhibitory neurons raises the excitability of individual cells and elevates the activation level of the network. To conclude, our simulations suggest that the impairment of both neurons and astrocytes disturbs the neuronal network activity in schizophrenia.

Dataset Information

Dopaminergic contributions to hippocampal pathophysiology in schizophrenia: a computational study.

Publications

Dopaminergic contributions to hippocampal pathophysiology in schizophrenia: a computational study.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets