Ionotropic Receptor Antagonist

In the presence of ionotropic glutamate receptor antagonists, ON-evoked, mGluR1-mediated synaptic responses were markedly enhanced by inhibition of glutamate transporters (e.g., TBOA) (Figure 5).

From: The Senses: A Comprehensive Reference , 2008

PLASTICITY | Inositol Lipid Signaling in Synaptic Activity, Neuronal Plasticity and Epileptogenesis

N.G. Bazan , A.E. Musto , in Encyclopedia of Basic Epilepsy Research, 2009

Introduction

Excessive glutamatergic neurotransmission is a major factor underlying the pathophysiology of seizures and of epilepsy. The use of ionotropic glutamate receptor antagonists as potential antiepileptic drugs has shown therapeutic potential in animal models of epilepsy, but this strategy has failed in early clinical trials. Recent studies have suggested that the modulation of metabotropic glutamate receptors (in addition to drug effects at glutamatergic ionotropic receptors) could ameliorate seizures. Specifically, metabotropic glutamate (mGlu) receptor (possibly mGlu5) agonists (as accessed in basolateral amygdala neurons from brain slices of kindled rats) activate the Na+–Ca2+ exchanger, suggesting that the mechanism for removal of the excess intracellular Ca2+ occurs during periods of high glutamate release such as seizures. mGluR1 and mGluR5, both linked to phosphoinositide hydrolysis, show perturbations in mRNA expression in hippocampus of amygdala-kindled animals, studied at different time points after the last generalized seizure (stage 5 from Racine's score). Inositol hydrolysis leads to sustained increase in protein kinase C activity following amygdala kindling, suggesting that these agonists trigger inositol lipid hydrolysis, and enhance protein kinase C activity during early stage of epileptogenesis. Given these results, there is an interesting potential for ameliorating seizures with the combination of mGlu receptor ligands with other glutamatergic (and non-glutamatergic) agents.

The exploration of second-messenger signaling, mediated through activation of mGlu receptors, will expand our understanding of the modulation of seizures and epileptogenesis. mGlu receptor activation is correlated with an increase of intracellular diacylglycerol (DAG) because of hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) ( Figure 1 , wild type). The molecular species 1-stearoyl-2-arachidonoyl-sn-glycerol comprises 80% of brain PIP2. Arachidonoyldiacylglycerol (AA-DAG) is a second messenger derived from phosphatidylinositol 4,5-bisphosphate and generated by stimulation of glutamate metabotropic receptors linked to G protein and activation of phospholipase C. AA-DAG signaling is terminated by its phosphorylation to phosphatidic acid, catalyzed by diacylglycerol kinase (DGK). The significance of DGK family in synaptic function has been investigated in mice with targeted disruption of the DGKϵ gene. DGKϵ−/− mice showed a higher resistance to electroconvulsive shock, with shorter tonic seizures and faster recovery than do DGKϵ+/+ mice. The phosphatidylinositol 4,5-bisphosphate-signaling pathway in cerebral cortex was greatly affected by the DGKϵ gene deletion, leading to lower accumulation of AA-DAG and free AA. Also, long-term potentiation (LTP) and kindling epileptogenesis were attenuated in these DGKϵ−/− mice. On the basis of these studies, we propose that DGKϵ contributes to modulate neuronal signaling pathways linked to synaptic activity, neuronal plasticity, and epileptogenesis.

Figure 1. Diagram depicting seizure-induced inositol lipid signaling in wild-type and DGKϵ deficient mice (DGKϵ KO). In wild-type mice, metabotropic glutamate receptor interacts with G proteins, which in turn activate PLC, resulting in the hydrolysis of PIP2 that generates DAG and IP3. DGKϵ is a lipid kinase that modulates multiple signaling functions related to epileptogenesis, such as synaptic plasticity and excitability. DGKϵ catalyze the phosphorylation of DAG to PA. Inositol cycle is interrupted leading to decreased availability of bioactive molecules: DAG, PKC, IP3, CA2, PA and lyso-PA. PI phosphatidylinositol; PIP, phosphatidylinositol 4-phosphate; PIP2, phosphatidylinositol 4,5 phosphate; PLC, phospholipase C; G, G protein; IP3, inositol 1,4,5 phosphate; CDP-DG, cytidine diphosphate-diacylglycerol; PA, phosphatidic acid; lyso-PA, lyso-phosphatidic acid.

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Progress in the Medicinal Chemistry of Group III Metabotropic Glutamate Receptors

Kevin G. Liu , Darío Doller , in Annual Reports in Medicinal Chemistry, 2011

6 mGlu8 Receptor Ligands

(S)-3,4-DCPG (40), originally synthesized to search for potential selective ionotropic glutamate receptor (iGlu) antagonists [65], was found to be a subtype-selective mGlu8 agonist (EC50  =   31   nM, >   100-fold selectivity over other mGlu receptors) [66] and has been widely used as a tool compound to selectively activate this receptor. Though effects on several regions of the brain were observed through systemic administrations (e.g., ip dosing) [67], the majority of the in vivo studies with 40 were carried out via central administration due to the poor brain penetration of this polar amino acid with additional hydrophilic carboxylic acid groups [68–72]. To date there are no additional reports of mGlu8 ligands.

