The role of voltage dependence of the NMDA receptor in cellular and network oscillation

Abstract

Unraveling the mechanisms underlying oscillatory behavior is critical for understanding normal and pathological brain processes. Here we used electrophysiology in mouse neocortical slices and principles of nonlinear dynamics to demonstrate how an increase in the N‐methyl‐d‐aspartic acid receptor (NMDAR) conductance can create a nonlinear whole‐cell current–voltage (I–V) relationship which leads to changes in cellular stability. We discovered two behaviorally and morphologically distinct pyramidal cell populations. Under control conditions, both cell types responded to depolarizing current injection with regular spiking patterns. However, upon NMDAR activation, an intrinsic oscillatory (IO) cell type (n = 44) showed a nonlinear whole‐cell I–V relationship, intrinsic voltage‐dependent oscillations plus amplification of alternating input current, and these properties persisted after disabling action potential generation with tetrodotoxin (TTX). The other non‐oscillatory (NO) neuronal population (n = 24) demonstrated none of these behaviors. Simultaneous intra‐ and extracellular recordings demonstrated the NMDAR’s capacity to promote low‐frequency seizure‐like network oscillations via its effects on intrinsic neuronal properties. The two pyramidal cell types demonstrated different relationships with network oscillation – the IO cells were leaders that were activated early in the population activity cycle while the activation of the NO cell type was distributed across network bursts. The properties of IO neurons disappeared in a low‐magnesium environment where the voltage dependence of the receptor is abolished; concurrently, the cellular contribution to network oscillation switched to synchronous firing. Thus, depending upon the efficacy of NMDAR in altering the linearity of the whole‐cell I–V relationship, the two cell populations played different roles in sustaining network oscillation.

A systematic review of the effects of NMDA receptor antagonists on oscillatory activity recorded in vivo

“…Improved understanding of the specific neuronal networks that underlie oscillations is essential for understanding how oscillations of different frequencies are generated. Due to the methodological limitations with the current in vivo techniques, insights into specific neural circuits may be best assessed using other methods, mainly in vitro and modeling studies (Gonzalez-Burgos and Lewis, 2012;Martell et al, 2012;Neymotin et al, 2011;Wolf et al, 2005). Important theoretical and experimental advances were made using these complimentary techniques.…”

The Integrative Role of the Sigh in Psychology, Physiology, Pathology, and Neurobiology

“…But this was another misconception, because in invertebrate networks also, pacemaker neurons are everything but simple (Hobbs and Hooper, 2008; Prinz et al, 2003; Ramirez and Pearson, 1991a,b, 1993; Rinberg et al, 2013). Moreover, within the mammalian nervous system, pacemaker neurons are not unique to the respiratory network, and are found in many areas of the CNS; some of these networks are concerned with complex higher functions (Brocard et al, 2013; Kolta et al, 2010; Llano and Sherman, 2009; Marcuccilli et al, 2010; Martell et al, 2010, 2012; Mrejeru et al, 2011; Ramcharan et al, 2005; Ramirez et al, 2004; Ziskind-Conhaim et al, 2010). Indeed, there is probably no region in the mammalian brain that does not contain pacemaker neurons (Ramirez et al, 2011).…”

Modeling Neural Activity

“…; therefore, the experimentally determined I-V relationship can be interpreted as the . − phase space for membrane potential dynamics (e.g., [15,51]).…”