Forebrain cholinergic neurons play important roles as striatal local circuit neurons and basal telencephalic projection neurons. The genetic mechanisms that control development of these neurons suggest that most of them are derived from the basal telencephalon where Lhx8, a LIM-homeobox gene, is expressed. Here we report that mice with a null mutation of Lhx8 are deficient in the development of forebrain cholinergic neurons. Lhx8 mutants lack the nucleus basalis, a major source of the cholinergic input to the cerebral cortex. In addition, the number of cholinergic neurons is reduced in several other areas of the subcortical forebrain in Lhx8 mutants, including the caudate-putamen, medial septal nucleus, nucleus of the diagonal band, and magnocellular preoptic nucleus. Although cholinergic neurons are not formed, initial steps in their specification appear to be preserved, as indicated by a presence of cells expressing a truncated Lhx8 mRNA and mRNA of the homeobox gene Gbx1. These results provide genetic evidence supporting an important role for Lhx8 in development of cholinergic neurons in the forebrain.T he mammalian forebrain contains two general types of cholinergic neurons. One group is composed of local circuit neurons, such as the cholinergic interneurons of the striatum (1). These neurons play an important role in the regulation of locomotor behavior through their modulation of ␥-aminobutyric acid (GABA)ergic projection neurons in the striatum (2). The other group consists of projection neurons whose cell bodies can be found in a series of nuclei in the subcortical telencephalon, including the medial septum (also designated as Ch1 cholinergic group by Mesulam et al., ref. 3), the vertical and horizontal limbs of the nucleus of the diagonal band (designated as Ch2 and Ch3, respectively; ref.3), and the basal magnocellular complex (designated as Ch4; ref.3), which comprises cholinergic neurons scattered through the magnocellular preoptic nucleus, substantia innominata, ventral pallidum, and nucleus basalis. The axonal projections of these neurons provide the cerebral cortex and hippocampus with their principal cholinergic input (3-6), which has a critical role in cognitive functions (for reviews, see refs. 7 and 8). Accordingly, abnormalities of the cholinergic projection neurons in the basal forebrain are implicated in neurodegenerative disorders such as Alzheimer's disease (9, 10).The genetic and developmental mechanisms that control the formation of forebrain cholinergic neurons are just beginning to be elucidated. The vast majority of forebrain cholinergic neurons derive from a region of the subcortical telencephalon that expresses the Nkx2-1 homeobox gene (11,12). This region contains different progenitor zones, including the medial ganglionic eminence (MGE), anterior entopeduncular area and preoptic area (POa) (13). It has been proposed that these progenitor domains contribute projection neurons to the globus pallidus, ventral pallidum, nucleus of the diagonal band, and parts of the septum and amygd...

This study demonstrates a novel mechanism behind endothelial dysfunction in T2DM that is induced by RBC arginase I and ROS. Targeting arginase I in RBCs may serve as a novel therapeutic tool for the treatment of endothelial dysfunction in T2DM.

Summary:Purpose: The possible role of gap junctions in the manifestation and control of the duration of seizures was tested on the 4-aminopyridine-induced epilepsy model in rats in vivo, by using electrophysiologic, pharmacologic, and molecular biologic techniques.Methods: In electrophysiologic experiments, the functional states of the gap junctions were manipulated with a specific blocker (carbenoxolone) or opener (trimethylamine) at the already active focus of adult, anesthetized rats, 60 min after the induction of the first seizure, which was repeated spontaneously thereafter. Semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR) amplification was used to measure the levels of connexin (Cx) 32, 43, and 36 messenger RNAs (mRNAs) prepared from the areas of the already active primary and mirror foci.Results: After repeated seizures, the expression levels of Cx32, Cx43, and Cx36 mRNAs at the epileptic foci were increased significantly. Blockade of the gap junctions with carbenoxolone shortened the duration of seizures and decreased the amplitude of the seizure discharges, whereas their opening with trimethylamine lengthened the duration and increased the amplitude. Secondary epileptogenesis was facilitated when the gap junctions were opened.Conclusions: Our findings support the idea that, in epileptic foci, the gap junctions are involved in the expression of rhythmic ictal discharges and in the control of the duration and propagation of the individual seizures in vivo. Key Words: Connexins-Gap junctions-4-AP-induced seizureCarbenoxolone-Trimethylamine.Gap junctions are dynamic structures that can be modulated by a number of intracellular and extracellular factors (1-6). The extent of coupling in the in vitro seizure models (7-10) is periodic: it is increased by alkalinization at the start of a seizure, and decreased as acidification occurs toward the end of an ictal period.Our previous work (11) revealed noteworthy upregulations of connexin (Cx)32 and Cx43 mRNAs after repeated seizures both at the primary focus (Pf) and at the mirror focus (Mf, homotopic area contralateral to the Pf). Accordingly, we examined whether manipulation of the functional state of the gap junctions with a specific blocker (carbenoxolone) or opener (trimethylamine, TMA) influences the manifestation, duration, and propagation of seizures. We also were interested in whether repeated seizures influence the expression of the Cx36 gene, coding for a gap-junction protein existing predominantly in neuronal cells of the mature brain (13).

