Etienne Pralong

Cellular perspectives on the glutamate–monoamine interactions in limbic lobe structures and their relevance for some psychiatric disorders

Dopaminergic, serotonergic and noradrenergic nuclei form the trimonoamine modulating system (TMMS). This system modulates emotional/motivational activities mediated by the limbic circuitry, where glutamate is the major excitatory neurotransmitter. Two main concepts are the basis of this review. First, since 1950 and the discovery of the antipsychotic activity of the dopamine D2 receptor antagonist chlorpromazine, it appears that drugs that can modulate the TMMS possess therapeutic psychiatric properties. Second, the concept of glutamate/trimonoamine imbalance in the cortico-striato-thalamo-cortical loop that has been so successful in explaining the pathophysiology of Parkinson disease has been applied in the pathophysiology of schizophrenia. This review will focus on the complex interactions between the fast synaptic glutamatergic transmission and the TMMS in specific parts of the limbic lobe and we will try to link these interactions to some psychiatric disorders, mainly depression, schizophrenia and drug addiction.

Noradrenaline modulates glutamate-mediated neurotransmission in the rat basolateral amygdala in vitro

The entorhinal cortex and the amygdala are interconnected structures of the limbic system in which paroxysmal activity occurs during temporal lobe epilepsy. Conflicting evidence shows that noradrenaline (i) inhibits the spreading to other parts of the limbic system of paroxysmal activity generated in the amygdala or the entorhinal cortex, but also (ii) increases glutamatergic transmission in the basolateral amygdala. Given our previous work on the inhibitory effect of noradrenaline on entorhinal cortex neurons, we developed an in vitro slice preparation to study the synaptic transmission in the basolateral amygdala and its modulation by noradrenaline. Noradrenaline reduced the fast excitatory postsynaptic potential (EPSP) by ∼40% at 100 μM and the slow EPSP by ∼50% at 50 μM. A similar effect was obtained with the α2‐agonist UK 14304 at 100 and 50 μM respectively. In contrast, the β‐agonist isoproterenol increased the fast EPSP by ∼40% at 100 μM and the slow EPSP by ∼20% at 50 μM. Accordingly, the effect of noradrenaline on the EPSPs was blocked by the α2‐antagonist yohimbine (10 μM) but not by the α1‐antagonist prazosine (10 μM) and the β‐antagonist propranolol (10 μM). Noradrenaline (50–100 μM) was ineffective on most (14/16) of the isolated inhibitory postsynaptic potentials (IPSPs). These experiments provide evidence that noradrenaline inhibits the excitatory synaptic response of basolateral amygdala neurons. A pharmacological analysis revealed that the noradrenergic modulation of the excitatory transmission in the basolateral amygdaia can be dissected into a predominant α2‐adrenoreceptor‐mediated inhibition and a β‐adrenoreceptor‐mediated excitation.

Chronic deep brain stimulation in mesial temporal lobe epilepsy

The objective of this study was to evaluate the efficiency and the effects of changes in parameters of chronic amygdala-hippocampal deep brain stimulation (AH-DBS) in mesial temporal lobe epilepsy (TLE). Eight pharmacoresistant patients, not candidates for ablative surgery, received chronic AH-DBS (130 Hz, follow-up 12-24 months): two patients with hippocampal sclerosis (HS) and six patients with non-lesional mesial TLE (NLES). The effects of stepwise increases in intensity (0-Off to 2 V) and stimulation configuration (quadripolar and bipolar), on seizure frequency and neuropsychological performance were studied. The two HS patients obtained a significant decrease (65-75%) in seizure frequency with high voltage bipolar DBS (≥1 V) or with quadripolar stimulation. Two out of six NLES patients became seizure-free, one of them without stimulation, suggesting a microlesional effect. Two NLES patients experienced reductions of seizure frequency (65-70%), whereas the remaining two showed no significant seizure reduction. Neuropsychological evaluations showed reversible memory impairments in two patients under strong stimulation only. AH-DBS showed long-term efficiency in most of the TLE patients. It is a valuable treatment option for patients who suffer from drug resistant epilepsy and who are not candidates for resective surgery. The effects of changes in the stimulation parameters suggest that a large zone of stimulation would be required in HS patients, while a limited zone of stimulation or even a microlesional effect could be sufficient in NLES patients, for whom the importance of the proximity of the electrode to the epileptogenic zone remains to be studied. Further studies are required to ascertain these latter observations.

