Ornella Valenti

Allosteric modulation of group III metabotropic glutamate receptor 4: A potential approach to Parkinson's disease treatment

Parkinsons disease (PD) is a debilitating movement disorder that afflicts >1 million people in North America. Current treatments focused on dopamine-replacement strategies ultimately fail in most patients because of loss of efficacy and severe adverse effects that worsen as the disease progresses. The recent success of surgical approaches suggests that a pharmacological intervention that bypasses the dopamine system and restores balance in the basal ganglia motor circuit may provide an effective treatment strategy. We previously identified the metabotropic glutamate receptor 4 (mGluR4) as a potential drug target and predicted that selective activation of mGluR4 could provide palliative benefit in PD. We now report that N-phenyl-7-(hydroxylimino)cyclopropa[b]chromen-1a-carboxamide (PHCCC) is a selective allosteric potentiator of mGluR4. This compound selectively potentiated agonist-induced mGluR4 activity in cultured cells expressing this receptor and did not itself act as an agonist. Furthermore, PHCCC potentiated the effect of l-(+)-2-amino-4-phosphonobutyric acid in inhibiting transmission at the striatopallidal synapse. Modulation of the striatopallidal synapse has been proposed as a potential therapeutic target for PD, in that it may restore balance in the basal ganglia motor circuit. Consistent with this, PHCCC produced a marked reversal of reserpine-induced akinesia in rats. The closely related analogue 7-(hydroxylimino)cyclopropachromen-1a-carboxamide ethyl ester, which does not potentiate mGluR4, had no effect in this model. These results are evidence for in vivo behavioral effects of an allosteric potentiator of mGluRs and suggest that potentiation of mGluR4 may be a useful therapeutic approach to the treatment of PD.

Behavior-dependent specialization of identified hippocampal interneurons

A large variety of GABAergic interneurons control information processing in the hippocampal circuits governing the formation of neuronal representations. Whether distinct hippocampal interneuron types contribute differentially to information processing during behavior is not known. We employed a new technique for recording and labeling interneurons and pyramidal cells in drug-free, freely moving rats. Recorded parvalbumin-expressing basket interneurons innervated somata and proximal pyramidal cell dendrites, whereas nitric oxide synthase– and neuropeptide Y–expressing ivy cells provided synaptic and extrasynaptic dendritic modulation. Basket and ivy cells showed distinct spike-timing dynamics, firing at different rates and times during theta and ripple oscillations. Basket, but not ivy, cells changed their firing rates during movement, sleep and quiet wakefulness, suggesting that basket cells coordinate cell assemblies in a behavioral state–contingent manner, whereas persistently firing ivy cells might control network excitability and homeostasis. Different interneuron types provide GABA to specific subcellular domains at defined times and rates, thereby differentially controlling network activity during behavior.

Distinct physiological roles of the Gq‐coupled metabotropic glutamate receptors co‐expressed in the same neuronal populations

The group I metabotropic glutamate receptors, mGluR1 and mGluR5, exhibit a high degree of sequence homology, and are often found co‐expressed in the same neuronal populations. These receptors couple to a broad array of effector systems, and are implicated in diverse physiological and pathophysiological functions. Due to the high degree of sequence homology, and the findings that these receptors couple identically in recombinant systems, it has been generally assumed that these two group I mGluR subtypes would exhibit redundant function when co‐expressed in the same neurons. With the advent of subtype‐selective pharmacological tools, it has become possible to tease apart the functions of mGluR1 and mGluR5 in the same neuron. The emerging picture is one of diverse function, which implies differential regulation. Interestingly, the group I mGluRs are modulated by a rich variety of regulatory systems, which may explain how these receptors can mediate divergent actions when present in the same cell. J. Cell. Physiol. 191: 125–137, 2002.

Aversive Stimuli Alter Ventral Tegmental Area Dopamine Neuron Activity via a Common Action in the Ventral Hippocampus

Stress is a physiological, adaptive response to changes in the environment, but can also lead to pathological alterations, such as relapse in psychiatric disorders and drug abuse. Evidence demonstrates that the dopamine (DA) system plays a role in stress; however, the nature of the effects of sustained stressors on DA neuron physiology has not been adequately addressed. By using a combined electrophysiological, immunohistochemical and behavioral approach, we examined the response of ventral tegmental area DA neurons in rats to acute as well as repeated stressful events using noxious (footshock) and psychological (restraint) stress. We found that aversive stimuli induced a pronounced activation of the DA system both electrophysiologically (population activity; i.e., number of DA neurons firing spontaneously) and behaviorally (response to psychostimulants). Moreover, infusion of TTX into the ventral hippocampus (vHPC) reversed both behavioral and electrophysiological effects of stress, indicating that the hyperdopaminergic condition associated with stress is driven by hyperactivity within the vHPC. Therefore, the stress-induced activation of the DA system may underlie the propensity of stress to exacerbate psychotic disorders or predispose an individual to drug-seeking behavior. Furthermore, the vHPC represents a critical link between context-dependent DA sensitization, stress-induced potentiation of amphetamine responsivity, and the increase in DA associated with stressors.