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TRANSPORTERS | Function of Cell-Surface Glutamate Transporters in the Brain: An Important Role for Development and Preventing Seizures

L. Aniksztejn , ... N. Villeneuve , in Encyclopedia of Basic Epilepsy Research, 2009

GluTs Function is Essential for Normal Brain Development

A recent study has provided convincing evidence that glial glutamate transporter function is essential for normal brain development. In that study, deletion of both GLAST and GLT-1 genes in mice reduced cell proliferation and radial neuronal migration (leading to a disturbed laminar organization of the cortex). In addition, neuronal differentiation appears to be strongly affected in these mice. This cortical malformation seen in these animals involved, in part, the activation of both AMPA and NMDA receptors, since the GLAST−/−/GLT1−/− phenotype was partially rescued by injection of ionotropic glutamate receptor antagonists. These results indicate that glutamate may act as a neurotransmitter at a very early stage of development, even before synapse formation; these actions of glutamate must be tightly controlled – by GLAST and GLT1 – for normal brain development. In keeping with this view are the following observations: (1) Immunoreactivity for glutamate in the maturing cortex is found in the neuroepithelium during neurogenesis, and later on is present in the intermediate zone (zone of migration), subplate, the cortical plate, and the marginal zone; (2) Functional glutamate receptors are expressed by neuronal precursor cells and neurons, in several structures, at a very early stage of development; (3) Glutamate is released before synapse formation by growing axons and growth cones; (4) GluTs are functional during the perinatal period and contribute to the clearance of glutamate; and (5) In the absence of efficient transport, glutamate diffuses through the extracellular space and activates distant cells in paracrine manner. All these factors suggested that GluTs play an important role in normal brain development, controlling the maturing cortical network activity when synaptogenesis is just getting started. Recent studies support this hypothesis and show that this control is fundamental, as it prevents the generation of seizures.

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Maturation of the hippocampal network

Yehezkel Ben Ari , in Cellular and Molecular Neurophysiology (Fourth Edition), 2015

20.3.2 Giant depolarizing potentials result from GABAergic and glutamatergic synaptic activity

GDPs are network-driven (in contrast to pacemaker patterns that are generated by the recorded neuron independently of its synaptic inputs), since (i) they are blocked by tetrodotoxin (TTX) ( Figure 20.10 b); (ii) their amplitude but not their frequency is modified by alterations of the resting membrane potential as expected from a synaptic current in contrast to an endogenous pacemaker oscillation; (iii) they are often blocked by the GABAA-receptor antagonist bicuculline (see Figure 20.6 a) but also by ionotropic glutamate receptor antagonists (CNQX and APV), suggesting that both GABA and glutamate participate in their generation; (iv) they are blocked by an antagonist of the chloride importer NKCC1 that reduces [Cl−]i levels indicating that the depolarizing actions of GABA are instrumental in the generation of GDPs; and (v) they disappear roughly around the end of the first postnatal week when the depolarizing/hyperpolarizing shift has taken place (Figure 20.10 c).

Figure 20.10. Spontaneous giant depolarizing potentials (GDPs) are generated in a polysynaptic circuit in neonatal hippocampus.

(a) Spontaneous GDPs are recorded from a CA3 pyramidal neuron with an intracellular electrode filled with K methyl sulfate. The inset shows a GDP on an extended timescale. (b) Spontaneous GDPs are blocked by TTX. (c) Histogram of the number of pyramidal cells with GDPs as a function of the age of the rat. The number of recorded cells is in parentheses.

 Part (a) JL Gaiarsa, personal communication. Parts (b) and (c) adapted from Ben-Ari Y, Cherubini E, Corradetti, Gaiarsa JL (1989) Giant synaptic potentials in immature rat CA3 hippocampal neurones. J. Physiol. (Lond.) 416, 303–325, with permission.

Determination of the currents underlying GDPs with patch clamp recordings (voltage-clamp mode) reveals that GABAA currents are present either alone or in conjunction with AMPA- and NMDA-receptor-mediated currents. The relative participation of GABA and glutamate most likely depends on the maturational stage of the recorded neuron, reflecting the heterogeneity of the neuronal population.

The mechanism underlying the generation of GDPs therefore includes a network-driven barrage of depolarizing GABA and glutamate postsynaptic currents impinging on to pyramidal neurons and in turn leading to a recurrent GABAergic excitation from the GABAergic interneurons. This is also suggested by paired recordings from a pyramidal neuron and an interneuron that show synchronous GDPs in connected neurons and very few action potentials generated outside the GDPs ( Figure 20.11 a). Therefore, GDPs are triggered by the combined depolarizing effects of GABA- and glutamate-mediated currents and by a basic circuit that includes feedforward excitation of pyramidal neurons and interneurons followed by the recurrent depolarization produced by the recurrent collaterals of GABAergic interneurons ( Figure 20.11 b).

