Losing control under ketamine: suppressed cortico-hippocampal drive following acute ketamine in rats

Abstract

Systemic doses of the psychotomimetic ketamine alter the spectral characteristics of hippocampal and prefrontal cortical network activity. Using dynamic causal modeling (DCM) of cross-spectral densities, we quantify the putative synaptic mechanisms underlying ketamine effects in terms of changes in directed, effective connectivity between dorsal hippocampus and medial prefrontal (dCA1-mPFC) cortex of freely moving rats. We parameterize dose-dependent changes in spectral signatures of dCA1-mPFC local field potential recordings, using neural mass models of glutamatergic and GABAergic circuits. Optimizing DCMs of theta and gamma frequency range responses, model comparisons suggest that both enhanced gamma and depressed theta power result from a reduction in top-down connectivity from mPFC to the hippocampus, mediated by postsynaptic NMDA receptors (NMDARs). This is accompanied by an alteration in the bottom-up pathway from dCA1 to mPFC, which exhibits a distinct asymmetry: here, feed-forward drive at AMPA receptors increases in the presence of decreased NMDAR-mediated inputs. Setting these findings in the context of predictive coding suggests that NMDAR antagonism by ketamine in recurrent hierarchical networks may result in the failure of top-down connections from higher cortical regions to signal predictions to lower regions in the hierarchy, which consequently fail to respond consistently to errors. Given that NMDAR dysfunction has a central role in pathophysiological theories of schizophrenia and that theta and gamma rhythm abnormalities are evident in schizophrenic patients, the approach followed here may furnish a framework for the study of aberrant hierarchical message passing (of prediction errors) in schizophrenia-and the false perceptual inferences that ensue.

Figure 1

Dynamic causal Modeling. (a) Top: the neural mass model used to represent each source. Three neuronal sub-populations represent each source, with two pyramidal cell populations. Glutamatergic within source (intrinsic: gray arrows) and between source (extrinsic: gray arrows) connections are mediated by AMPARs and NMDARs. Intrinsic GABAergic currents (red arrows) are mediated through GABA_A receptors. In our model, comparison of 10 possible effects of ketamine were tested (blue text): all models allowed for extrinsic NMDA and AMPA mediation. Models 1–5 allowed extrinsic modulation at pyramidal cells, whereas models 6–10 allowed for extrinsic modulations at pyramidal cells and interneurons. Within these groups, models were tested which had ketamine effecting either inhibitory connections intrinsically (models 1, 2, 6, and 7) or local feedback inhibition onto particular cells types (models 3, 4, 5, 8, 9, and 10). All models included intrinsic ketamine effects at NMDARs. Bottom: tetrode electrodes in dorsal CA1 and medial PFC were analyzed using DCM. Cross-spectral densities were computed and served as data features to optimize a network model comprising a multi-layered hippocampal formation and mPFC. (b) Bayesian model comparison was used to assess the intrinsic modulation that best described ketamine-induced changes in spectral (theta and gamma) responses. Model 5, the winning model included parametric dose effects at intrinsic NMDAR channels and of local feedback inhibition at the output pyramidal cell layer (in dCA1 in HPC and deep layers of mPFC). Extrinsic connections in model 5 targeted the pyramidal sub-populations only. (c) Locomotion measured for five animals in the open-field arena over four dose levels (vehicle, 2, 4, 8 mg/kg). Significant increases in locomotive activity were evident at 8 mg/kg compared with a dose level of 2 mg/kg and compared with vehicle; **P<0.05 corrected Wilcoxon rank sum test.

Figure 2

Cross-spectral densities and model fits. (a) Grand-averaged data (n=10) in the gamma band (dashed line) were computed from 40 to 75 Hz. Ketamine dose (black lines: vehicle, navy lines: 2 mg/kg, cyan lines: 4 mg/kg, green lines: 8 mg/kg, red lines 30 mg/kg) increases gamma power in both auto and cross-spectral measures. DCM fits (full line) recapitulated this key feature of ketamine modulation. (b) Theta band cross-spectral densities from 2 to 10 Hz were computed for vehicle (n=10) and ketamine doses at 2 (n=5) and 4 (n=5) mg/kg (dashed lines). In contrast to gamma, these densities showed a profound decrease in power in both regions, particularly in the hippocampus. DCM fits captured this theta effect (solid line).

Figure 3

Parametric effects of ketamine on cortico-hippocampal connections. (a) Consistent (positive or negative) modulatory effects of theta and gamma optimized parameters were investigated. Overall top-down connections were reduced and bottom-up connections increased (at fast ionotropic receptors) under ketamine. Parametric effects of ketamine that were consistent across theta and gamma ranges, included (top two panels, black bars) NMDAR-mediated responses, which decreased parametrically with dose from HPC to mPFC and from mPFC to HPC. In contrast, AMPAR-mediated forward connection from CA1 to mPFC increased with increasing ketamine dose (bottom panel, green bars). (b) Consistent modulations of intrinsic connections by ketamine. Only hippocampal parameters were consistent across the two data ranges. These exhibited a dose-dependent decrease in intrinsically excited NMDARs (top panel, black bars). This was accompanied by an increase in local feedback inhibition onto CA1 pyramidal cells (red bars). This latter effect is a lumped representation of several putative synaptic mechanisms, including GABAergic effects, dopaminergic neuromodulation, and hyperpolarizing currents.