The receptor architecture of the pigeons' nidopallium caudolaterale: an avian analogue to the mammalian prefrontal cortex.

The avian nidopallium caudolaterale is a multimodal area in the caudal telencephalon that is apparently not homologous to the mammalian prefrontal cortex but serves comparable functions. Here we analyzed binding-site densities of glutamatergic AMPA, NMDA and kainate receptors, GABAergic GABA(A), muscarinic M(1), M(2) and nicotinic (nACh) receptors, noradrenergic α(1) and α(2), serotonergic 5-HT(1A) and dopaminergic D(1)-like receptors using quantitative in vitro receptor autoradiography. We compared the receptor architecture of the pigeons' nidopallial structures, in particular the NCL, with cortical areas Fr2 and Cg1 in rats and prefrontal area BA10 in humans. Our results confirmed that the relative ratios of multiple receptor densities across different nidopallial structures (their "receptor fingerprints") were very similar in shape; however, the absolute binding densities (the "size" of the fingerprints) differed significantly. This finding enables a delineation of the avian NCL from surrounding structures and a further parcellation into a medial and a lateral part as revealed by differences in densities of nACh, M(2), kainate, and 5-HT(1A) receptors. Comparisons of the NCL with the rat and human frontal structures showed differences in the receptor distribution, particularly of the glutamate receptors, but also revealed highly conserved features like the identical densities of GABA(A), M(2), nACh and D(1)-like receptors. Assuming a convergent evolution of avian and mammalian prefrontal areas, our results support the hypothesis that specific neurochemical traits provide the molecular background for higher order processes such as executive functions. The differences in glutamate receptor distributions may reflect species-specific adaptations.

Treatment of intracardiac thrombi with argatroban.

Intracardiac thrombi are well known complications associated with diverse cardiac diseases and venous thromboembolism. Therapeutic recommendations like thrombolysis, surgical thrombectomy, or treatment with low molecular heparin and intravenous unfractionated heparin based on small numbers of patients or retrospective case series have failed to reach a consensus. We report on the use of argatroban, a new direct thrombin inhibitor in 4 patients with intracardiac thrombi. Therapy was effective in all patients with complete resolution of thrombi. Treatment was complicated by recurrent strokes with complete neurological recovery in one patient. Therapy of intracardiac thrombi by argatroban is safe and effective. The drug requires no dosage adjustments for age, sex, or renal impairment, including in dialysis-dependent patients. Argatroban has been found to increase predictably activated partial thromboplastin time (aPTT) and activated clotting time (ACT) in a dose-dependent manner.

Dopamine modulation of prefrontal cortex interneurons occurs independently of DARPP-32.

Dopamine (DA) exerts a strong influence on inhibition in prefrontal cortex. The main cortical interneuron subtype targeted by DA are fast-spiking gamma-aminobutyric acidergic (GABAergic) cells that express the calcium-binding protein parvalbumin. D1 stimulation depolarizes these interneurons and increases excitability evoked by current injection. The present study examined whether this direct DA-dependent modulation of fast-spiking interneurons involves DARPP-32. Whole-cell patch-clamp recordings were made from fast-spiking interneurons in brain slices from DARPP-32 knockout (KO) mice, wild-type mice, and rats. Low concentrations of DA (100 nM) increased interneuron excitability via D1 receptors, protein kinase A, and cyclic adenosine 3',5'-monophosphate in slices from both normal and DARPP-32 KO mice. Immunohistochemical staining of slices from normal animals revealed a lack of colocalization of DARPP-32 with calcium-binding proteins selective for fast-spiking interneurons, indicating that these interneurons do not express DARPP-32. Therefore, although DARPP-32 impacts cortical inhibition through a previously demonstrated D2-dependent regulation of GABAergic currents in pyramidal cells, it is not involved in the direct D1-mediated regulation of fast-spiking interneurons.

Dopamine increases inhibition in the monkey dorsolateral prefrontal cortex through cell type-specific modulation of interneurons.

