Research reportDevelopment of NMDA-induced theta rhythm in hippocampal formation slices
Introduction
The basic phenomena that accompany the production of all EEG patterns in the brain tissue are the cellular mechanisms of oscillations and synchrony (Bland and Colom, 1993, Lopes da Silva, 1991). Knowledge of these phenomena is important for understanding the relationship between specific EEG patterns and the activity of neuronal populations in brain structures, including hippocampal formation (HPC). This limbic structure generates a synchronized EEG activity, termed the theta rhythm. The theta rhythm is a sinusoidal, high-voltage activity (from 0.2 to 2 mV) with a frequency band ranging from 3 to 12 Hz (Bland, 1986, Bland and Oddie, 2001, Bland and Colom, 1993, Lopes da Silva, 1991). Theta waves are one of the best examples of oscillations and synchrony occurring in neuronal networks of the central nervous system (Bland, 1986, Bland and Colom, 1993). This activity occurs in the hippocampal formation during the planning and initiation of movement sequences (Bland, 1986, McNaughton et al., 2007, Oddie et al., 1997), plays a role in attention and sensorimotor integration (Ekstrom et al., 2005, Oddie et al., 1997), and affects formation of memory traces (Dusek and Eichenbaum, 1997, Huang and Kandel, 2005, Tracy et al., 2001).
Numerous studies carried out in vivo and in vitro have demonstrated that the appearance of theta rhythm requires a certain level of excitation of local neuronal networks (Bland and Colom, 1993, Bland, 2008, Cobb et al., 1995, Konopacki et al., 2006, Konopacki and Gołębiewski, 1993, Yoder and Pang, 2005). Many years of research conducted with the use of models of HPC slice preparations have allowed us to determine the specific role of the cholinergic (Kazmierska et al., 2012, Konopacki et al., 1987, Konopacki et al., 2006, Konopacki, 1998, Kowalczyk et al., 2001) and GABAergic systems (Gołębiewski et al., 1996, Konopacki and Gołębiewski, 1993, Konopacki et al., 1997) in providing the adequate level of neuronal excitation necessary for theta to appear. Our findings are supported by a large body of data from other laboratories, in which carbachol-induced theta rhythm in hippocampal slices (Bland et al., 1988, Cappaert et al., 2009, Fellous and Sejnowski, 2000, McQuiston, 2010, Natsume and Kometani, 1999) and urethanized rats (Kinney et al., 1998, Leung and Péloquin, 2010, Monmaur et al., 1997, Yoder and Pang, 2005) were observed. Interestingly, Bland (2008) proposed that cholinergic projections provide a steady tonic excitatory afferent drive for HPC theta-related cells while GABAergic projections act to reduce the overall level of inhibition by inhibiting hippocampal GABAergic interneurons (Cappaert et al., 2009, Smythe et al., 1992).
Recent evidence indicates that beside the cholinergic and GABA-ergic transmission, hippocampal formation may also receive the glutamatergic input directly from the median raphe nuclei (MRn) (Crooks et al., 2012), or indirectly through the complex of the medial septum and diagonal band of Broca (MS/DBB) (Huh et al., 2010, Leung and Shen, 2004). The latter authors concluded that both the N-methyl-d-aspartic acid (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors in the HPC are involved in programming the amplitude of hippocampal theta, while on the level of the septum the amplitude of theta is probably controlled only by NMDA receptors. An NMDA receptor is a type of ionotropic glutamate receptor, named after the specific agonist – N-methyl-d-aspartate, and consists of NR1 subunits combined with one or more NR2 (A-D) subunits, forming channels permeable to sodium and calcium ions. At rest, the pore of this receptor is blocked by magnesium ions, which are removed after membrane depolarization (Lasoń et al., 2011). In addition to the recognized role of these receptors in controlling the mechanisms of neuroplasticity such as LTP (Davis et al., 1992, Harris et al., 1984, Jin and Feig, 2010), it is commonly believed that the activation of NMDA receptors plays a significant role in epileptogenesis (Bradford, 1995, Jones, 1988, Makarska-Białek et al., 2005, Moschovos et al., 2008, Wojtal et al., 2006), excitotoxicity (Cheng et al., 1999, Tian et al., 2012) and attention processing (Deco and Thiele, 2009). Recent studies have also reported the existence of NMDA-evoked membrane voltage oscillations in spinal locomotory neurons (Hochman et al., 1994, Schmidt et al., 1998), gamma oscillations (Carlén et al., 2012, Lazarewicz et al., 2010, Phillips et al., 2012), high frequency oscillations (Papatheodoropoulos, 2007) and sharp wave-ripples (Papatheodoropoulos, 2010) in hippocampal slices as well as frequency shifts in human EEG (Tsuda et al., 2007).
