Ten-Hour Exposure to Low-Dose Ketamine Enhances Corticostriatal Cross-Frequency Coupling and Hippocampal Broad-Band Gamma Oscillations

Abstract

Introduction: Treatment-resistant depression, post-traumatic stress disorder, chronic pain, and L-DOPA-induced dyskinesia in Parkinson’s disease are characterized by hypersynchronous neural oscillations. Sub-anesthetic ketamine is effective at treating these conditions, and this may relate to ketamine’s capacity to reorganize oscillatory activity throughout the brain. For example, a single ketamine injection increases gamma (∼40 Hz) and high-frequency oscillations (HFOs, 120–160 Hz) in the cortex, hippocampus, and striatum. While the effects of single injections have been investigated, clinical ketamine treatments can involve 5-h up to 3-day sub-anesthetic infusions. Little is known about the effects of such prolonged exposure on neural synchrony. We hypothesized that hours-long exposure entrains circuits that generate HFOs so that HFOs become sustained after ketamine’s direct effects on receptors subside.Methods: Local-field recordings were acquired from motor cortex (M1), striatum, and hippocampus of behaving rats (n = 8), and neural responses were measured while rats received 5 ketamine injections (20 mg/kg, i.p., every 2 h, 10-h exposure). In a second experiment, the same animals received injections of D1-receptor antagonist (SCH-23390, 1 mg/kg, i.p.) prior to ketamine injection to determine if D1 receptors were involved in producing HFOs.Results: Although HFOs remained stable throughout extended ketamine exposure, broad-band high-frequency activity (40–140 Hz) in the hippocampus and delta-HFO cross-frequency coupling (CFC) in dorsal striatum increased with the duration of exposure. Furthermore, while ketamine-triggered HFOs were not affected by D1 receptor blockade, ketamine-associated gamma in motor cortex was suppressed, suggesting involvement of D1 receptors in ketamine-mediated gamma activity in motor cortex.Conclusion: Prolonged ketamine exposure does not enhance HFOs in corticostriatal circuits, but, instead, enhances coordination between low and high frequencies in the striatum and reduces synchrony in the hippocampus. Increased striatal CFC may facilitate spike-timing dependent plasticity, resulting in lasting changes in motor activity. In contrast, the observed wide-band high-frequency “noise” in the hippocampus suggests that ketamine disrupts action-potential timing and reorganizes connectivity in this region. Differential restructuring of corticostriatal and limbic circuits may contribute to ketamine’s clinical benefits.

Venlafaxine stimulates PNN proteolysis and MMP‐9‐dependent enhancement of gamma power; relevance to antidepressant efficacy

“…; Ye et al . ). Similarly, intermittent theta burst transcranial magnetic stimulation reduces PV expression and increases EEG gamma power (Benali et al .…”

Long-term potentiation prevents ketamine-induced aberrant neurophysiological dynamics in the hippocampus-prefrontal cortex pathway in vivo

“…In our study, gamma increase after KET injection was robust in the PFC, with subtle effects in the HPC (see also Figure S1A). Robust gamma increases have been previously reported in the HPC following NMDAr antagonism in freely moving 51,52 and anesthetized animals 17 as well. To our knowledge, none of these studies tested the effects of S+ ketamine, which has a higher affinity to NMDAr compared to racemic ketamine 53 .…”

Spectral Signatures of L-DOPA-Induced Dyskinesia Depend on L-DOPA Dose and are Suppressed by Ketamine

“…A frozen microtome was used to produce coronal sections (40 µM) for tyrosine hydroxylase (TH; Bartlett et al, 2016) (Fig. 1D) and Nissl staining (Ye et al, 2018) (Fig. 1C) verification of dopamine-depleted striatum and electrode placement, respectively.…”

“…The combined effect of ketamine+L-DOPA on glutamatergic neurons may partially account for enhanced oscillatory activity. Dopamine may also be involved as ketamine-induced locomotion and gamma in M1 were eliminated when ketamine was delivered after administration of a D1R antagonist (Ye et al, 2018).…”