Noradrenaline increases K-conductance and reduces glutamatergic transmission in the mouse entorhinal cortex by activation of alpha 2-adrenoreceptors

The entorhinal cortex is a gateway to the hippocampus; it receives inputs from several cortical associative areas as well as subcortical areas. Since there is evidence showing that noradrenaline reduces the epileptic activity generated in the entorhinal cortex, we have examined the action of noradrenaline in the superficial layer of the entorhinal cortex, which is the main source of afferents to the hippocampus. In a previous study we showed that noradrenaline hyperpolarized layer II entorhinal cortex neurons and reduced global synaptic transmission via α2‐adrenoreceptors. Here we present a detailed analysis of the effect of noradrenaline on membrane resistance and on the pharmacologically isolated postsynaptic potentials in layer II entorhinal cortex neurons of mice. Noradrenaline (50 μM) hyperpolarized most layer II entorhinal cortex neurons. This hyperpolarization corresponded to an outward current with a reversal potential following the Nernst equilibrium potential for potassium. The hyperpolarizing effect of noradrenaline was blocked by 10 μM yohimbine. These observations suggest that noradrenaline activates a potassium conductance via an α2‐adrenoreceptor. Noradrenaline (10–50 μM) reversibly reduced the amplitude of the pharmacologically isolated excitatory potentials mediated by both NMDA and α‐amino‐3‐hydroxy‐5‐methyl‐isoxazole‐propionic acid (AMPA) receptors, the former being more strongly affected. Again this effect was blocked by 10 μM yohimbine. In contrast, GABAA‐mediated synaptic transmission was virtually unaffected by noradrenaline. Thus, noradrenaline appears to strongly inhibit the glutamate‐mediated synaptic transmission in the entorhinal cortex without affecting inhibitory post‐synaptic potentials. These observations suggest that α2‐adrenergic receptor agonists may exert a beneficial effect in the control of hyperexcitability in temporal lobe epilepsy.

Functional connections and epileptic spread between hippocampus, entorhinal cortex and amygdala in a modified horizontal slice preparation of the rat brain

The hippocampus, the entorhinal cortex and the amygdala are interconnected structures of the limbic system that are implicated in memory and emotional behaviour. They demonstrate synaptic plasticity and are susceptible to development of temporal lobe epilepsy, which may lead to emotional and psychological disturbances. Their relative anatomical disposition has limited the study of neurotransmission and epileptic spread between these three regions in previous in vitro preparations. Here we describe a novel, modified‐horizontal slice preparation that includes in the same plane the hippocampus, entorhinal cortex and amygdala. We found that, following application of bicuculline, each region in our preparation could generate spontaneous bursts that resembled epileptic interictal spikes. This spontaneous activity initiated in the hippocampal CA3/2 region, from where it propagated and controlled the activity in the entorhinal cortex and the amygdala. We found that this spontaneous bursting activity could spread via two different pathways. The first pathway comprises the well‐known subiculum–entorhinal cortex–perirhinal cortex–amygdala route. The second pathway consists of a direct connection between the CA1 region and perirhinal cortex, through which the hippocampal bursting activity can spread to the amygdala while bypassing the entorhinal cortex. Thus, our experiments provide a new in vitro model of initiation and spread of epileptic‐like activity in the ventral part of the limbic system, which includes a novel, fast and functional connection between the CA1 region and perirhinal cortex.

Determination of group I metabotropic glutamate receptor subtypes involved in the frequency of epileptiform activity in vitro using mGluR1 and mGluR5 mutant mice.

