Neuronal nicotinic acetylcholine receptors and autosomal dominant nocturnal frontal lobe epilepsy: a critical review.

Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is a distinct human epileptic syndrome. In some families, it is associated with mutations of the alpha4 or the beta2 subunit of the neuronal nicotinic acetylcholine receptor (nAChR). It has been suggested that these mutations are the causative factors responsible for the induction and expression of this syndrome. However, the pathogenic mechanisms leading to ADNFLE are unknown and, in this review, we discuss the following yet unresolved questions concerning the involvement of mutated nAChRs in the phenotypic development of the disorder: (1) why do seizures associated with ADNFLE arise explicitly from the frontal lobe of the neocortex? (2) why do the seizures arise mainly from sleep? (3) why does ADNFLE starts predominantly during childhood? A survey of our current knowledge on neocortical and thalamic cholinergic systems, including their ontogenetic development, leads us to the conclusion that there are, at least at the moment, no convincing answers to these questions. Furthermore, we believe that, even in those cases where mutations of the alpha4 or the beta2 subunit of the nAChR cosegregate with ADNFLE, there must be some crucial additional factors contributing to the development of the specific symptoms of ADNFLE.

Assessment and management of behavioral disturbances in nursing home patients with dementia.

Behavioral disturbances among nursing home patients with dementia are common and substantially affect patients and caregivers. Assessing the environmental, medical, and psychiatric causes of problematic behaviors and implementing a plan of behavioral, medical, and psychiatric management can reduce difficult target behaviors. This article presents a multifaceted approach to assessing patients with dementia who have behavioral problems, reviews medical and pharmacological management of these problems, and presents a multidisciplinary approach to developing treatment plans aimed at reducing such behaviors among nursing home patients with dementia.

Electroconvulsive therapy-responsive depression in a patient with progressive supranuclear palsy.

We report the case of a 68-year-old woman with progressive supranuclear palsy whose depression was successfully treated with electroconvulsive therapy. She tolerated the treatments well and showed neither improvement nor decline in the neurologic symptoms of her illness.

Activation of mu- and delta-opioid receptors causes presynaptic inhibition of glutamatergic excitation in neocortical neurons.

BACKGROUND: The mechanism underlying the depressant effect of opioids on neuronal activity within the neocortex is still not clear. Three modes of action have been suggested: (1) inhibition by activation of postsynaptic potassium channels, (2) interaction with postsynaptic glutamate receptors, and (3) presynaptic inhibition of glutamate release. To address this issue, the authors investigated the effects of mu- and delta-receptor agonists on excitatory postsynaptic currents (EPSCs) and on membrane properties of neocortical neurons. METHODS: Intracellular recordings were performed in rat brain slices. Stimulus-evoked EPSCs mediated by different glutamate receptor subtypes were pharmacologically isolated, and opioids were applied by addition to the bathing medium. Possible postsynaptic interactions between glutamate and opioid receptors were investigated using microiontophoretic application of glutamate on neurons functionally isolated from presynaptic input. RESULTS: delta-Receptor activation by d-Ala2-d-Leu5-enkephalin (DADLE) reduced the amplitudes of EPSCs by maximum 60% in a naltrindole-reversible manner (EC50: 6-15 nm). In 30-40% of the neurons investigated, higher concentrations (0.1-1 micrometer) of DADLE activated small outward currents. The mu-receptor selective agonist d-Ala2-N-MePhe5-Gly5-ol-enkephalin (0.1-1 micrometer) depressed the amplitudes of EPSCs by maximum 30% without changes in postsynaptic membrane properties. In the absence of synaptic transmission, inward currents induced by microiontophoretic application of glutamate were not affected by DADLE. CONCLUSIONS: Activation of mu- and delta-opioid receptors depresses glutamatergic excitatory transmission evoked in neocortical neurons by presynaptic inhibition. A weak activation of a postsynaptic potassium conductance becomes evident only at high agonist concentrations. There is no evidence for a postsynaptic interaction between glutamate and opioid receptors.

Myelination defects and neuronal hyperexcitability in the neocortex of connexin 32-deficient mice.

