NMDAR antagonist action in thalamus imposes δ oscillations on the hippocampus

Abstract

Work on schizophrenia demonstrates the involvement of the hippocampus in the disease and points specifically to hyperactivity of CA1. Many symptoms of schizophrenia can be mimicked by N-methyl-d-aspartate receptor (NMDAR) antagonist; notably, delta frequency oscillations in the awake state are enhanced in schizophrenia, an abnormality that can be mimicked by NMDAR antagonist action in the thalamus. Given that CA1 receives input from the nucleus reuniens of the thalamus, we sought to determine whether an NMDAR antagonist in the thalamus can affect hippocampal processes. We found that a systemic NMDAR antagonist (ketamine; 50 mg/kg) increased the firing rate of cells in the reuniens and CA1 in awake rats. Furthermore, ketamine increased the power of delta oscillations in both structures. The thalamic origin of the change in hippocampal properties was demonstrated in three ways: 1) oscillations in the two structures were coherent; 2) the hippocampal changes induced by systematic ketamine were reduced by thalamic injection of muscimol; and 3) the hippocampal changes could be induced by local injection of ketamine into the thalamus. Lower doses of ketamine (20 mg/kg) did not evoke delta oscillations but did increase hippocampal gamma power, an effect not dependent on the thalamus. There are thus at least two mechanisms for ketamine action on the hippocampus: a low-dose mechanism that affects gamma through a nonthalamic mechanism and a high-dose mechanism that increases CA1 activity and delta oscillations as a result of input from the thalamus. Both mechanisms may be important in producing symptoms of schizophrenia.

Fig. 1.

Systemic ketamine injection (50 mg/kg) enhanced delta and gamma oscillations in the LFP in the hippocampal CA1 region. A: stain section of the hippocampus shows the electrode position in the CA1 pyramidal cell body layer (red arrow). B: raw LFP traces (noisy) and band-pass filtered traces (smooth) before (top) and after (bottom) ketamine injection. C: power (in pseudocolor) at different frequencies as a function of time. Top: expanded power spectrum of delta band (1–4 Hz); delta and gamma power are increased by ketamine. D: summary data of relative increase in delta power (10 min after injection, n = 28, P < 0.05). E: time course of ketamine-induced increase in delta power; each bin is 1 min (n = 28). F: a power spectrum showing that, using the same animal 48 h later, low-dose ketamine (20 mg/kg) did not change delta power, whereas it increased gamma power.

Fig. 2.

Systemic ketamine injection (50 mg/kg) enhanced delta oscillation in the nucleus reuniens. A: LFP traces before (black) and after (gray) ketamine injection; filtered and unfiltered traces are superposed. B: summary data showing that ketamine increased delta power in the reuniens (10 min after injection; normalized to before injection, n = 9, P < 0.05).

Fig. 3.

Relationship between delta oscillations in the reuniens and hippocampus. A: the fold increase in delta power in the hippocampus and reuniens in nine different experiments is correlated (r² = 0.42, P < 0.05). B: the coherence of LFP between hippocampus and reuniens was selectively increased in the delta frequency range by ketamine. Solid lines are mean coherence; light background areas are 95% confidence intervals.

Fig. 4.

Ketamine increased LFP delta phase synchronization between the hippocampus and reuniens. A, top: filtered traces of delta oscillation in hippocampus and reuniens before ketamine injection (black: hippocampus; gray: reuniens). Bottom: scaled delta oscillations show phase relation. B: same as A, but after ketamine injection. C: histogram of phase difference between the hippocampus and reuniens (black: before ketamine; gray: after ketamine). D: summary data (n = 9) of width at half maximum in C.

Fig. 5.

Ketamine-induced delta oscillations in the reuniens and hippocampus can be seen in the spiking of single units. A, left: an individual hippocampal neuron shows weak delta-phase modulation before ketamine (black) and stronger delta-phase modulation after ketamine (gray). Right: the mean resultant length, a measure of delta phase-specific firing, is increased by ketamine (black: before ketamine; gray: after ketamine, n = 54 cells). B: same illustration as A, but in reuniens (n = 32 cells).

Fig. 6.

Tests of the causal role of the reuniens in increasing delta power in the hippocampus. A: picture shows the position of guiding canulae; ST, striatum; IC, internal capsule; nRT, nucleus reticularis of thalamus; RE, reuniens nucleus; V3, the third ventricle. B: power (pseudocolor) as a function of frequency and time. Injection of muscimol into reuniens prevented the subsequent elevation of delta power by systemic ketamine. C: power spectrum shows that, with pretreatment of muscimol, ketamine failed to increase delta power, whereas gamma power was still increased. D: ketamine was still able to increase delta power in the same animal 48 h later. E: time course of delta power. Injection of muscimol into reuniens prevents the large increase in delta power caused by a subsequent systemic injection of ketamine (n = 6). F: power spectrum shows that local injection of ketamine into the reuniens was sufficient to increase delta power in the hippocampus, whereas gamma oscillation was not affected (n = 5). Inset: filtered delta traces before (blue) and after (red) local ketamine injection into the reuniens.