Figure 20.11. GDPs are synchronous in pyramidal cells and interneurons.

(a) Dual recordings of spontaneous currents (voltage clamp mode) in a CA3 pyramidal neuron (whole-cell configuration, upper trace) and a neighboring interneuron (cell-attached configuration, lower trace). Note that bursts of currents of action potentials in the interneuron are synchronous with currents of GDPs in the pyramidal cell. (b) Schematic explaining the generation of GDPs.

 Part (a) adapted from Khazipov R, Leinekugel X, Khalilov I et al. (1997) Synchronization of GABAergic interneuronal network in CA3 subfield of neonatal rat hippocampal slices. J. Physiol. (Lond.) 498, 763–772, with permission.

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Biomarkers of Alzheimer's disease

Jason Pitt , in Biomarkers in Toxicology, 2014

Long-term potentiation impairments and excitotoxicity through glutamatergic dysfunction

Aβ oligomers (AβOs) bind at or near synapses and induce a biphasic alteration in glutamatergic signaling. Initially, AβOs potentiate glutamatergic signaling, through activation of both ionotropic (Alberdi et al., 2010) and metabotropic (Renner et al., 2010) glutamate receptors. This leads to calcium dysregulation and inevitably loss of synapses. This is evidenced by experiments in transgenic AD mice which showed impaired synaptic transmission in the Schaffer collateral that coincides with a decreased AMPA:NMDA ratio (Hsia et al., 1999). This early synaptic impairment can be relieved by the ionotropic glutamate receptor antagonist kynurenate (Fitzjohn et al., 2001), demonstrating that, early on, AβOs activate glutamatergic signaling.

After initiating synaptic loss through potentiated glutamatergic signaling, AβOs alter synaptic plasticity and decrease glutamatergic transmission. In a mouse model of AD, synaptic loss precedes impairments in long-term potentiation (LTP) by roughly one month (Jacobsen et al., 2006). Interestingly, while LTP is inhibited, mechanisms of long-term depression remain intact (Wang et al., 2002). Although a vast oversimplification, this suggests that AβOs make synapses unable to store memory (i.e. disrupt LTP formation) while leaving them fully capable of losing memories (i.e. LTP is unaffected). In addition to inhibiting LTP, AβOs also impair baseline transmission by reducing CaMKII-dependent AMPA receptor phosphorylation at a site that increases its single-channel conductance (Benke et al., 1998; Derkach et al., 1999; Zhao et al., 2004).

While it is possible that AβOs potentiate ionotrophic glutamate receptor activity directly, it may also be the case that AβOs increase glutamate receptor activation by inhibiting glutamate uptake. Indeed, there is evidence that AβOs impair glutamate uptake at hippocampal synapses. One study reported a 30% reduction of glutamate uptake in hippocampal synaptosomes in the presence of AβOs (Li et al., 2009). It should be noted that synaptosomes contain pre- and post-synaptic components, as well as associated astrocytic processes, so it is unclear whether AβOs are targeting neurons, astrocytes, or both. Based on work from isolated cell cultures, it seems that AβOs are capable of reducing glutamate uptake in both cell types (Harris et al., 1996; Harkany et al., 2000; Fernández-Tomé et al., 2004; Matos et al., 2008). These data demonstrate multiple ways in which AβOs alter synaptic transmission: (1) potentiating glutamatergic signaling, (2) inducing synapse loss, (3) reducing glutamatergic signaling and impairing synaptic potentiation, and (4) preventing glutamate uptake in neurons and astrocytes.

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Classical Conditioning of Timed Motor Responses