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The mammalian pituitary gland originates from two separate germinal tissues during embryonic development. The anterior and intermediate lobes of the pituitary are derived from Rathke's pouch, a pocket formed by an invagination of the oral ectoderm. The posterior lobe is derived from the infundibulum, which is formed by evagination of the neuroectoderm in the ventral diencephalon. Previous studies have shown that development of Rathke's pouch and the generation of distinct populations of hormone-producing endocrine cell lineages in the anterior/intermediate pituitary lobes is regulated by a number of transcription factors expressed in the pouch and by inductive signals from the ventral diencephalon/infundibulum. However, little is known about factors that regulate the development of the posterior pituitary lobe. In this study, we show that the LIM-homeobox gene Lhx2 is extensively expressed in the developing ventral diencephalon, including the infundibulum and the posterior lobe of the pituitary. Deletion of Lhx2 gene results in persistent cell proliferation, a complete failure of evagination of the neuroectoderm in the ventral diencephalon, and defects in the formation of the distinct morphological features of the infundibulum and the posterior pituitary lobe. Rathke's pouch is formed and endocrine cell lineages are generated in the anterior/intermediate pituitary lobes of the Lhx2 mutant. However, the shape and organization of the pouch and the anterior/intermediate pituitary lobes are severely altered due to the defects in development of the infundibulum and the posterior lobe. Our study thus reveals an essential role for Lhx2 in the regulation of posterior pituitary development and suggests a mechanism whereby development of the posterior lobe may affect the development of the anterior and intermediate lobes of the pituitary gland.

These data provide morphological, functional, and molecular evidence that the endothelial cells in capillaries adjacent to the MP is a target of diabetic damage in a regional manner.

Summary: Purpose:The functional significance of gapjunction (GJ) channels in seizure susceptibility and induction and maintenance of seizures in the developing rat brain was investigated on the 4-aminopyridine (4-AP) in vivo epilepsy model. Methods:In electrophysiological experiments, GJs were manipulated with a blocker or opener before induction or at the active epileptic foci between postnatal days 9 and 28 (P9-28). Semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR) amplification was used to measure the levels of connexin (Cx) 26, 32, 36, and 43 mRNAs at the untreated cortex or epileptic foci.Results: The basic electrocorticogram (ECoG) and Cx messenger RNA (mRNA) expression patterns exhibited characteristic maturation; the 4-AP-induced epileptiform activity correlated well with these changes. Cx mRNA expressions were significantly upregulated around P16 (except for Cx26). The Cx26, 36, and 43 gene inducibility was highest around P16 and then declined significantly. In the youngest animals, the GJ opener induced rhythmic synchronous cortical activity. On maturation, the seizures became focalized and periodic; the discharges accelerated their amplitude and frequency increase. A transient decrease (P13-14) and then increase (P15-16) in seizure susceptibility were followed by a tendency to periodicity and focalization.Conclusions: The study suggests that GJ communication is involved in rhythm genesis and synchronization of cortical activity and may enhance the epileptogenicity of the developing brain.Key Words: Gap junction channelsSynchrony-Connexins-Development-Epileptogenicity-4-Aminopyridine.Clinical experience and various experimental data indicate that the developing nervous system is more sensitive than the mature one to different convulsive effects (1-5). Although the physiological factors underlying this differential epileptogenicity have not been fully clarified, the higher susceptibility of the immature brain can be explained by certain characteristic neurobiologic features. The developing brain exhibits a high metabolic rate, abundant neuronal and synaptic networks, the overexpression of receptors and enzymes, the depolarizing effect of γ -amino-acid, the hypersynchrony of neuronal circuits, and enhanced synaptic plasticity (6,7). In addition, the immature cerebral cortex and hippocampus have higher densities of excitatory amino acid receptors and gap junction (GJ) channels as compared with the adult organs (4,8).Intercellular communication via GJ channels is an important form of cell-to-cell communication in early brain development (8)(9)(10)(11)(12)(13)(14). Electrical coupling via GJ channels has been reported both between pairs of inhibitory neurons and among inhibitory and excitatory neurons during the Accepted January 30, 2006. Address correspondence and reprint requests to Dr. M. Szente at Department of Comparative Physiology, University of Szeged, Közép fasor 52, H-6726 Szeged, Hungary. E-mail: szente@bio.u-szeged.hu early postnatal days in the rat cortex (10). Moreover,...