In mouse hippocampal slices, bicuculline elicited spontaneous epileptiform bursts with a duration of 200-300 ms and with a frequency of five to six events per minute. Application of group I metabotropic glutamate receptor agonist (RS)-3,5-dihydroxyphenylglycine ((RS)-DHPG) increased the burst frequency up to 300% at concentrations of 50 to 100 microM, while it decreased the burst duration below 100 ms. In slices of subtype I mGluR1 or subtype I mGluR5 knockout mice, bicuculline elicited spontaneous epileptiform bursts with similar duration and frequency as those measured in wild-type mice but without the previous effects seen following application of DHPG at concentrations up to 100 microM. Likewise, in slices of wild-type mice, preincubation with mGluR1 antagonist, 1-aminoindan-1,5-dicarboxylic acid (AIDA) or mGluR5 receptor antagonist, 2-methyl-6-(phenylethynyl)-pyridine (MPEP) blocked in both cases completely the increase in frequency following DHPG application. These findings suggest an interactive mechanism between mGluR1 and mGluR5 receptors in the modulation of epileptiform bursting activity by DHPG that could indicate a common intracellular signaling mechanism or possibly direct interaction between these two receptors.

Noradrenaline reduces synaptic responses in normal and tottering mouse entorhinal cortex via α2 receptors

The effects of noradrenaline (NA) on synaptic responses in layer II of the entorhinal cortex (EC) were studied in normal and spontaneously epileptic mutant mice tottering using intracellular recording in a slice preparation. Neither the membrane properties of neurones nor the responses to NA differed between normal and tottering mice. NA (50 microM) hyperpolarized most (29/54) of the neurones via alpha 2 adrenergic receptors. Synaptic responses of EC neurones were complex. NA (10-100 microM) reduced all the components of the synaptic response in a concentration-dependent and reversible manner. The pharmacological properties of the inhibitory effect of NA were characterised and quantified on one component of the complex synaptic response, the fast excitatory postsynaptic potential. The effect of NA was mimicked by the alpha 2 agonist UK 14,304 and blocked by the alpha 2 antagonist yohimbine. It is concluded that NA can inhibit via an alpha 2 receptor-mediated action synaptic responses in the superficial layers of the EC.

Electrophysiological localization of the subthalamic nucleus in parkinsonian patients.

Deep brain stimulation of the subthalamic nucleus (STN) is becoming the procedure of choice to reduce symptoms of Parkinsons disease such as rigidity, akinesia and tremor. We present here a series of electrophysiological recordings performed in 34 patients along a standardized electrode trajectory. Neuronal activity along the trajectory consists of a first heterogeneous population of thalamic cells with a mean frequency of 24.8+/-1.4 Hz followed by a silent zone and a second population of STN neurones with a significantly higher spiking frequency (P<0.001) of 42.3+/-1.8 Hz. This study confirms previous findings and suggests that rapid measurement of neuronal spiking frequency and burst index is sufficient to determine precisely the vertical position of the STN.

Recording of ventral posterior lateral thalamus neuron response to contact heat evoked potential in patient with neurogenic pain.

Microrecording of single unit response to contact heat-evoked potential (CHEP) were performed in right ventral posterior lateral (VPL) thalamus during deep brain stimulation (DBS) surgery in a patient with chronic neurogenic pain. In our patient, neurons (n = 10) recorded in the ventral thalamus fired at a higher rate of 40 Hz compared to neurons recorded in Parkinsonian patients (24 Hz). Contact heat was applied by a fast heating and cooling probe of 5 cm2 area on the dermatome C6 territory of the left hand. One out of four thalamic cells located in the VPL responded repetitively 325 ms after the peak temperature was reached with a burst of action potential, suggesting A-delta fibre activation. This observation supports the use of CHEP for mapping nociceptive neurons location during DBS surgery for intractable pain.

Opposite effects of internal globus pallidus stimulation on pallidal neurones activity

Besides clinical efficacy, the mechanisms of action of deep brain stimulation (DBS) are still debated. To shed light on this complex issue, we have taken the opportunity to record the response of globus pallidus internus (GPi) neurones to 100 Hz stimulations in a case of Lesch–Nyhan syndrome (LNS) where four pallidal electrodes were implanted. Three types of response were observed, 2/19 neurones were unaffected by DBS. About 7/19 neurones were inhibited during DBS stimulation and 10/19 neurones were excited during DBS stimulation. Both effects ceased when DBS was turned off. Inhibited neurones were situated lower that exited ones on the trajectory (1.25 and 4.65 mm above the center of GPi respectively). These observations suggest that locally DBS induces a reversible inhibition of neurone firing rate while at the same time distantly exciting the main afferents to and/or efferents from the GPi. Both actions would result in a strong GPi inhibition that does not preclude increased outflow from the GPi.