H.J. Boele , ... C.I. De Zeeuw , in The Neuronal Codes of the Cerebellum, 2016

Lesions of the Cerebellar Cortex

Yeo et al. (1985b) demonstrated that unilateral electrolytic lesions of the cerebellar cortical lobule HVI, sparing the cerebellar nuclei, completely abolished CRs. Lesions of other parts of the cerebellar cortex did not affect CRs (Yeo et al., 1985b). Attwell, Rahman, and Yeo (2001) and Attwell, Ivarsson, Millar, and Yeo (2002) replicated these findings, showing that blocking Purkinje cell input to the AIN by infusions with PTX (picrotoxin; a GABAA chloride channel blocker) or gabazine (a GABAA receptor antagonist) completely abolished CRs; no remnant CRs with short latency to onset and peak were observed, neither in the nictitating membrane response nor in the eyelid response (Attwell et al., 2001, 2002). Mostofi et al. showed in rabbits that extremely small infusions of CNQX (6-cyano-7-nitroquinoxaline-2,3-dione; a non-NMDA ionotropic glutamate receptor antagonist) in the D0 zone of lobule HVI, the eyeblink-controlling microzone, were sufficient to completely abolish eyeblink CRs (Mostofi, Holtzman, Grout, Yeo, & Edgley, 2010). Other groups, however, initially reported that lesions of the cerebellar cortex would have no effect on eyeblink CRs (Clark, McCormick, Lavond, & Thompson, 1984; McCormick, Clark, Lavond, & Thompson, 1982; McCormick et al., 1981; McCormick & Thompson, 1984), which might be explained by the fact that the lesioned areas in these studies spared the eyeblink-controlling microzone. Instead, Lavond and colleagues found that both the amplitude and timing of eyeblink CRs would be affected following lesions of the eyeblink-controlling microzone, albeit in an incomplete fashion (Lavond & Steinmetz, 1989; Lavond, Steinmetz, Yokaitis, & Thompson, 1987). In line with this finding, Mauk and co-workers reported that both permanent lesions of the cerebellar cortex and reversible disconnections of the AIN from the cerebellar cortex by PTX infusions in the AIN or muscimol infusions in the cerebellar cortex mainly disrupted the learning-dependent timing of eyeblink CRs: after cortical inputs were removed from the AIN, rabbits still showed CRs, but these residual CRs had an extremely short latency to onset and latency to peak and therefore are called short-latency responses (SLRs) (Bao, Chen, Kim, & Thompson, 2002; Garcia & Mauk, 1998; Medina, Garcia, & Mauk, 2001; Ohyama, Nores, & Mauk, 2003; Ohyama, Nores, Medina, Riusech, Mauk, 2006; Perrett, Ruiz, & Mauk, 1993). In short, inactivation of the interposed nucleus generally severely affects eyeblink CRs, whereas inactivation of the cerebellar cortex leads to more conflicting results, with some groups reporting a full abolishment of eyeblink CRs and others reporting residual SLRs.

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Molecular and Cellular Mechanisms

Jeffrey G. Tasker , ... William E. Armstrong , in Hormones, Brain and Behavior (Third Edition), 2017

3.15.6.1 Glutamatergic Afferents

Immunocytochemical studies at the light and electron microscopic levels, coupled to morphometric analysis, established that under basal conditions of neurosecretion, about 20% of all synapses on both OT and VP magnocellular neurons in the SON are glutamatergic, and that there are twice as many glutamatergic synapses on the dendrites as on the somata (Meeker et al., 1993; El Majdoubi et al., 1996, 1997; Jourdain et al., 1999). A major source of these afferents is a local pool of intrahypothalamic glutamate neurons located in the perinuclear zones of the SON and PVN (Boudaba et al., 1997; Jourdain et al., 1999; Csaki et al., 2000, 2002; Boudaba and Tasker, 2006). Activation of noradrenergic receptors stimulates a subset of glutamatergic inputs to PVN magnocellular neurons that derive from local glutamate neurons located within the PVN (Daftary et al., 1998). Glutamate levels in the SON positively correlate with the activation of OT neurons during parturition, rising abruptly just prior to parturition and declining before delivery is terminated (Herbison et al., 1997). Similarly, blocking glutamate receptors in the brain via intracerebroventricular injection of a glutamate receptor antagonist inhibits the suckling-induced release of OT into the circulation (Parker and Crowley, 1993a). Spontaneous and evoked excitatory postsynaptic currents (EPSCs) in magnocellular neurons are blocked completely by ionotropic glutamate receptor antagonists (van Den Pol et al., 1990; Wuarin and Dudek, 1993), while direct application of receptor agonists excites the neurons, enhancing their firing rate and increasing hormone release from their terminals (reviewed in Shibuya et al., 2000; and Yamashita, this volume). Evoked EPSCs are generated by the activation of glutamate AMPA and NMDA receptors on magnocellular somata and dendrites (for review, see Pak and Curras-Collazo, 2002). Currents mediated by AMPA receptor activation tend to be larger and show faster decay kinetics in OT than in VP neurons (Stern et al., 1999). They are modulated by OT and VP themselves in a cell-specific manner, VP inhibiting EPSCs in VP neurons via postsynaptic V1a receptor activation, and OT facilitating EPSCs in OT neurons via activation of OT receptors (Hirasawa et al., 2003). It is noteworthy that spontaneous glutamate-mediated EPSCs increase in incidence in the SON during lactation (Stern et al., 2000), which may be a result of the increased number of glutamatergic synapses on OT neurons at this time (El Majdoubi et al., 1996, 1997) (see also Section 3.15.9.2) as well as a possible increase in the probability of synaptic glutamate release (Stern et al., 2000). The glutamate sensitivity of OT neurons diminishes during late lactation and is restored to its normal level by estrogens acting presumably via a rapid, nontranscriptional effect (Israel and Poulain, 2000). Glutamatergic synapses on magnocellular neurons exhibit activity-dependent long-term synaptic changes, such as long-term potentiation and long-term depression (Kombian et al., 2000; Panatier et al., 2006), which are NMDA receptor dependent and require the NMDA receptor coagonist d-serine released by neighboring SON astrocytes (Panatier et al., 2006) (see Section 3.15.10). Synaptically released glutamate is cleared from synapses in the magnocellular nuclei and prevented from spilling over onto adjacent synapses under normal conditions by astrocytic uptake mechanisms mediated by the glutamate transporters GLAST and GLT-1 (Reye et al., 2002; Piet et al., 2003; Boudaba et al., 2003b).

