Rodent Mismatch Negativity/theta Neuro-Oscillatory Response as a Translational Neurophysiological Biomarker for N-Methyl-D-Aspartate Receptor-Based New Treatment Development in Schizophrenia

Abstract

Deficits in the generation of auditory mismatch negativity (MMN) generation are among the most widely replicated neurophysiological abnormalities in schizophrenia and are linked to underlying dysfunction of N-methyl-D-aspartate receptor (NMDAR)-mediated neurotransmission. Here, we evaluate physiological properties of rodent MMN, along with sensitivity to NMDAR agonist and antagonist treatments, relative to known patterns of dysfunction in schizophrenia. Epidural neurophysiological responses to frequency and duration deviants, along with responses to standard stimuli, were obtained at baseline and following 2 and 4 weeks' treatment in rats treated with saline, phencyclidine (PCP, 15 mg/kg/d by osmotic minipump), or PCP+glycine (16% by weight diet) interventions. Responses were analyzed using both event-related potential (ERP) and neuro-oscillatory (evoked power) approaches. At baseline, rodent duration MMN was associated with increased theta (θ)-frequency response similar to that observed in humans. PCP significantly reduced rodent duration MMN (p<0.001) and θ-band (p<0.01) response. PCP effects were prevented by concurrent glycine treatment (p<0.01 vs PCP alone). Effects related to stimulus-specific adaptation (SSA) were observed primarily in the alpha (α) and beta (β) frequency ranges. PCP treatment also significantly reduced α-frequency response to standard stimuli while increasing θ-band response, reproducing the pattern of deficit observed in schizophrenia. Overall, we demonstrate that rodent duration MMN shows neuro-oscillatory signature similar to human MMN, along with sensitivity to the NMDAR antagonist and agonist administration. These findings reinforce recent human studies linking MMN deficits to θ-band neuro-oscillatory dysfunction and support utility of rodent duration MMN as a translational biomarker for investigation of mechanisms underlying impaired local circuit function in schizophrenia.

Translational neurophysiological biomarkers of N-methyl-D-aspartate receptor dysfunction in serine racemase knockout mice

“…In humans, N1 responses map primarily to the theta frequency range, and thus may interrelate with circuit motifs involving non-PV interneurons, especially SOMs (Javitt et al, submitted). Our finding of significant aERP response in mice following NMDAR blockade is consistent with prior studies in monkey (Javitt et al, 2000) and rodent (Bickel et al, 2008;Connolly et al, 2004;Lee et al, 2018;Maxwell et al, 2006). The lack of effect of SRKO on the rodent N1 response may thus suggest that the model recapitulates the PV-related aspects of NMDAR dysfunction in Sz more fully than it captures dysfunction of other neuronal populations.…”

“…Like ASSR, deficits in auditory N1/P2 response have been extensively documented in Sz (Ford et al, 2001;Javitt et al, 2008;Shelley et al, 1999;Turetsky et al, 2009). Also like ASSR, Sz-like deficits in auditory N1 generation are induced by NMDAR antagonists in both monkey (Javitt et al, 2000) and rodent (Connolly et al, 2004;Lee et al, 2018;Maxwell et al, 2006;Schuelert et al, 2018) models. However, as opposed to ASSR, power associated with the auditory N1/P2 component maps predominantly to the theta frequency range, implicating somatostatin (SOM) interneuron related circuits Javitt and Sweet, 2015;Womelsdorf et al, 2014).…”

Electrophysiology as a theoretical and methodological hub for the neural sciences

“…The MMN is a theta-dominant response with separable frontal and temporal processes (Fuentemilla, Marco-Pallarés, Münte, & Grau, 2008;Ko et al, 2012) that may interact with theta-band phase synchrony (Choi et al, 2013). The neural systems underlying auditory novelty detection are well detailed in rodent models (Escera & Malmierca, 2014;Featherstone, Melnychenko, & Siegel, 2018;Lee et al, 2018), facilitating further cross-species translation. Auditory evoked responses are already routinely used in brainstem auditory testing for hearing acuity in newborns, again demonstrating that clinical infrastructure and expertise exists for applying relevant tasks to patient groups when using EEG as a diagnostic tool.…”

Sound frequency dependence of duration mismatch negativity recorded from awake rats

“…Therefore, MMN research in nonhuman animals can help reveal the neural mechanisms of MMN generation and its deficits . Currently, the few studies observing MMN evoked by duration deviance in rats have produced inconsistent results in the response latency window and polarity of MMN . Acoustic stimuli used in these studies (1‐ to 4‐kHz tones) were located at the lower end of the hearing range in rats; therefore, it was possible that the frequency of these sound stimuli was not suitable for MMN induction.…”

“…13 Currently, the few studies observing MMN evoked by duration deviance in rats have produced inconsistent results in the response latency window and polarity of MMN. [14][15][16][17] Acoustic stimuli used in these studies (1-to 4-kHz tones) were located at the lower end of the hearing range in rats 18 ; therefore, it was possible that the frequency of these sound stimuli was not suitable for MMN induction. Notably, a recent study using 7-to 18-kHz sound stimuli observed large MMN-like potentials to pitch changes.…”