Effects of aberrant gamma frequency oscillations on prepulse inhibition

Abstract

Emerging literature implicates abnormalities in gamma frequency oscillations in the pathophysiology of schizophrenia, with hypofunction of N-methyl-D-aspartate (NMDA) receptors implicated as a key factor. Prepulse inhibition (PPI) is a behavioural measure of sensorimotor gating, which is disrupted in schizophrenia. We studied relationships between ongoing and sensory-evoked gamma oscillations and PPI using pharmacological interventions designed to increase gamma oscillations (ketamine, MK-801); reduce gamma oscillations (LY379268); or disrupt PPI (amphetamine). We predicted that elevating ongoing gamma power would lead to increased 'neural noise' in cortical circuits, dampened sensory-evoked gamma responses and disrupted behaviour. Wistar rats were implanted with EEG recording electrodes. They received ketamine (5 mg/kg), MK-801 (0.16 mg/kg), amphetamine (0.5 mg/kg), LY379268 (3 mg/kg) or vehicle and underwent PPI sessions with concurrent EEG recording. Ketamine and MK-801 increased the power of ongoing gamma oscillations and caused time-matched disruptions of PPI, while amphetamine marginally affected ongoing gamma power. In contrast, LY379268 reduced ongoing gamma power, but had no effect on PPI. The sensory gamma response evoked by the prepulse was reduced following treatment with all psychotomimetics, associating with disruptions in PPI. This was most noticeable following treatment with NMDA receptor antagonists. We found that ketamine and MK-801 increase ongoing gamma power and reduce evoked gamma power, both of which are related to disruptions in sensorimotor gating. This appears to be due to antagonism of NMDA receptors, since amphetamine and LY379268 differentially impacted these outcomes and possess different neuropharmacological substrates. Aberrant gamma frequency oscillations caused by NMDA receptor hypofunction may mediate the sensory processing deficits observed in schizophrenia.

Brain‐derived neurotrophic factor haploinsufficiency impairs high‐frequency cortical oscillations in mice

“…The most striking observation from this study was impaired generation and regulation of high‐frequency oscillations in BDNF +/− mice – specifically reduced ERPs and evoked beta power following auditory stimuli, as well as reduced ongoing gamma power. The impaired ability to generate appropriate responses to brief auditory stimuli may underlie sensorimotor gating and cognitive deficits previously observed in these mice (Manning & van den Buuse, ; Wu et al ., ), because these behaviours may rely on such responses (Jones et al ., ). Further, given post‐mortem findings of reduced BDNF levels in the brains of patients with schizophrenia (Weickert et al ., ), these findings promote this mouse model as one which could be used to study the relationships between deficits in BDNF signalling and oscillatory abnormalities which are relevant to schizophrenia.…”

“…We have previously identified behavioural phenotypes caused by BDNF heterozygosity (Manning & van den Buuse, ) and NMDAR hypofunction (Hakami et al ., ), but without correlative analyses, it is challenging to directly demonstrate causal relationships between electrophysiological phenotypes (including oscillatory responses and ERP components) to functional consequences. Some of our recent endeavours attempt to achieve this (Jones et al ., ; Hudson et al ., ).…”

“…This is based on the observations that NMDAR antagonists replicate and exacerbate many of the symptoms of schizophrenia (Adler et al, 1998;Newcomer et al, 1999). NMDAR antagonists produce an electrophysiological phenotype in rodents and healthy humans reminiscent of that observed in schizophrenia patients, with increased ongoing, or 'baseline', gamma oscillations diffusely throughout the brain (Hakami et al, 2009;Jones et al, 2012Jones et al, , 2014Anderson et al, 2014), as well as reduced sensory-evoked gamma responses (Ehrlichman et al, 2009;Hong et al, 2010;Kulikova et al, 2012;Long et al, 2015;Anderson et al, 2016). Beta oscillations (20-30 Hz) may also be affected and relevant to schizophrenia (Roopun et al, 2008;Kulikova et al, 2012), although oscillations of this frequency band have been less studied with respect to NMDAR hypofunction.…”

Convergent Mechanisms Underlying Rapid Antidepressant Action

“…Indeed, MK-801 administration enhances cortical gamma EEG power in rats [153, 154], characterized by synchronized high frequency firing as a result of pyramidal neuron disinhibition. Notably, non-selective and GluN2A-NMDAR antagonists, but not GluN2B-, or GluN2C/2D selective subunit inhibitors increase gamma power in rats [155], suggesting NMDAR subunit-specific modulation of cortical EEG activity.…”

Speech‐in‐noise understanding in older age: The role of inhibitory cortical responses

“…Simultaneous intracranial recordings of P50 and gamma responses (Trautner et al., ) showed a poor correlation between the amplitudes of the two responses, and the authors rejected the hypothesis of a common nature of evoked responses and the gamma‐band response. Another study found that sensory gating was reduced in mice when gamma power was elevated through pharmacological modulation (Jones et al., ). The latter results are consistent with our findings that aging was associated with reduced sensory gating and enhanced gamma amplitudes.…”