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Ketamine Mediates Psychosis through the Medial Septum, Hippocampus, and Nucleus Accumbens

L. Stan Leung , Jingyi Ma , in Neuropathology of Drug Addictions and Substance Misuse, 2016

Medial Septal Lesion or Inactivation Attenuates Psychosis-Related Effects of an NMDA Receptor Antagonist

The behavioral disruptions and hippocampal gamma power enhancement induced by a systemic NMDA receptor antagonist were attenuated by activation of GABAA receptors in the medial septum. Ma et al. (2004) showed that the PPI impairment and hyperlocomotion induced by PCP were normalized by microinfusion of 0.25   μg (in 0.5   μl) of GABAA receptor agonist, muscimol, into the medial septum. The latter dose of muscimol in the medial septum significantly attenuated the walking hippocampal theta and gamma rhythms at 30–90   min after infusion (Figure 4(B); Ma & Leung, 2007). Similarly, the changes in locomotion, PPI and gamma waves induced by ketamine (6   mg/kg s.c.) were antagonized by preinfusion of 0.25   μg muscimol, but not saline, into the medial septum (Ma & Leung, 2007; Figures 2, 4 and 5). Muscimol infusion into the supramammillary area, part of the hypothalamus that projects to the medial septum, also attenuated the effect of ketamine or MK-801 on hyperlocomotion, PPI decrease, and hippocampal gamma power increase. Infusion of ionotropic glutamate receptor antagonists into the medial septum, blocking both nonNMDA and NMDA receptors, did not affect the PPI deficit or the gamma wave increase after MK-801 (Ma & Leung, 2007). Rats with selective lesion of the cholinergic septohippocampal neurons by 192 immunoglobulin G (IgG)–saporin were not different from sham lesion rats in their PPI during baseline condition or after PCP (Ma et al., 2004).

Figure 5. Ketamine-induced prepulse inhibition (PPI) decrease was accompanied by hippocampal gamma power increase.

(A) PPI, in percent (%) of startle response, was decreased by ketamine (6   mg/kg s.c.) with medial septal saline infusion ("Sal   +   Ket"), compared with "Sal   +   sc-Sal" (septal saline   +   saline s.c.). Ketamine induced PPI decrease was attenuated by septal muscimol infusion ("Mus   +   Ket"). (B) Gamma power in logarithmic units shows a large increase (compared to predrug baseline) after "Sal   +   Ket," a decrease after "Mus   +   Ket," and no change after "Sal   +   sc-Sal." ∗∗P   <   0.01, ∗P   <   0.05; NS, not significant.

 Adapted from Ma and Leung (2007), with permission.

Ketamine's effect in decreasing auditory gating (increasing T/C ratio) in the hippocampus was blocked by prior infusion of muscimol (0.25   μg/0.6   μl) into the medial septum (Figure 3; Ma et al., 2009). Infusion of muscimol into the medial septum alone did not affect the T/C ratio. However, rats with selective lesion of the cholinergic septohippocampal neurons by 192 IgG–saporin showed significantly higher T/C ratio that did not change significantly after ketamine (Table 1).

Rats with selective lesion of GABAergic septohippocampal neurons by septal orexin–saporin infusion were muted in their behavioral and electrophysiological response to systemic NMDA receptor antagonists (Ma, Tai, & Leung, 2012). Rats with lesion of GABAergic septohippocampal neurons, compared with sham lesion rats, showed little change in locomotion and PPI after MK-801, no loss of hippocampal auditory gating, and no increase in hippocampal gamma activity induced by ketamine (Ma et al., 2012; Table 1). Baseline PPI, auditory gating and hippocampal gamma activity in the septal orexin–saporin lesioned rats were not significantly different from sham-lesion or intact rats.

Deep brain stimulation (DBS) of the medial septum attenuated the PPI deficit and hyperlocomotion induced by 3   mg/kg s.c. ketamine (Ma & Leung, 2014). Bursts of 100-Hz pulses (1   s on and 5   s off) were used for DBS of the medial septum. Medial septal DBS also prevented the loss of hippocampal auditory gating and the increase in hippocampal gamma waves induced by ketamine, which can be interpreted as preserving the baseline state of the hippocampal neural circuit. Continuous 130-Hz stimulation of the NAc also attenuated the PPI deficit and hyperlocomotion induced by ketamine (Ma & Leung, 2014). Neither septal nor accumbens DBS alone, without ketamine injection, affected spontaneous locomotion or PPI.

The above results show that medial septal inactivation or DBS normalized the behavioral and hippocampal electrophysiological changes induced by a systemic NMDA receptor antagonist. Combined with the literature that septohippocampal system is involved in the different psychosis-related symptoms (behavioral hyperactivity, decrease in PPI, and hippocampal auditory gating), these results suggest that the septohippocampal system is a critical participant in generating these psychosis-related behaviors.

