NMDA receptors on parvalbumin-positive interneurons and pyramidal neurons both contribute to MK-801 induced gamma oscillatory disturbances: Complex relationships with behaviour

Hudson, Matthew R.; Sokolenko, Elysia; O’Brien, Terence J.; Jones, Nigel C.

doi:10.1016/j.nbd.2019.104625

Cited by 26 publications

(32 citation statements)

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“…Further, administration of NMDAR antagonists such as ketamine (Pinault, 2008;Hakami et al, 2009;Kulikova et al, 2012;Caixeta et al, 2013;Picard et al, 2019;Lopes-Aguiar et al, 2020;Mahdavi et al, 2020;McNally et al, 2020), or MK-801 (Carlén et al, 2012;Molina et al, 2014;Hudson et al, 2020), is associated with increased power in spontaneous broadband gamma oscillations in both anesthetized and awake rodents, and also in humans (Rivolta et al, 2015). Importantly, lack of NMDAR in PV neurons blunts this response (Carlén et al, 2012;Picard et al, 2019;Hudson et al, 2020), confirming that cortical PV interneurons are a central target of NMDAR antagonists. However, it is unclear if pharmacologically-induced increases in broadband gamma oscillations are distinct from the increased spontaneous broadband gamma oscillations observed in genetic models of deficient PV inhibition, e.g.…”

Section: Introductionmentioning

confidence: 92%

“…Increased spontaneous broadband gamma oscillations have also been demonstrated in other mouse models of PV neuron dysfunctions (del Pino et al, 2013;Cho et al, 2015), and in individuals with schizophrenia (Mathalon and Sohal, 2015;Grent-'t-Jong et al, 2018). Further, administration of NMDAR antagonists such as ketamine (Pinault, 2008;Hakami et al, 2009;Kulikova et al, 2012;Caixeta et al, 2013;Picard et al, 2019;Lopes-Aguiar et al, 2020;Mahdavi et al, 2020;McNally et al, 2020), or MK-801 (Carlén et al, 2012;Molina et al, 2014;Hudson et al, 2020), is associated with increased power in spontaneous broadband gamma oscillations in both anesthetized and awake rodents, and also in humans (Rivolta et al, 2015). Importantly, lack of NMDAR in PV neurons blunts this response (Carlén et al, 2012;Picard et al, 2019;Hudson et al, 2020), confirming that cortical PV interneurons are a central target of NMDAR antagonists.…”

Section: Introductionmentioning

confidence: 96%

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Network asynchrony underlying increased broadband gamma power

Guyon

Zacharias

Oliveira

et al. 2020

Preprint

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Synchronous activity of cortical inhibitory interneurons expressing parvalbumin (PV) underlies the expression of cortical gamma rhythms. Paradoxically, deficient PV inhibition is associated with increased broadband gamma power. Increased baseline broadband gamma is also a prominent characteristic in schizophrenia, and a hallmark of network alterations induced by N-methyl-D-aspartate receptor (NMDAR) antagonists such as ketamine. It has been questioned if enhanced broadband gamma power is a true rhythm, and if rhythmic PV inhibition is involved or not. It has been suggested that asynchronous and increased firing activities underlie broadband power increases spanning the gamma band. Using mice lacking NMDAR activity specifically in PV neurons to model deficient PV inhibition, we here show that local LFP (local field potential) oscillations and neuronal activity with decreased synchronicity generate increases in prefrontal broadband gamma power. Specifically, reduced spike time precision of both local PV interneurons and wide-spiking (WS) excitatory neurons contribute to increased firing rates, and spectral leakage of spiking activity (spike “contamination”) affecting the broadband gamma band. Desynchronization was evident at multiple time scales, with reduced spike-LFP entrainment, reduced cross-frequency coupling, and fragmentation of brain states. While local application of S(+)-ketamine in wildtype mice triggered network desynchronization and increases in broadband gamma power, our investigations suggest that disparate mechanisms underlie increased power of broadband gamma caused by genetic alteration of PV interneurons, and ketamine-induced power increases in broadband gamma. Our studies, thus, confirm that broadband gamma increases can arise from asynchronous activities, and demonstrate that long-term deficiency of PV inhibition can be a contributor.

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Section: Introductionmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 96%

Network asynchrony underlying increased broadband gamma power

Guyon

Zacharias

Oliveira

et al. 2020

Preprint

View full text Add to dashboard Cite

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“…In rodents, acute or repeated administration of NMDA receptor antagonists such as ketamine, PCP, and MK-801, have been used to model schizophrenia ( 97 ). The schizophrenia-like signs induced by these drugs are proposed to depend on NMDA receptors blockade in parvalbumin containing inhibitory GABAergic interneurons ( 98 , 99 ). A decrease in parvalbumin expression is one of the most robust findings in post-mortem brains of schizophrenia patients ( 100 ).…”

Section: Cb2 Receptors and Schizophreniamentioning

confidence: 99%

Are CB2 Receptors a New Target for Schizophrenia Treatment?

et al. 2020

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Schizophrenia is a complex disorder that involves several neurotransmitters such as dopamine, glutamate, and GABA. More recently, the endocannabinoid system has also been associated with this disorder. Although initially described as present mostly in the periphery, cannabinoid type-2 (CB2) receptors are now proposed to play a role in several brain processes related to schizophrenia, such as modulation of dopaminergic neurotransmission, microglial activation, and neuroplastic changes induced by stress. Here, we reviewed studies describing the involvement of the CB2 receptor in these processes and their association with the pathophysiology of schizophrenia. Taken together, these pieces of evidence indicate that CB2 receptor may emerge as a new target for the development of antipsychotic drugs.

