SUMMAR Y The aim of the investigations was to explore the nature and the severity of cognitive deficits in narcolepsy patients. In two studies, narcolepsy patients were compared with matched control subjects on a range of attention, memory and executive control tasks. Impairments were only observed on attention and executive function tasks which involved higher demands on inhibition or task management abilities whereas relatively routine memory and attention tasks yielded intact performance in narcolepsy patients. The overall pattern of results indicates an executive control deficit in narcolepsy which might be related to a reduction of available cognitive processing resources because of the need for continuous allocation of resources to monitoring and maintenance of vigilance.

The HMG-domain-containing transcription factor Sox9 is an important regulator of chondrogenesis, testis formation and development of several other organs. Sox9 is expressed in the otic placodes, the primordia of the inner ear, and studies in Xenopus have provided evidence that Sox9 is required for otic specification. Here we report novel and different functions of Sox9 during mouse inner ear development. We show that in mice with a Foxg1(Cre)-mediated conditional inactivation of Sox9 in the otic ectoderm, otic placodes form and express markers of otic specification. However, mutant placodes do not attach to the neural tube, fail to invaginate, and subsequently degenerate by apoptosis, resulting in a complete loss of otic structures. Transmission-electron microscopic analysis suggests that cell-cell contacts in the Sox9 mutant placodes are abnormal, although E-cadherin, N-cadherin, and beta-catenin protein expression are unchanged. In contrast, expression of Epha4 was downregulated in mutant placodes. In embryos with a Keratin-19(Cre)-mediated mosaic inactivation of Sox9, Sox9-negative and Sox9-positive cells in the otic ectoderm sort out from one another. In these embryos only Sox9-positive cells invaginate and form one or several micro-vesicles, whereas Sox9-negative cells stay behind and die. Our findings demonstrate that, in contrast to Xenopus, Sox9 is not required for the initial specification of the otic placode in the mouse, but instead controls adhesive properties and invagination of placodal cells in a cell-autonomous manner.

Ca(2+)-buffer proteins (CaBPs) modulate the temporal and spatial characteristics of transient intracellular Ca(2+)-concentration changes in neurons in order to fine-tune the strength and duration of the output signal. CaBPs have been used as neurochemical markers to identify and trace neurons of several brain loci including the mammalian retina. The CaBP content of retinal neurons, however, varies between species and, thus, the results inferred from animal models cannot be utilised directly by clinical ophthalmologists. Moreover, the shortage of well-preserved human samples greatly impedes human retina studies at the cellular and network level. Our purpose has therefore been to examine the distribution of major CaBPs, including calretinin, calbindin-D28, parvalbumin and the recently discovered secretagogin in exceptionally well-preserved human retinal samples. Based on a combination of immunohistochemistry, Neurolucida tracing and Lucifer yellow injections, we have established a database in which the CaBP marker composition can be defined for morphologically identified cell types of the human retina. Hence, we describe the full CaBP make-up for a number of human retinal neurons, including HII horizontal cells, AII amacrine cells, type-1 tyrosine-hydroxylase-expressing amacrine cells and other lesser known neurons. We have also found a number of unidentified cells whose morphology remains to be characterised. We present several examples of the colocalisation of two or three CaBPs with slightly different subcellular distributions in the same cell strongly suggesting a compartment-specific division of labour of Ca(2+)-buffering by CaBPs. Our work thus provides a neurochemical framework for future ophthalmological studies and renders new information concerning the cellular and subcellular distribution of CaBPs for experimental neuroscience.

Connexin36 (Cx36) constituent gap junctions (GJ) throughout the brain connect neurons into functional syncytia. In the retina they underlie the transmission, averaging and correlation of signals prior conveying visual information to the brain. This is the first study that describes retinal bipolar cell (BC) GJs in the human inner retina, whose function is enigmatic even in the examined animal models. Furthermore, a number of unique features (e.g. fovea, trichromacy, midget system) necessitate a reexamination of the animal model results in the human retina. Well-preserved postmortem human samples of this study are allowed to identify Cx36 expressing BCs neurochemically. Results reveal that both rod and cone pathway interneurons display strong Cx36 expression. Rod BC inputs to AII amacrine cells (AC) appear in juxtaposition to AII GJs, thus suggesting a strategic AII cell targeting by rod BCs. Cone BCs serving midget, parasol or koniocellular signaling pathways display a wealth of Cx36 expression to form homologously coupled arrays. In addition, they also establish heterologous GJ contacts to serve an exchange of information between parallel signaling streams. Interestingly, a prominent Cx36 expression was exhibited by midget system BCs that appear to maintain intimate contacts with bistratified BCs serving other pathways. These findings suggest that BC GJs in parallel signaling streams serve both an intra- and inter-pathway exchange of signals in the human retina.

Narcolepsy is now recognized as a distinctive disorder with specific pathophysiology and neurochemical abnormalities. Findings on the role of the neuropeptide hypocretin are opening new avenues of research and new strategies for therapy. Recently, neuropsychological and electrophysiological studies have provided evidence for reduced memory performance on standard memory tests in addition to subjective complaints of forgetfulness which may be related to changes in attentional processing. Further studies are, however, necessary to clarify the neuropsychological profile in narcolepsy. This review focuses on the recent advances in understanding narcolepsy.