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Epilepsy

Roger J. Porter , ... Michael A. Rogawski , in Handbook of Clinical Neurology, 2012

Topiramate

Topiramate is a structurally novel antiseizure agent; it is a sulfamate-substituted fructose-related monosaccharide. Topiramate has a broad spectrum of activity, with efficacy in partial and generalized tonic–clonic seizures as well as in various specific epilepsy syndromes including the Lennox–Gastaut syndrome. The drug exhibits protective activity in the maximal electroshock test, in amygdala-kindled seizures, and in sound-induced seizures. It is ineffective against clonic seizures induced by pentylenetetrazol, bicuculline, or picrotoxin. Therefore, its spectrum of activity in animal models is similar to sodium channel-blocking antiseizure agents and also ionotropic glutamate receptor antagonists. However, topiramate has several properties that are atypical for sodium channel-blocking drugs: it is effective in a rat genetic model of absence epilepsy and can also raise the threshold for clonic seizures induced by intravenous pentylenetetrazol in mice (White et al., 1997). Nevertheless, the relatively restricted profile in animal models is surprising given topiramate's broad clinical antiseizure activity.

Several cellular targets have been proposed to be relevant to the therapeutic activity of topiramate: (1) voltage-gated sodium channels; (2) high-voltage-activated calcium channels; (3) GABAA receptors; (4) AMPA/kainate receptors; and (5) carbonic anhydrase isoenzymes (Macdonald and Rogawski, 2008). Effects of topiramate on sodium channels occur at relatively low, therapeutically relevant concentrations (Zona et al., 1997; McLean et al., 2007). There is evidence that topiramate may alter the activity of the various receptors and ion channels with which it interacts by affecting their phosphorylation state rather than through direct binding, as is typically the case for antiseizure drugs (Mikael et al., 2005). Given its profile in animal models, an action on sodium channels could contribute to the clinical efficacy of topiramate. Indeed, the effect of topiramate on sodium channels is comparable to that of other sodium channel-blocking antiseizure agents except that recovery from the block of fast transient sodium currents may be more rapid. In addition to its action on fast inactivating sodium currents, topiramate, like phenytoin, blocks persistent sodium currents at low concentrations which, as noted previously, is a potentially important action for seizure protection. Although topiramate may block high-voltage-activated calcium channels (Zhang et al., 2005), the relevance of this action to the clinical activity of the drug is uncertain (White, 2005; Macdonald and Rogawski, 2008).

Although the profile of topiramate in animal models is not characteristic of antiseizure agents that act on the GABA system, the effect of the drug in an absence model and on pentylenetetrazol seizure threshold is compatible with an action on GABAA receptors. Indeed, topiramate has been found to produce variable effects on GABA receptor currents. A recent study has suggested that the variability relates to the drug's specific actions on different heteromeric GABAA receptor isoforms (Simeone et al., 2006b). In particular, topiramate potentiated GABAA receptors containing β2 or β3 subunits whereas receptors containing the β1 subunit could be enhanced or inhibited. Recently, topiramate was found to enhance muscimol and synaptically-evoked GABAA receptor currents in basolateral amygdala principal (pyramidal) neurons (Braga et al., 2009). The timecourse of the effect was compatible with the possibility that topiramate acts through a direct action on GABAA receptors. Overall, the clinical activity of topiramate appears to reside, at least in part, in an action on GABAA receptors. Interestingly, topiramate therapy has been found to be associated with elevations in GABA concentrations in diverse brain regions (Petroff et al., 1999, 2001; Kuzniecky et al., 2002), but the clinical significance of these changes is unclear.

In addition to its actions on GABAA receptors, topiramate influences glutamate-mediated excitatory neurotransmission. Therefore, like felbamate, topiramate seems to have dual actions on inhibitory and excitatory neurotransmission. There is no evidence that topiramate affects NMDA receptors. However, topiramate was reported to inhibit responses to kainate (an agonist of AMPA and kainate receptors) and AMPA in cultured neurons (Gibbs et al., 2000; Poulsen et al., 2004). More recently, the drug was found to selectively inhibit pharmacologically isolated GluK1 (GluR5) kainate receptor-mediated postsynaptic currents, whereas AMPA receptor-mediated currents were only modestly reduced (Gryder and Rogawski, 2003). GluK1 kainate receptors are a type of ionotropic glutamate receptor within the class of kainate non-NMDA receptors. The drug's effect on GluK1 kainate receptors has also been demonstrated in recordings from basolateral amygdala interneurons, which, like principal neurons, express GluK1 kainate receptors (Braga et al., 2009). Topiramate provided protection against seizures induced by intravenous infusion of the selective GluK1 kainate receptor agonist ATPA, but was less effective against seizures induced by AMPA or NMDA, indicating that the selective interaction of topiramate with GluK1 kainate receptors is relevant to its anticonvulsant properties (Kaminski et al., 2004b). Therefore, topiramate is the first antiseizure agent with a relatively specific action on ionotropic glutamate receptors of the kainate type. The action of topiramate on interneuron GluK1 kainate receptors appears to be relevant also to the ability of the drug to modulate inhibitory function. Thus, the action of topiramate on GluK1 kainate receptors evoked GABA release from interneurons through an action on presynaptic GluK1 receptors (Braga et al., 2009).