Dopaminergic modulation of the dorsolateral prefrontal cortex (DLPFC) plays an important role in cognitive functions, including working memory. At optimal concentrations, dopamine (DA) enhances pyramidal cell (PC) firing to increase task-related activity. However, spatial and temporal "tuning" of the persistent firing that underlies this mnemonic activity requires inhibitory control from gamma-aminobutyric acidergic (GABAergic) interneurons. How DA modulates the inhibitory control provided by different types of interneurons in the primate cortex is not known. We studied the effects of DA and DA receptor-specific agonists and antagonists on GABAergic inhibition and interneuron excitability in slices from primate DLPFC. Using whole-cell voltage-clamp recordings from layer 2/3 pyramidal neurons, we examined the effects of DA on spontaneous (action potential dependent) and miniature (action potential independent) inhibitory postsynaptic currents. We found that DA can increase inhibition via a presynaptic, action potential-dependent mechanism. In current-clamp recordings from physiologically and morphologically identified interneurons, we investigated the pharmacology and cell type specificity of this effect. DA increased the excitability of fast-spiking (FS), nonadapting interneurons via activation of D1- but not D2-type receptors. In contrast, DA had no effect on interneurons with adapting firing patterns. Thus, DA and D1 receptor activation affect local recurrent circuits by selectively modulating FS interneurons that control the firing of PCs through perisomatic innervation.

Cluster analysis-based physiological classification and morphological properties of inhibitory neurons in layers 2-3 of monkey dorsolateral prefrontal cortex.

In primates, little is known about intrinsic electrophysiological properties of neocortical neurons and their morphological correlates. To classify inhibitory cells (interneurons) in layers 2-3 of monkey dorsolateral prefrontal cortex we used whole cell voltage recordings and intracellular labeling in slice preparation with subsequent morphological reconstructions. Regular spiking pyramidal cells have been also included in the sample. Neurons were successfully segregated into three physiological clusters: regular-, intermediate-, and fast-spiking cells using cluster analysis as a multivariate exploratory technique. When morphological types of neurons were mapped on the physiological clusters, the cluster of regular spiking cells contained all pyramidal cells, whereas the intermediate- and fast-spiking clusters consisted exclusively of interneurons. The cluster of fast-spiking cells contained all of the chandelier cells and the majority of local, medium, and wide arbor (basket) interneurons. The cluster of intermediate spiking cells predominantly consisted of cells with the morphology of neurogliaform or vertically oriented (double-bouquet) interneurons. Thus a quantitative approach enabled us to demonstrate that intrinsic electrophysiological properties of neurons in the monkey prefrontal cortex define distinct cell types, which also display distinct morphologies.

Dopamine modulates excitability of basolateral amygdala neurons in vitro.

The amygdala plays a role in affective behaviors, which are modulated by the dopamine (DA) innervation of the basolateral amygdala complex (BLA). Although in vivo studies indicate that activation of DA receptors alters BLA neuronal activity, it is unclear whether DA exerts direct effects on BLA neurons or whether it acts via indirect effects on BLA afferents. Using whole cell patch-clamp recordings in rat brain slices, we investigated the site and mechanisms through which DA regulates the excitability of BLA neurons. Dopamine enhanced the excitability of BLA projection neurons in response to somatic current injections via a postsynaptic effect. Dopamine D1 receptor activation increased excitability and evoked firing, whereas D2 receptor activation increased input resistance. Current- and voltage-clamp experiments in projection neurons showed that D1 receptor activation enhanced excitability by modulating a 4-aminopyridine- and alpha-dendrotoxin-sensitive, slowly inactivating K+ current. Furthermore, DA and D1 receptor activation increased evoked firing in fast-spiking BLA interneurons. Consistent with a postsynaptic modulation of interneuron excitability, DA also increased the frequency of spontaneous inhibitory postsynaptic currents recorded in projection neurons without changing release of GABA. These data demonstrate that DA exerts direct effects on BLA projection neurons and indirect actions via modulation of interneurons that may work in concert to enhance the neuronal response to large, suprathreshold inputs, while suppressing weaker inputs.