Glutamate Receptors and Parkinson's Disease Opportunities for Intervention

Parkinson’s disease is a debilitating neurodegenerative movement disorder that is the result of a degeneration of dopaminergic neurons in the substantia nigra pars compacta. The resulting loss of striatal dopaminergic tone is believed to underlie a series of changes in the circuitry of the basal ganglia that ultimately lead to severe motor disturbances due to excessive basal ganglia outflow. Glutamate plays a central role in the disruption of normal basal ganglia function, and it has been hypothesised that agents acting to restore normal glutamatergic function may provide therapeutic interventions that bypass the severe motor side effects associated with current dopamine replacement strategies. Analysis of the effects of glutamate receptor ligands in the basal ganglia circuit suggests that both ionotropic and metabotropic glutamate receptors could have antiparkinsonian actions. In particular, NMDA receptor antagonists that selectively target the NR2B subunit and antagonists of the metabotropic glutamate receptor mGluR5 appear to hold promise and deserve future attention.

Different stressors produce excitation or inhibition of mesolimbic dopamine neuron activity: Response alteration by stress pre-exposure

Stressors can exert a wide variety of responses, ranging from adaptive responses to pathological changes; moreover, recent studies suggest that mild stressors can attenuate the response of a system to major stressful events. We have previously shown that 2‐week exposure to cold, a comparatively mild inescapable stressor, induced a pronounced reduction in ventral tegmental area (VTA) dopamine (DA) neuron activity, whereas restraint stress increases DA neuron activity. However, it is not known if these stressors differentially impact the VTA in a region‐specific manner, if they differentially impact behavioral responses, or whether the effects of such different stressors are additive or antagonistic with regard to their impact on DA neuron firing. To address these questions, single‐unit extracellular recordings were performed in anesthetized control rats and rats exposed to chronic cold, and tested after delivery of a 2‐h restraint session. Chronic cold stress strongly attenuated the number of DA neurons firing in the VTA, and this effect occurred primarily in the medial and central VTA regions that preferentially project to reward‐related ventral striatal regions. Chronic cold exposure also prevented the pronounced increase in DA neuron population activity without affecting the behavioral sensitization to amphetamine produced by restraint stress. Taken together, these data show that a prolonged inescapable mild stressor can induce plastic changes that attenuate the DA system response to acute stress.

Antipsychotic Drugs Rapidly Induce Dopamine Neuron Depolarization Block in a Developmental Rat Model of Schizophrenia

Repeated administration of antipsychotic drugs to normal rats has been shown to induce a state of dopamine neuron inactivation known as depolarization block, which correlates with the ability of the drugs to exhibit antipsychotic efficacy and extrapyramidal side effects in schizophrenia patients. Nonetheless, in normal rats depolarization block requires weeks of antipsychotic drug administration, whereas schizophrenia patients exhibit initial effects soon after initiating antipsychotic drug treatment. We now report that, in a developmental disruption rat model of schizophrenia [methyl-azoxymethanol acetate (20 mg/kg, i.p.) injected into G17 pregnant female rats, with offspring tested as adults], the extant hyperdopaminergic state combines with the excitatory actions of a first- (haloperidol; 0.6 mg/kg, i.p.) and a second- (sertindole; 2.5 mg/kg, i.p.) generation antipsychotic drug to rapidly induce depolarization block in ventral tegmental area dopamine neurons. Acute injection of either antipsychotic drug induced an immediate reduction in the number of spontaneously active dopamine neurons (cells per electrode track; termed population activity). Repeated administration of either antipsychotic drug for 1, 3, 7, 15, and 21 d continued to reduce dopamine neuron population activity. Both acute and repeated effects on population activity were reversed by acute apomorphine injections, which is consistent with the reversal of dopamine neuron depolarization block. Although this action may account for the effects of D2 antagonist drugs on alleviating psychosis and the lack of development of tolerance in humans, the drugs appear to do so by inducing an offsetting deficit rather than attacking the primary pathology present in schizophrenia.

