Effects of NMDA and GABA-A Receptor Antagonism on Auditory Steady-State Synchronization in Awake Behaving Rats

Abstract

Background:The auditory steady-state response, which measures the ability of neural ensembles to entrain to rhythmic auditory stimuli, has been used in human electroencephalogram studies to assess sensory processing and electrical oscillatory deficits. Patients with schizophrenia show a deficit in auditory steady-state response at 40 Hz, and therefore this may be a useful biomarker to study this disorder.Methods:We used auditory steady-state response recordings from the primary auditory cortex, hippocampus, and vertex electroencephalogram sites in awake behaving rats to determine whether pharmacological impairment of excitatory or inhibitory neurotransmission mimics auditory steady-state response abnormalities in schizophrenia.Results:We found the most robust response to auditory stimuli in the primary auditory cortex, in line with previous studies suggesting this region is the primary generator of the auditory steady-state response in humans. Acute MK-801 (0.1mg/kg i.p.) increased primary auditory cortex intertrial coherence during auditory steady-state response at 20 and 40 Hz. Chronic MK-801 (21-day exposure at this daily dose) had no significant effect on 40-Hz auditory steady-state response. Furthermore, we found no effect of acute or chronic picrotoxin (a GABA-A antagonist) on intertrial coherence.Conclusions:Our data indicate that acute N-methyl-d-aspartate receptor antagonism increases synchronous activity in the primary auditory cortex in a frequency-specific manner, supporting the widely held view that acute N-methyl-d-aspartate antagonism augments gamma oscillations. Thus, rodent auditory steady-state response could be a valuable method to study the cortical ability to support synchronous activity at specific frequencies.

40 Hz Auditory Steady-State Response Is a Pharmacodynamic Biomarker for Cortical NMDA Receptors

“…However, this has been recently challenged (Ding and Simon, 2013). Although we do not completely understand the dynamics behind these measures, PLF may be a more sensitive index of neuropsychiatric dysfunction associated with NMDA transmission (Hirano et al, 2015;Kirihara et al, 2012;Spencer et al, 2008;Sullivan et al, 2015).…”

“…This line of reasoning also presupposes that in the baseline condition, the evoked ASSR PLF is likely to be submaximal and that it can be increased by exogenous factors such as augmenting synaptic glutamate. This assumption seems reasonable as the NMDA receptors on PV+ neurons have been shown to be critical for entrainment at 40 Hz in empirical as well as modeling studies (Carlen et al, 2012;Kirli et al, 2014;Nakao and Nakazawa, 2014;Spencer, 2009), and because baseline 40 Hz ASSR can be improved by exogenous modulators like attention (Albrecht et al, 2013;Skosnik et al, 2007;Ross et al, 2004) or by pharmacological intervention that affect key neurotransmitters (Albrecht et al, 2013;Sivarao et al, 2013;Sullivan et al, 2015;Vohs et al, 2012). As the two intermediate doses of ketamine produced 34 and 62% of NMDA block while not significantly affecting ASSR PLF, we speculate that a baseline PLF response involves engagement of ∼ 38-66% of the available cortical NMDA receptors.…”

“…Taking advantage of this important validation, preclinical studies often employ a short-term disruption in NMDA neurotransmission to mimic a psychosis-like state (Adell et al, 2012;Frohlich and Van Horn, 2014;Gunduz-Bruce, 2009). Several groups have used this approach to understand the role of NMDA receptors in the 40 Hz ASSR (Sivarao et al, 2013;Sullivan et al, 2015;Vohs et al, 2012). Unfortunately, these studies reported opposite modulation of the ASSR signal with NMDA antagonists while employing divergent methodology.…”

“…Unfortunately, these studies reported opposite modulation of the ASSR signal with NMDA antagonists while employing divergent methodology. Sivarao et al (2013) showed that a low dose of the potent NMDA antagonist MK-801 attenuated ASSR at 40 Hz in anesthetized rats, Sullivan et al (2015) reported that a single dose of MK-801 increased phase locking at 40 Hz in awake behaving rats, whereas Vohs et al (2012) reported an increase in phase locking at multiple frequencies after a single dose of ketamine in conscious rats. Thus, anesthetized and awake rats produced opposite effects on 40 Hz ASSR following acute administration of an NMDA antagonist.…”

Acute Phencyclidine Alters Neural Oscillations Evoked by Tones in the Auditory Cortex of Rats

“…Secondly, subchronic or chronic administration using either multiple single doses or continuous delivery of NMDAr antagonists may have quite different physiological effects [29]. Studies using MK-801 [30] and PCP found that acute, but not subchronic administration of a NMDAr antagonist, reduced ASSR gamma phase synchrony in rats [30][28]. …”