The research concerning the neurochemical substrates of hippocampal theta, has sparked an interest in the role of NMDA receptors in the development of this particular EEG pattern. First reports concerning the influence of NMDA receptors on hippocampal EEG come from the late 1980s. Those early studies demonstrated that intraventricular injections of NMDA receptors’ antagonist APV blocked the hippocampal theta in vivo (Leung and Desborough, 1988), while the synthetic aspartate analogue of NMDA triggered a rhythmic firing burst of CA1 pyramidal neurons in rat hippocampal slices (Peet et al., 1987). Interestingly, recent reports by Bland et al. (2007) have provided evidence of the generation of a new, pharmacologically distinct type of theta rhythm after intrahippocampal administration of N-methyl-d-aspartate in urethanized rats, suggesting the existence of a new independent pathway responsible for the synchronization of hippocampal EEG. These results are in agreement with other in vivo findings, which reveal that ablation of NMDA receptors on parvalbumin-positive hippocampal interneurons causes altered theta oscillations in freely behaving mice (Korotkova et al., 2010). Similarly, research by Pitkänen et al. (1995) has shown that a noncompetitive NMDA receptor antagonist MK-801 decreased both the power and the frequency of type 2 hippocampal theta in freely moving rats. In addition, microiontophoresis of NMDA to the region of CA1 pyramidal HPC cells induced rhythmic action potential (AP) bursts at a frequency of ≈6 Hz (Bonansco et al., 2002), an activity reminiscent of the “intracellular theta rhythm” (Nuñez et al., 1987, Nuñez et al., 1991, Ylinen et al., 1995).
In light of the above discussion, the question arises whether the HPC neuronal network is capable of generating theta oscillations in the presence of NMDA in a brain slice preparation. To address this issue, electrophysiological experiments were conducted on HPC slice preparations in the presence of different concentrations of NMDA. Portions of this research have been presented in an abstract form (Kazmierska et al., 2011).
Section snippets
Animals and HPC slice preparation procedure
The experiments were performed on 237 hippocampal formation (HPC) slices obtained from 38 male Wistar rats (100–150 g). All the experiments described below were monitored by a Local Ethical Commission (permission no. 24/ŁB 547/2011; in accordance with the European Communities Council Directive of 24 November 1986). Before the experimental procedure animals were housed in groups on a controlled light/dark cycle (the light on: 7:00–19:00) and had free access to standard food and tap water. Each
Experiment I: NMDA-induced field potentials in HPC slice preparations
In Experiment I the effect of different concentrations of NMDA on the HPC slice preparations’ field potentials was studied. The NMDA-induced field potentials were analyzed both qualitatively and quantitatively. When perfused with NMDA at a concentration of 1 μM, the hippocampal formation slice preparations (n = 23 slices) responded with EEG “silence” (i.e. the field activity did not differ from control recordings in ACSF) (Fig. 1, Fig. 2). After application of 3–80 μM of NMDA two different patterns
Discussion
The present study was aimed at investigating whether the hippocampal neuronal network, when isolated from ascending theta-synchronizing pathways, is capable of generating theta oscillations in the presence of NMDA. To answer this question the NMDA-induced field potentials (Experiment I) and the effect of interaction between NMDA and GABAA/B agonists and antagonists on field potentials recorded in the CA3c region of HPC slice preparations (Experiment II) were examined.
We demonstrated that apart
Conflict of interest
The authors declare that they have no competing financial interests.