Morphological and electrophysiological studies were performed on neocortices of adult Connexin 32 (Cx32)-deficient mice and wild-type mice to investigate the consequences of a lack of the gap junction subunit Cx32 on neocortical structure and function. Morphometrical analysis revealed a reduced volume fraction of myelin within the neuropil and a decreased thickness of the axonal myelin sheaths in the neocortex of Cx32-deficient mice. Intracellular recordings from neurons in neocortical slice preparations provided evidence for an increased membrane input resistance in neurons of Cx32-null mutant mice as compared to neurons of wild-type mice. Consequently, neurons of Cx32-deficient mice displayed an enhanced intrinsic excitability. In addition, approximately 50% of the neurons investigated in slices of Cx32-deficient mice responded to afferent stimulation with delayed and large glutamatergic excitatory postsynaptic potentials resembling paroxysmal depolarizations. GABAergic inhibition sufficient to efficiently control synaptic excitability was virtually absent in these cells. The changes in intrinsic membrane properties observed in neurons of Cx32-null mutant mice were independent of the alterations in synaptic function, since increased membrane resistances were observed also in neurons with normal synaptic response pattern. Thus, in the neocortex, lack of Cx32 correlates with myelination defects, alterations in intrinsic membrane properties and dysfunction of inhibitory synaptic transmission.

Time-related changes in connexin mRNA abundance in the rat neocortex during postnatal development.

Gap junction coupling between neurons is important for the temporal and spatial co-ordination of neocortical development and can be visualised by dye-coupling. Neuronal dye-coupling in the rat neocortex is extensive during the first 2 postnatal weeks and diminishes rapidly thereafter. We used RT (reverse transcriptase)-PCR to investigate the time-related changes in mRNA expression for the connexins (Cx) Cx 26, Cx 30, Cx 32, Cx 36, Cx 37, Cx 40, Cx 43, Cx 45 and Cx 46 as well as for beta-actin and GAPDH in rat neocortex during the first 6 postnatal weeks. The time courses for mRNA expression for GAPDH, Cx 30, Cx 36 and Cx 43 were also investigated by northern blotting. Cx 30 and Cx 45 mRNA abundance showed no time-dependent changes during the early postnatal period. The relative abundance of Cx 32, Cx 43 and Cx 46 mRNA increased significantly during the first 2-3 weeks and then remained relatively constant during weeks 3-6. The relative abundance of Cx 26, Cx 36, Cx 37 and Cx 40 mRNA also increased significantly during the first 10-15 postnatal days but then declined significantly from their peak values during weeks 3-6. beta-actin mRNA expression showed no time-related changes but GAPDH mRNA expression increased significantly during the first postnatal week, then remained constant. The time-dependent changes in mRNA relative abundance for GAPDH, Cx 36 and Cx 43 determined by northern blotting corroborate the results from the RT-PCR study. None of the Cx exhibited time-dependent changes in mRNA expression in homogenates of rat neocortex which parallel the changes in neuronal dye-coupling during postnatal development.

Management of patients with bipolar mood disorder and substance dependence.

UNLABELLED: Nine patients with bipolar mood disorder and concurrent substance dependence were treated in an 18-bed inpatient addiction unit over a 3-month period. A multidisciplinary team approach used a medicalized Minnesota model and stressed the establishment of a positive diagnosis and individualization of management strategies for each patient. Clinically significant affective symptoms that required acute psychiatric intervention developed in several patients during hospitalization. Manic symptoms developed in three patients during sedative withdrawal, requiring the team to differentiate manic symptoms from physiologic withdrawal; and two patients became severely depressed, requiring pharmacologic management and suicide-prevention strategies. SUMMARY: Our experience with the patients in this case series supports the contention that there is no simple, uniform approach to the substance-dependent patient with bipolar disorder. Treatment teams must be prepared to differentiate complex syndromes and to manage manic, depressive, and addictive behaviors.

Local disinhibition of neocortical neuronal circuits causes augmentation of glutamatergic and GABAergic synaptic transmission in the rat neostriatum in vitro.

Intra- and extracellular recordings were performed to investigate the influence of local disinhibition of neocortical circuits on corticostriatal synaptic transmission. In rat brain slices with preserved corticostriatal connections, electrical stimulation of the neocortex elicited composed postsynaptic responses in neostriatal neurons consisting of glutamatergic excitatory postsynaptic potentials (EPSPs) and weakly expressed GABAA receptor-mediated inhibitory postsynaptic potentials (IPSPs). Following local application of the GABAA receptor antagonist bicuculline to the neocortex, neocortical neurons responded to intracortical stimulation with transient paroxysmal depolarizations. Simultaneously, the amplitude of neocortically evoked EPSPs recorded from neostriatal neurons was found to be enhanced without changes in duration. Similarly, the amplitude of IPSPs increased following disinhibition of neocortical circuits. In addition and in contrast to EPSPs, the duration of the IPSPs was found to be markedly prolonged. The results demonstrate that local disinhibition of neocortical neuronal circuits potentiates both excitatory and inhibitory synaptic transmission in striatal neurons. However, compared to AMPA receptor-mediated excitation, GABAA receptor-mediated inhibition becomes more efficient due to a marked prolongation of IPSPs. The pronounced augmentation of inhibition can be attributed to a strong activation of inhibitory interneurons within the striatum.