The action of topiramate on carbonic anhydrase isoenzymes may contribute to the drug's side-effects, including its propensity to cause metabolic acidosis and calcium phosphate kidney stones (Vega et al., 2007). Carbonic anhydrase inhibition is presumably related to the sulfamate structure, which includes a sulfonamide group common to acetazolamide and zonisamide (see below). Topiramate selectively inhibits cytosolic (type II) and membrane associated (type IV) forms of carbonic anhydrase (Dodgson et al., 2000). Carbonic anhydrase inhibition is expected to reduce bicarbonate. GABAA receptors are permeable to bicarbonate, and activation of GABAA receptors ordinarily causes an inward (depolarizing) bicarbonate current owing to efflux of bicarbonate. Therefore, inhibition of carbonic anhydrase would reduce the tendency of GABAA receptors to produce excitation and allow for a greater net outward (inhibitory) current. This inhibition could be one of the mechanisms underlying the topiramate-induced enhancement of the amplitude of GABAA receptor-mediated inhibitory synaptic responses. However, a recent study failed to provide support for this hypothesis (Braga et al., 2009). Tolerance develops to the anticonvulsant action of carbonic anhydrase inhibitors such as acetazolamide; these drugs, therefore, have limited utility in chronic epilepsy therapy. In contrast, topiramate exhibits continuing effectiveness. Thus, carbonic anhydrase inhibition is unlikely to be a major factor in its clinical activity.

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Olfaction & Taste

M. Ennis , A. Hayar , in The Senses: A Comprehensive Reference, 2008

4.37.2.2.1.(i) ON glutamatergic synaptic input to JG and mitral/tufted cells

All studies to date have identified glutamate as the major transmitter at ON synapses onto the dendrites of JG neurons, as well as those of mitral/tufted cells in the GL. Release of glutamate from ON terminals is controlled by N- and P/Q-type Ca2+ channels (Isaacson, J. S. and Strowbridge, B. W., 1998; Murphy, G. J. et al., 2004). Each glomerulus contains the apical dendritic tufts of about 20 mitral cells, 200 tufted cells, and 1500–2000 JG cells (reviewed in Ennis, M. et al., 2007). A variety of studies demonstrated that sensory transmission from ON axon terminals to these dendrites is mediated by glutamate acting primarily at alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and N-methyl d-aspartate (NMDA) ionotropic glutamate receptor subtypes (Bardoni, R. et al., 1996; Ennis, M. et al., 1996; Aroniadou-Anderjaska, V. et al., 1997; Chen, W. R. and Shepherd, G. M., 1997; Keller, A. et al., 1998; Aroniadou-Anderjaska, V. et al., 1999a; Ennis, M. et al., 2001). Thus, JG and mitral/tufted cell responses to ON input are excitatory (Figures 4 and 5). In addition, metabotropic glutamate receptors (mGluRs) are expressed by nearly all MOB neurons (see Ennis, M. et al., 2007 for review). Comparatively less is known about the role of mGluRs at ON synapses. Electrophysiological and Ca2+-imaging studies have reported that ON stimulation evokes an mGluR1-sensitive synaptic component in ∼40% of mitral cells in normal physiological conditions in the slice (De Saint Jan, D. and Westbrook, G. L., 2005; Ennis, M. et al., 2006; Yuan, Q. and Knopfel, T., 2006). In the presence of ionotropic glutamate receptor antagonists, ON-evoked, mGluR1-mediated synaptic responses were markedly enhanced by inhibition of glutamate transporters (e.g., TBOA) (Figure 5). Thus, activation of mGluR1 is tightly regulated by glutamate uptake mechanisms. mGluR1-mediated responses were maximal with bursts of 50–100   Hz ON spikes, similar to frequencies of odor-induced spikes in ORNs in vivo (Duchamp-Viret, P. et al. 1999). Activation of mGluRs has also been suggested to produce long-term depression at ON to mitral cell synapses (Mutoh, H. et al., 2005).

Figure 4. Olfactory nerve (ON)-evoked synaptic responses in juxtaglomerular (JG) cell subtypes. Panels a–c show six superimposed voltage-clamp traces (holding potential   =   −60   mV in this and subsequent panels) of ON-evoked EPSCs in external tufted (ET), short axon (SA), and periglomerular (PG) cells, respectively. Arrows indicate time of stimulation. Cell morphology is shown at right. Scale bars, 100   μm. ON stimulation produced short, constant latency EPSCs in the ET cell (a, left panel), indicative of monosynaptic input. In current clamp, ON stimulation evoked a constant, short latency EPSPs of variable amplitude (a, middle panel). The largest EPSPs triggered the generation of a burst of action potentials (truncated for clarity). Panels b and c show that ON stimulation evoked longer, variable latency EPSCs bursts in SA (b) and PG (c) cells, indicative of di- or polysynaptic responses. Adapted from Hayar, A. et al., 2004, J. Neurosci. 24, 6676–6685., with permission from The Society for Neuroscience.

