J. Neurochem. (2012) 121, 99–114. Abstract The microtubule‐associated Stable Tubulie Only Polypeptide (STOP; also known as MAP6) protein plays a key role in neuron architecture and synaptic plasticity, the dysfunctions of which are thought to be implicated in the pathophysiology of psychiatric diseases. The deletion of STOP in mice leads to severe disorders reminiscent of several schizophrenia‐like symptoms, which are also associated with differential alterations of the serotonergic tone in somas versus terminals. In STOP knockout (KO) compared with wild‐type mice, serotonin (5‐HT) markers are found to be markedly accumulated in the raphe nuclei and, in contrast, deeply depleted in all serotonergic projection areas. In the present study, we carefully examined whether the 5‐HT imbalance would lead to behavioral consequences evocative of mood and/or cognitive disorders. We showed that STOP KO mice exhibited depression‐like behavior, associated with a decreased anxiety‐status in validated paradigms. In addition, although STOP KO mice had a preserved very short‐term memory, they failed to perform well in all other learning and memory tasks. We also showed that STOP KO mice exhibited regional imbalance of the norepinephrine tone as observed for 5‐HT. As a consequence, mutant mice were hypersensitive to acute antidepressants with different selectivity. Altogether, these data indicate that the deletion of STOP protein in mice caused deep alterations in mood and cognitive performances and that STOP protein might have a crucial role in the 5‐HT and norepinephrine networks development.

J. Neurochem. (2010) 115, 1579–1594. Abstract The deletion of microtubule‐associated protein stable tubule only polypeptide (STOP) leads to neuroanatomical, biochemical and severe behavioral alterations in mice, partly alleviated by antipsychotics. Therefore, STOP knockout (KO) mice have been proposed as a model of some schizophrenia‐like symptoms. Preliminary data showed decreased brain serotonin (5‐HT) tissue levels in STOP KO mice. As literature data demonstrate various interactions between microtubule‐associated proteins and 5‐HT, we characterized some features of the serotonergic neurotransmission in STOP KO mice. In the brainstem, mutant mice displayed higher tissue 5‐HT levels and in vivo synthesis rate, together with marked increases in 5‐HT transporter densities and 5‐HT1A autoreceptor levels and electrophysiological sensitivity, without modification of the serotonergic soma number. Conversely, in projection areas, STOP KO mice exhibited lower 5‐HT levels and in vivo synthesis rate, associated with severe decreases in 5‐HT transporter densities, possibly related to reduced serotonergic terminals. Mutant mice also displayed a deficit of adult hippocampal neurogenesis, probably related to both STOP deletion and 5‐HT depletion. Finally, STOP KO mice exhibited a reduced anxiety‐ and, probably, an increased helpness‐status, that could be because of the strong imbalance of the serotonin neurotransmission between somas and terminals. Altogether, these data suggested that STOP deletion elicited peculiar 5‐HT disconnectivity.

Acetylcholinesterase (AChE) rapidly hydrolyzes acetylcholine. At the neuromuscular junction, AChE is mainly anchored in the extracellular matrix by the collagen Q, whereas in the brain, AChE is tethered by the proline-rich membrane anchor (PRiMA).The AChE-deficient mice, in which AChE has been deleted from all tissues, have severe handicaps. Surprisingly, PRiMA KO mice in which AChE is mostly eliminated from the brain show very few deficits. We now report that most of the changes observed in the brain of AChE-deficient mice, and in particular the high levels of ambient extracellular acetylcholine and the massive decrease of muscarinic receptors, are also observed in the brain of PRiMA KO. However, the two groups of mutants differ in their responses to AChE inhibitors. Since PRiMA-KO mice and AChE-deficient mice have similar low AChE concentrations in the brain but differ in the AChE content of the peripheral nervous system, these results suggest that peripheral nervous system AChE is a major target of AChE inhibitors, and that its absence in AChE-deficient mice is the main cause of the slow development and vulnerability of these mice. At the level of the brain, the adaptation to the absence of AChE is nearly complete.