Involvement of GABA(B) receptors in convulsant-induced epileptiform activity in rat neocortex in vitro.

The role of gamma-aminobutyric acid B (GABA(B)) receptors in the generation and maintenance of bicuculline-induced epileptiform activity in rat neocortical slices was studied using electrophysiological methods. A block of GABA(B) receptors in the presence of functional GABA(A) receptor-mediated inhibition was not sufficient to induce epileptiform activity. In the presence of the GABA(A) receptor antagonist bicuculline (10 microM) and at suprathreshold stimulation, the GABA(B) receptor antagonist CGP 35348 (10-300 microM) significantly potentiated epileptiform activity. With stimulation at threshold intensity, low concentrations of CGP 35348 (10-30 microM) potentiated bicuculline-induced activity, whereas higher concentrations (100-300 microM) invariably led to a reversible suppression of stimulus-evoked epileptiform discharges. CGP 35348 also enhanced picrotoxin-induced epileptiform activity, but at higher concentrations it was considerably less effective in suppressing such epileptiform discharges. The GABA uptake inhibitor nipecotic acid partially mimicked the actions of CGP 35348: with stimulation at threshold intensity, it reversibly suppressed bicuculline-induced epileptiform field potentials, but it did not influence epileptiform activity induced by picrotoxin. We conclude that a postsynaptic blockade of GABA(B) receptors induces an amplification of epileptiform activity in neocortical slices disinhibited by GABA(A) receptor antagonists. An additional blockade of presynaptic GABA(B) receptors, especially under conditions of weak stimulation of the neurons, reduces the inhibitory auto-feedback control of GABA release, leading to a displacement of competitive antagonists from the postsynaptic GABA(A) receptor and hence, to a suppression of epileptiform activity induced by competitive GABA(A) receptor antagonists.

Evidence for the activity of five adenosine-3',5'-monophosphate-degrading phosphodiesterase isozymes in the adult rat neocortex.

In the present study, the expression of the activity of adenosine-3',5'-monophosphate-degrading phosphodiesterases (cAMP-PDEs) was analyzed in rat neocortex homogenates. Following separation by anion-exchange chromatography, the isozymes were characterized by their sensitivity to modulators and by their kinetic properties. We identified the activity of five distinct cAMP-PDE isozymes: two calcium/calmodulin-dependent forms (PDE 1), one PDE 2 isozyme stimulated by guanosine-3',5'-monophosphate (cGMP), one cGMP-inhibited form (PDE 3) and a cAMP-specific, rolipram-sensitive form (PDE 4). Our study provides, for the first time, evidence for the existence of PDE 3 enzyme activity in rat neocortex and predicts the expression of at least two isoforms (splice variants) of PDE 1A in this brain area. The existence of different cAMP-degrading phosphodiesterases modulated by different intracellular second messengers (calcium and cGMP) suggests that the activity of neocortical neurons and glia cells is regulated, inter alia, by a 'crosstalk' between calcium-, cGMP- and cAMP-dependent second messenger pathways.

Pattern and pharmacology of propagating epileptiform activity in mouse cerebral cortex.

Multiple extracellular recording electrodes were used to study the intra- and interhemispheric spread of stimulus-evoked epileptiform responses in adult mouse neocortical slices. Bath application of 20 microM bicuculline methiodide induced epileptiform activity that propagated at approximately 0.08 m/s over several millimeters in rostro-caudal and medio-lateral direction within the ipsilateral hemisphere and across the corpus callosum to the contralateral hemisphere. A vertical incision from layer II to subcortical regions did not prevent the spread to remote cortical regions, indicating that layer I plays a major role in the lateral propagation of epileptiform activity. The intra- and interhemispheric spread was not influenced by application of an N-methyl-d-aspartate (NMDA) receptor antagonist, but blocked by an antagonist acting at the (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)-type glutamate receptor. The potential role of potassium channel activation in controlling the generation or spread of epileptiform activity was tested by applying the potassium channel opener cromakalim and the serotonin type 1A (5-HT1A) receptor agonist (+/-)-8-hydroxydipropylaminotetralin (8-OH-DPAT) to the disinhibited slices. Whereas cromakalim reduced the neuronal excitability and blocked all epileptiform responses, 8-OH-DAPT did not affect the activity pattern. Our results suggest that propagating epileptiform activity in disinhibited neocortical structures is predominantly mediated by activation of AMPA receptors and controllable by activation of a voltage-dependent potassium current.