Antipsychotic drug-induced increases in ventral tegmental area dopamine neuron population activity via activation of the nucleus accumbens-ventral pallidum pathway.

Acute administration of antipsychotic drugs increases dopamine (DA) neuron activity and DA release via D2 receptor blockade. However, it is unclear whether the DA neuron activation produced by antipsychotic drugs is due to feedback from post-synaptic blockade or is due to an action on DA neuron autoreceptors. This was evaluated using two drugs: the first-generation antipsychotic drug haloperidol that has potent D2 blocking properties, and the second-generation drug sertindole, which is unique in that it is reported to fail to reverse the apomorphine-induced decrease in firing rate typically associated with DA neuron autoreceptor stimulation. Using single-unit extracellular recordings from ventral tegmental area (VTA) DA neurons in anaesthetized rats, both drugs were found to significantly increase the number of spontaneously active DA neurons (population activity). Apomorphine administered within 10 min either before or after sertindole reversed the sertindole-induced increase in population activity, but had no effect when administered 1 h after sertindole. Moreover, both sertindole- and haloperidol-induced increase in population activity was prevented when nucleus accumbens feedback was interrupted by local infusion of the GABAA antagonist bicuculline into the ventral pallidum. Taken together, these data suggest that antipsychotics increase DA neuron population activity via a common action on the nucleus accumbens-ventral pallidum-VTA feedback pathway and thus provide further elucidation on the mechanism by which antipsychotic drugs affect DA neuron activity. This provides an important insight into the relationship between altered DA neuron activity and potential antipsychotic efficacy.

Behavior-dependent activity patterns of GABAergic long-range projecting neurons in the rat hippocampus

Long‐range glutamatergic and GABAergic projections participate in temporal coordination of neuronal activity in distributed cortical areas. In the hippocampus, GABAergic neurons project to the medial septum and retrohippocampal areas. Many GABAergic projection cells express somatostatin (SOM+) and, together with locally terminating SOM+ bistratified and O‐LM cells, contribute to dendritic inhibition of pyramidal cells. We tested the hypothesis that diversity in SOM+ cells reflects temporal specialization during behavior using extracellular single cell recording and juxtacellular neurobiotin‐labeling in freely moving rats. We have demonstrated that rare GABAergic projection neurons discharge rhythmically and are remarkably diverse. During sharp wave‐ripples, most projection cells, including a novel SOM+ GABAergic back‐projecting cell, increased their activity similar to bistratified cells, but unlike O‐LM cells. During movement, most projection cells discharged along the descending slope of theta cycles, but some fired at the trough jointly with bistratified and O‐LM cells. The specialization of hippocampal SOM+ projection neurons complements the action of local interneurons in differentially phasing inputs from the CA3 area to CA1 pyramidal cell dendrites during sleep and wakefulness. Our observations suggest that GABAergic projection cells mediate the behavior‐ and network state‐dependent binding of neuronal assemblies amongst functionally‐related brain regions by transmitting local rhythmic entrainment of neurons in CA1 to neuronal populations in other areas.

Temporal Organization of GABAergic Interneurons in the Intermediate CA1 Hippocampus During Network Oscillations

Travelling theta oscillations and sharp wave-associated ripples (SWRs) provide temporal structures to neural activity in the CA1 hippocampus. The contribution of rhythm-generating GABAergic interneurons to network timing across the septotemporal CA1 axis remains unknown. We recorded the spike-timing of identified parvalbumin (PV)-expressing basket, axo-axonic, oriens-lacunosum moleculare (O-LM) interneurons, and pyramidal cells in the intermediate CA1 (iCA1) of anesthetized rats in relation to simultaneously detected network oscillations in iCA1 and dorsal CA1 (dCA1). Distinct interneuron types were coupled differentially to SWR, and the majority of iCA1 SWR events occurred simultaneously with dCA1 SWR events. In contrast, iCA1 theta oscillations were shifted in time relative to dCA1 theta oscillations. During theta cycles, the highest firing of iCA1 axo-axonic cells was followed by PV-expressing basket cells and subsequently by O-LM together with pyramidal cells, similar to the firing sequence of dCA1 cell types reported previously. However, we observed that this temporal organization of cell types is shifted in time between dCA1 and iCA1, together with the respective shift in theta oscillations. We show that GABAergic activity can be synchronized during SWR but is shifted in time from dCA1 to iCA1 during theta oscillations, highlighting the flexible inhibitory control of excitatory activity across a brain structure.