Acknowledgments
The authors wish to thank Jacek Grebowski, MSc, for helpful comments and assistance in the data analysis. This study was financially supported by the National Science Centre Grant No. 2011/01/N/NZ4/01722.
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2021, Brain Research BulletinCitation Excerpt :It is commonly believed that glutamatergic and GABAergic neurons are involved in the generation and modulation of theta and gamma oscillations (Leung and Shen, 2010; White et al., 2000). The glutamatergic and GABAergic systems provide the adequate level of neural excitation necessary for theta oscillation to appear (Kazmierska and Konopacki, 2013; Konopacki et al., 1997). Steady excitation is driven by the activation of glutamatergic neurons while the GABAergic system reduces the overall level of inhibition by inhibiting hippocampal GABAergic interneurons (Hinman et al., 2012).
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2021, Brain Research BulletinCitation Excerpt :Accordingly, it is generally believed that both glutamatergic and GABAergic systems are involved in the generation and regulation of either theta oscillation or gamma oscillation. Moreover, they provide sufficient levels of excitability for theta oscillations to occur (Kazmierska and Konopacki, 2013). Stable excitation is driven by the activation of glutamatergic neurons, while GABAergic system reduces the overall inhibition level by inhibiting GABAergic interneurons in hippocampus (Hunt and Kasicki, 2013).
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2020, Experimental NeurologyPhase relations of theta oscillations in a computer model of the hippocampal CA1 field: Key role of Schaffer collaterals
2019, Neural NetworksCitation Excerpt :In contrast to other models, which explain phase locking of neural populations in the CA1 by lateral interactions (Bezaire, Raikov, Burk, Vyas, & Soltesz, 2016; Ferguson, Chatzikalymniou, & Skinner, 2017; Orbán, Kiss, & Erdi, 2006; Rotstein et al., 2005), we focus on external inputs to the CA1 assuming that these inputs play a major role in the formation of phase relations observed in experiments. We also prefer not to take into account the evidence obtained in experiments in vitro under strong excitatory agents such as carbacholine (Konopacki, Bland, MacIver, & Roth, 1987; Williams & Kauer, 1997) or agonists of glutamatergic receptors (Cobb, Larkman, Bulters, Oliver, Gill, & Davies, 2003; Figenschou, Hu, & Storm, 1996; Kazmierska & Konopacki, 2013) since, as we suppose, these results are due to non-physiological (epileptiform) synchronization (see more details in Section 4.4). The local field potential (LFP) in the hippocampus appears as a result of electric currents between the layers of basal and apical dendrites of pyramidal neurons (Einevoll, Kayser, Logothetis, & Panzeri, 2013).
Fullerenol C<inf>60</inf>(OH)<inf>36</inf> at relatively high concentrations impairs hippocampal theta oscillations (in vivo and in vitro) and triggers epilepsy (in vitro) – A dose response study
2018, Experimental and Molecular PathologyCitation Excerpt :Moreover, cholinergic functions are also known to be altered in epilepsy (Friedman et al. 2007). Additionally, we have previously shown that the development of theta synchrony demands a specific level of neuronal excitation and that episodes of well synchronized theta are usually preceded and ended with single epileptiform discharges (Kazmierska and Konopacki 2013, 2015). This is in agreement with the conceptual model of the basic mechanisms of rhythmicity developed by Lopes DaSilva (1976) showing a hysteresis of two oscillatory states: one that corresponds to theta, and which is regular and well synchronized, and another that corresponds to epileptiform seizure activity.
Development of theta rhythm in hippocampal formation slices perfused with 5-HT<inf>1A</inf> antagonist, (S)WAY 100135
2015, Brain ResearchCitation Excerpt :The model shows a hysteresis of two oscillatory states: one that corresponds to theta, and which is regular and well synchronized; and another one that corresponds to epileptiform seizure activity. Our data, both that obtained previously (Kazmierska and Konopacki, 2013) and herein, confirms that model, suggesting that there is in fact a bifurcation point at which the hippocampal neuronal network can switch from epilepsy mode to theta mode. This transition from epilepsy state to theta state depends on the balance between the excitatory and inhibitory inputs (Lopes da Silva, 1992).