The intracellular tracer Neurobiotin alters electrophysiological properties of rat neostriatal neurons.

During whole-cell recordings from rat neostriatal neurons with Neurobiotin-filled patch-clamp electrodes, we observed markedly prolonged action potentials. Similar long-lasting action potentials were not detected when the tracer was omitted from the pipette solution. Resting membrane potential and input resistance remained unchanged in the presence of the tracer. The investigation of this effect revealed that Neurobiotin decreased the threshold for calcium spike generation probably by blocking a potassium conductance activated by depolarisation or by a direct action on calcium channels. The effect of Neurobiotin displayed a fast onset and was not observed during intracellular recordings using conventional microelectrodes.

Major depression in medically ill patients.

Major depression is one of the most common psychiatric problems complicating the treatment and prognosis of patients with active medical illness. Recognizing and treating major depressive conditions in this population can often be challenging, even for the most seasoned clinicians. This article reviews the medical and neurologic conditions that have been associated with the high prevalence rates of major depression. Highlights of the evaluation process that help confirm this suspected diagnosis are addressed, and management issues are discussed. Brief reviews of supportive psychotherapeutic tools that the clinician may find helpful are included, as well as current advances in pharmacologic interventions.

Spatial pattern of evoked synaptic excitation in the mouse neostriatum in vitro.

The spatial distribution of stimulus-evoked excitation in the mouse neostriatum was investigated in vitro by using voltage-sensitive dyes and an optical multi-site recording system (laser scanning microscopy). The scanning area (880 x 830 microns) was positioned in the center of coronal neostriatal slices and records were taken simultaneously from up to 20 detection sites. Stimulus-induced optical signals were blocked by tetrodotoxin (TTX) and disappeared following removal of Ca2+ from the extracellular medium. Furthermore, these responses were inhibited by the glutamate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) indicating that the evoked signals reflected mainly glutamatergic synaptic activity. Electrical stimulation at defined positions elicited characteristic spatial patterns of activity within the neostriatum. Stimulation of the medial subcortical white matter or stimulation at the dorsomedial corner or at the midpoint of the scanning area evoked synaptic activity at all recording sites. However, the largest response amplitudes were invariably observed in the ventrolateral part of the scanning area. In contrast, stimulation at the dorsolateral, ventrolateral or at the ventromedial corner induced synaptic responses which remained restricted to a relatively small area in close vicinity to the site of stimulation. The GABAA receptor antagonist bicuculline did not influence the pattern of activity distribution. However, in the presence of bicuculline, a N-methyl-D-aspartate (NMDA) receptor-mediated delayed signal component was observed which again was most pronounced in the ventrolateral part of the scanning area. These results, obtained in an in vitro slice preparation, demonstrate that spatially defined afferent activation of neostriatal neuronal circuits leads to a characteristic pattern of activity distribution within the neostriatum. Thus, our data complement observations from morphological investigations as well as from electrophysiological studies in vivo that suggest a functional compartmentalization of this brain area.

Serotonin regulates gap junction coupling in the developing rat somatosensory cortex.

To further elucidate the role of the neuromodulatory transmitter serotonin (5-HT) during early postnatal development of the neocortex, we investigated the effects of 5-HT on gap junction coupling in the somatosensory cortex of rats aged between postnatal days 7 and 10. The gap junction-permeable tracer neurobiotin was injected into single neurons via microelectrodes or patch pipettes. Under control conditions, clusters of about 25 tracer-coupled neurons were observed. Serotonin reduced dye-coupling between lamina II/III pyramidal cells in a concentration-dependent and reversible manner. The 1,4,5-inositol triphosphate (IP3) receptor antagonist heparin as well as the protein kinase C inhibitor NPC 15437 suppressed the uncoupling action of 5-HT, suggesting that the serotonergic effect involved IP3 receptor-mediated release of calcium ions from intracellular stores. In contrast, the 5-HT-induced reduction in gap junction coupling was not antagonized by Rp-adenosine-3',5'-cyclic monophosphothionate, an inhibitor of cAMP dependent protein kinase. The uncoupling effect of 5-HT was mimicked by 5-HT2 receptor agonists and antagonized by the 5-HT2 receptor antagonist ritanserin, indicating that 5-HT suppressed gap junction coupling via activation of 5-HT2 class receptors. Our results suggest that the developmental functions of 5-HT not only involve the modulation of chemical synaptic transmission but also include the regulation of the gap junctional communication system during differentiation of the neocortex.