Figure 5. Olfactory nerve (ON)-evoked EPSCs elicited in the presence of glutamate uptake inhibitors (TBOA and THA) are dependent on stimulation intensity and frequency. The four panels show plots of the peak amplitude of ON-evoked EPSCs as a function of ON stimulation intensity (10–1000   μA); each panel shows data for a different ON stimulation frequency. Insets in each graph show traces of ON-evoked EPSCs in different pharmacological conditions; traces are averages of five ON-evoked EPSCs. Colored lines correspond to the pharmacological conditions indicated at the top; note that control data are not plotted on the line graphs. TBOA–THA significantly increases the ON-evoked EPSCs at a threshold intensity of 60–100   μA for all frequencies. Residual responses remaining in the presence of LY341495 and CNQX, APV, and gabazine were abolished by low Ca2+-ACSF, as shown for the single-pulse and 200   Hz stimulation frequencies. *P  <   0.05, #P  <   0.001 vs. CNQX, APV, and gabazine. Adapted from Ennis, M., Zhu, M., Heinbockel, T., and Hayar, A. 2006. Olfactory nerve-evoked metabotropic glutamate receptormediated responses in olfactory bulb mitral cells. J. Neurophysiol. 95, 2233–2241, with permission from The American Physiological Society.

All ET cells receive monosynaptic ON input, which appears to be primarily mediated by AMPA and NMDA receptors in normal physiological conditions in vitro (Figure 4) (Hayar, A. et al., 2004a; 2004b; 2005). If the amplitude of an ON-evoked EPSP reaches threshold for spike generation, a spike burst is always triggered in ET cells (Hayar, A. et al, 2004a). Further increases in ON stimulation strength produce the same all-or-none burst. Thus, ET cells receive monosynaptic ON input that is converted into an all-or-none spike burst. Accordingly, ET cells amplify suprathreshold sensory input at the first stage of synaptic transfer in the olfactory system. ET cells also readily entrain to rhythmic ON input delivered at theta frequencies (5–10   Hz) characteristic of investigative sniffing in rodents. As noted above, the intrinsic spontaneous bursting rate of ET cells ranges from 1 to 8 bursts/s. This might suggest that ET cells with different spontaneous bursting rates may be preferentially entrained by repetitive sensory input at or near their intrinsic bursting frequency. This turns out not to be the case as ET cells, irrespective of their intrinsic spontaneous bursting frequencies, can be entrained by repetitive, 5–10   Hz ON input (Hayar, A. et al., 2004a).

The majority of PG cells exhibit longer latency, prolonged bursts of EPSP/Cs in response to ON stimulation than ET cells (Figure 4). The long, variable latency of these responses is indicative of di- or polysynaptic ON input. Thus, most SA and PG cells do not appear to receive direct ON input, perhaps because their dendrites ramify in glomerular compartments devoid of ON terminals. Only 20% of PG cells had short, relatively constant latency EPSCs following ON stimulation, and in some of these cells, the short latency synaptic response was followed by a delayed burst of EPSP/Cs. SA cells also responded to ON stimulation with long, variable latency, prolonged bursts of EPSP/Cs and never exhibited responses consistent with monosynaptic ON input (Figure 4). These findings indicate that (1) SA cells and most PG cells lack direct ON input and (2) ET cells along with mitral/tufted cells are the major postsynaptic targets of ON inputs.

Since most (∼80%) PG cells, and all SA cells, lack monosynaptic ON input, this suggests that most PG cells are functionally associated with glomerular compartments lacking ON terminals. Anatomical studies have revealed that the glomeruli have a bicompartmental organization. Each glomerulus has several interdigitating compartments, one of which is rich in ON terminals and the second of which is devoid of ON input (Kosaka, K. et al., 1997; Kasowski, H. J. et al., 1999). Calbindin-positive JG neurons extend their dendrites only into glomerular compartments devoid of ON terminals, suggesting that they do not receive direct sensory innervation (Toida, K. et al., 1998; 2000). It is reasonable to speculate, therefore, that the SA and PG cells that do not receive direct input (Hayar, A. et al., 2004b) may correspond to these calbindin-positive JG neurons. These PG cells might provide localized inhibition to mitral/tufted cell dendrites, or other nearby JG cells. Dopaminergic and GABAergic PG cells presynaptically inhibit ON terminals (Hsia, A. Y. et al., 1999; Wachowiak, M. and Cohen, L. B., 1999; Aroniadou-Anderjaska, V. et al., 2000; Berkowicz, D. A. and Trombley, P. Q., 2000; Ennis, M. et al., 2001; Murphy, G. J. et al., 2005; Wachowiak, M. et al., 2005). Since at least 20% of PG cells receive monosynaptic ON input, it is possible that these cells primarily mediate this presynaptic inhibition of the ON. In contrast to PG cells, SA cells extend dendrites and axons across multiple glomeruli and are thought to be involved in interglomerular functions, such as center-surround inhibition of neighboring glomeruli (Aungst, J. L. et al., 2003).

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