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“…Antagonism of NMDARs has been proposed to reduce PV-neuron activity and consequently, disinhibit M1 principal cells (Buzsáki and Wang, 2012;Homayoun and Moghaddam, 2007;Hudson et al, 2020;Korotkova et al, 2010;Pinault, 2008). This could engage local networks of non-parvalbumin inhibitory cells contributing to gamma generation (Whittington et al, 1995), such as somatostatin interneurons that, in the mPFC, contribute to the antidepressive action of ketamine (Gerhardt et al, 2020).…”

Section: Lid-associated Broadband Gamma Was Reduced When L-dopa Was Cmentioning

confidence: 99%

“…Focal 80-Hz gamma also differs from desynchronized broadband gamma (∼30-80 Hz) that is associated with increased excitability in neural circuits (Sohal and Rubenstein, 2019; Yizhar et al, 2011) and uncorrelated synaptic and spiking activity (Belluscio et al, 2012). Indeed, broadband gamma can be evoked through disinhibition of principal cells by reducing glutamatergic drive to parvalbumin-expressing inhibitory interneurons through genetic manipulations (Cho et al, 2015; delPino et al, 2013) and delivery of NMDAR antagonists such as ketamine or MK-801 (Caixeta et al, 2013; Carlén et al, 2012; Hakami et al, 2009; Hudson et al, 2020; Kulikova et al, 2012; McNally et al, 2020; Pinault, 2008; Rivolta et al, 2015; Ye et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

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

Bartlett

Sherman

et al. 2020

Preprint

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L-DOPA-induced dyskinesias (LID) are debilitating motor symptoms of dopamine-replacement therapy for Parkinson′s disease (PD) that emerge after years of L-DOPA treatment. While there is an abundance of research into the cellular and synaptic origins of LID, less is known about how LID impacts systems-level circuits and neural synchrony, how synchrony is affected by the dose and duration of L-DOPA exposure, or how potential novel treatments for LID, such as sub- anesthetic ketamine, alter this activity. Sub-anesthetic ketamine treatments have recently been shown to reduce LID, and ketamine is known to affect neural synchrony. To investigate these questions, we measured locomotor and local-field potential (LFP) activity from the motor cortex (M1) and the striatum of preclinical rodent models of PD and LID. In the first experiment, we investigated the effect of the LID priming procedures and L-DOPA dose on neural signatures of LID. Two common priming procedures were compared: a high-dose procedure that exposed unilateral 6-hydroxydopamine-lesioned rats to 12 mg/kg L-DOPA for 7 days, and a low-dose procedure that exposed rats to 7 mg/kg L-DOPA for 21 days. Consistent with reports from other groups, high-dose priming triggered LID and 80-Hz oscillations; however, these 80-Hz oscillations were not observed under the low-dose procedure despite clear evidence of LID, indicating that 80- Hz oscillations are not an exclusive signature of LID. Instead, the low-dose procedure resulted in the weeks-long gradual emergence of non-oscillatory broadband gamma activity (> 30 Hz) in the striatum and theta-to-high-gamma cross-frequency coupling (CFC) in M1. In a second set of experiments, we investigated how ketamine exposure affects spectral signatures of low-dose L- DOPA priming. During each neural recording session, ketamine was delivered through 5 injections (20 mg/kg, i.p.) administered every 2 hours. We found that ketamine exposure suppressed striatal broadband gamma associated with LID, but enhanced M1 broadband activity. We also found that M1 theta-to-high-gamma CFC associated with the LID on-state was suppressed by ketamine. These results suggest that ketamine′s therapeutic effects are region specific. Our findings also have clinical implications as we are the first to report novel oscillatory signatures associated with the common low-dose LID priming procedure that more closely models dopamine replacement therapy in individuals with PD, and as we identify neural correlates of the anti-dyskinetic activity of sub-anesthetic ketamine treatment.

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NMDA receptors on parvalbumin-positive interneurons and pyramidal neurons both contribute to MK-801 induced gamma oscillatory disturbances: Complex relationships with behaviour

Cited by 26 publications

References 50 publications

Network asynchrony underlying increased broadband gamma power

Network asynchrony underlying increased broadband gamma power

Are CB2 Receptors a New Target for Schizophrenia Treatment?

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

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