Regulation of gap junction coupling in the developing neocortex.

In the developing mammalian, neocortex gap junctions represent a transient, metabolic, and electrical communication system. These gap junctions may play a crucial role during the formation and refinement of neocortical synaptic circuitries. This article focuses on two major points. First, the influence of gap junctions on electrotonic cell properties will be considered. Both the time-course and the amplitude of synaptic potentials depend, inter alia, on the integration capabilities of the postsynaptic neurons. These capabilities are, to a considerable extent, determined by the electrotonic characteristics of the postsynaptic cell. As a consequence, the efficacy of chemical synaptic inputs may be crucially affected by the presence of gap junctions. The second major topic is the regulation of gap junctional communication by neurotransmitters via second messenger pathways. The monoaminergic neuromodulators dopamine, noradrenaline, and serotonin reduce gap junction coupling via activation of two different intracellular signaling cascades--the cAMP/protein kinase A pathway and the IP3/Ca2+/protein kinase C pathway, respectively. In addition, gap junctional communication seems to be modulated by the nitric oxide (NO)/cGMP system. Since NO production can be stimulated by glutamate-induced calcium influx, the NO/cGMP-dependent modulation of gap junctions might represent a functional link between developing glutamatergic synaptic transmission and the gap junctional network. Thus, it might be of particular importance in view of a role of gap junctions during the process of circuit formation.

Steroid-induced depressive psychosis responsive to electroconvulsive therapy.

We report the case of a 15-year-old girl with acute lymphoblastic leukemia who developed a severe steroid-induced depression, which was rapidly responsive to ECT. This report adds to the growing body of literature supporting ECT as a safe and effective treatment of affective and psychotic disorders in children.

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced dopaminergic denervation potentiates gabaergic inhibition in the mouse neostriatum in vitro.

Using the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson's disease, we investigated the long-term effects of dopaminergic denervation on synaptic transmission in an in vitro slice preparation of the mouse neostriatum. In control mice, electrical stimulation elicited an antidromic potential (N1) followed by a synaptically mediated field potential (N2). In many slices, a third component (N3) was observed. Determination of the maximum stimulus intensities unveiled that in 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine-pretreated animals, the stimulus strength necessary to evoke a maximum N2 response was significantly higher compared to control mice. Furthermore, 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine-pretreatment led to a less frequent appearance and/or to a reduction in the amplitude of the N3 component. Application of glutamate receptor agonists and antagonists revealed two additional differences between normal and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-pretreated mice. (1) Comparison of the efficacy of the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor antagonist 6-cyano-7-nitroquinoxaline-2, 3-dione demonstrated an increase in the inhibitory effect of 6-cyano-7-nitroquinoxaline-2,3-dione in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-pretreated mice. (2) In normal mice, removal of magnesium ions from the bathing solution invariably led to the appearance of late N-methyl-D-aspartate receptor-dependent synaptic components. There components were only slightly expressed or virtually absent in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-pretreated mice. The described differences between the electrophysiological and pharmacological properties of evoked field potentials in slices from normal and 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine-pretreated mice disappeared following blockade of GABAA receptor-dependent inhibition by bicuculline. In normal and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-pretreated mice, bicuculline did not influence the amplitude of the N2 component, but invariably unmasked late synaptic components mediated by glutamate receptors. However, the potentiating effect of bicuculline was significantly stronger in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-pretreated mice compared to the controls. In the presence of bicuculline, the frequency of occurrence of the N3 component was identical in both groups. Furthermore, the apparent efficiency of 6-cyano-7-nitroquinoxaline-2,3-dione was no longer different. Application of bicuculline in the absence of magnesium ions resulted in a similar disinhibition of N-methyl-D-aspartate receptor-dependent late components as observed in the controls in the absence of bicuculline. The data demonstrate that chronic dopaminergic denervation reduces glutamate receptor-dependent synaptic excitation in the mouse neostriatum. Since differences between normal and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-pretreated mice disappear in the presence of bicuculline, we conclude that this reduction in excitability is due to a potentiation of GABAA receptor-dependent inhibition.