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Blocking NMDAR Disrupts Spike Timing and Decouples Monkey Prefrontal Circuits: Implications for Activity-Dependent Disconnection in Schizophrenia.

ABSTRACT: We employed multi-electrode array recording to evaluate the influence of NMDA receptors (NMDAR) on spike-timing dynamics in prefrontal networks of monkeys as they performed a cognitive control task measuring specific deficits in schizophrenia. Systemic, periodic administration of an NMDAR antagonist (phencyclidine) reduced the prevalence and strength of synchronous (0-lag) spike correlation in simultaneously recorded neuron pairs. We employed transfer entropy analysis to measure effective connectivity between prefrontal neurons at lags consistent with monosynaptic interactions and found that effective connectivity was persistently reduced following exposure to the NMDAR antagonist. These results suggest that a disruption of spike timing and effective connectivity might be interrelated factors in pathogenesis, supporting an activity-dependent disconnection theory of schizophrenia. In this theory, disruption of NMDAR synaptic function leads to dysregulated timing of action potentials in prefrontal networks, accelerating synaptic disconnection through a spike-timing-dependent mechanism.

SUBMITTER: Zick JL

PROVIDER: S-EPMC6085178 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Blocking NMDAR Disrupts Spike Timing and Decouples Monkey Prefrontal Circuits: Implications for Activity-Dependent Disconnection in Schizophrenia.

Zick Jennifer L JL Blackman Rachael K RK Crowe David A DA Amirikian Bagrat B DeNicola Adele L AL Netoff Theoden I TI Chafee Matthew V MV

Neuron 20180531 6

We employed multi-electrode array recording to evaluate the influence of NMDA receptors (NMDAR) on spike-timing dynamics in prefrontal networks of monkeys as they performed a cognitive control task measuring specific deficits in schizophrenia. Systemic, periodic administration of an NMDAR antagonist (phencyclidine) reduced the prevalence and strength of synchronous (0-lag) spike correlation in simultaneously recorded neuron pairs. We employed transfer entropy analysis to measure effective connec ...[more]

PMID: 29861281

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Project description:Phonemic and semantic fluency are neuropsychological tests widely used to assess patients' language and executive abilities and are highly sensitive tests in detecting language deficits in glioma patients. However, the networks that are involved in these tasks could be distinct and suggesting either a frontal (phonemic) or temporal (semantic) involvement. 42 right-handed patients (26 male, mean age = 52.5 years, SD=±13.3) were included in this retrospective study. Patients underwent awake (54.8%) or asleep (45.2%) surgery for low-grade (16.7%) or high-grade-glioma (83.3%) in the frontal (64.3%) or temporal lobe (35.7%) of the left (50%) or right (50%) hemisphere. Pre-operative tractography was reconstructed for each patient, with segmentation of the inferior fronto-occipital fasciculus (IFOF), arcuate fasciculus (AF), uncinate fasciculus (UF), inferior longitudinal fasciculus (ILF), third branch of the superior longitudinal fasciculus (SLF-III), frontal aslant tract (FAT), and cortico-spinal tract (CST). Post-operative percentage of damage and disconnection of each tract, based on the patients' surgical cavities, were correlated with verbal fluencies scores at one week and one month after surgery. Analyses of differences between fluency scores at these timepoints (before surgery, one week and one month after surgery) were performed; lesion-symptom mapping was used to identify the correlation between cortical areas and post-operative scores. Immediately after surgery, a transient impairment of verbal fluency was observed, that improved within a month. Left hemisphere lesions were related to a worse verbal fluency performance, being a damage to the left superior frontal or temporal gyri associated with phonemic or semantic fluency deficit, respectively. At a subcortical level, disconnection analyses revealed that fluency scores were associated to the involvement of the left FAT and the left frontal part of the IFOF for phonemic fluency, and the association was still present one month after surgery. For semantic fluency, the correlation between post-surgery performance emerged for the left AF, UF, ILF and the temporal part of the IFOF, but disappeared at the follow-up. This approach based on the patients' pre-operative tractography, allowed to trace for the first time a dissociation between white matter pathways integrity and verbal fluency after surgery for glioma resection. Our results confirm the involvement of a frontal anterior pathway for phonemic fluency and a ventral temporal pathway for semantic fluency. Finally, our longitudinal results suggest that the frontal executive pathway requires a longer interval to recover compared to the semantic one.

Dataset Information

Blocking NMDAR Disrupts Spike Timing and Decouples Monkey Prefrontal Circuits: Implications for Activity-Dependent Disconnection in Schizophrenia.

Publications

Blocking NMDAR Disrupts Spike Timing and Decouples Monkey Prefrontal Circuits: Implications for Activity-Dependent Disconnection in Schizophrenia.

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