Recent evidence underlines the crucial role of neuronal cytoskeleton in the pathophysiology of psychiatric diseases. In this line, the deletion of STOP/MAP6 (Stable Tubule Only Polypeptide), a microtubule-stabilizing protein, triggers various neurotransmission and behavioral defects, suggesting that STOP knockout (KO) mice could be a relevant experimental model for schizoaffective symptoms. To establish the predictive validity of such a mouse line, in which the brain serotonergic tone is dramatically imbalanced, the effects of a chronic fluoxetine treatment on the mood status of STOP KO mice were characterized. Moreover, we determined the impact, on mood, of a chronic treatment by epothilone D, a taxol-like microtubule-stabilizing compound that has previously been shown to improve the synaptic plasticity deficits of STOP KO mice. We demonstrated that chronic fluoxetine was either antidepressive and anxiolytic, or prodepressive and anxiogenic, depending on the paradigm used to test treated mutant mice. Furthermore, control-treated STOP KO mice exhibited paradoxical behaviors, compared with their clear-cut basal mood status. Paradoxical fluoxetine effects and control-treated STOP KO behaviors could be because of their hyper-reactivity to acute and chronic stress. Interestingly, both epothilone D and fluoxetine chronic treatments improved the short-term memory of STOP KO mice. Such treatments did not affect the serotonin and norepinephrine transporter densities in cerebral areas of mice. Altogether, these data demonstrated that STOP KO mice could represent a useful model to study the relationship between cytoskeleton, mood, and stress, and to test innovative mood treatments, such as microtubule-stabilizing compounds. Keywords: antidepressant, anxiety/depression, corticosterone, microtubule-stabilizing compound, serotonin/ norepinephrine transporters, stress. J. Neurochem. (2012) 123, 982-996. Schizophrenia and mood disorders are common, chronic, and debilitating psychiatric illnesses, which have a high prevalence, regardless of countries and cultures, and have a considerable socioeconomic cost (Eaton et al. 2008). For example, unipolar major depression, bipolar disorder, and schizophrenia are ranked first, sixth, and ninth, respectively, in the World Health Organization estimates for diseaserelated lifetime disabilities, and 2% of humans are affected by schizophrenia or bipolar disorder (Lopez et al. 2006;Mathers and Loncar 2006 (Gardiner et al. 2011). Recently, it was found that microtubule deregulation and alterations were related to modifications of integrated brain functions both in animal models and in psychiatric diseases. The first evidence for such a role of cytoskeleton disorganization in psychiatric-like characteristics arises from the deletion in mice of the microtubule-stabilizing protein STOP (Stable Tubule Only Polypeptide, Andrieux et al. 2002). Indeed, STOP knockout (KO) mice exhibit abnormalities of glutamatergic, dopaminergic, acetylcholinergic/nicotinic, serotonergic, and noradrenergic...

Purpose The purpose of this study was to validate a new automated method to locate the fovea on normal and pathological fundus images. Compared to the normative anatomic measures (NAMs), our vessel-based fovea localization (VBFL) approach relies on the retina's vessel structure to make predictions. Methods The spatial relationship between the fovea location and vessel characteristics is learnt from healthy fundus images and then used to predict fovea location in new images. We evaluate the VBFL method on three categories of fundus images: healthy images acquired with different head orientations and fixation locations, healthy images with simulated macular lesions, and pathological images from age-related macular degeneration (AMD). Results For healthy images taken with the head tilted to the side, the NAM estimation error is significantly multiplied by 4, whereas VBFL yields no significant increase, representing a 73% reduction in prediction error. With simulated lesions, VBFL performance decreases significantly as lesion size increases and remains better than NAM until lesion size reaches 200 degrees 2 . For pathological images, average prediction error was 2.8 degrees, with 64% of the images yielding an error of 2.5 degrees or less. VBFL was not robust for images showing darker regions and/or incomplete representation of the optic disk. Conclusions The vascular structure provides enough information to precisely locate the fovea in fundus images in a way that is robust to head tilt, eccentric fixation location, missing vessels, and actual macular lesions. Translational Relevance The VBFL method should allow researchers and clinicians to assess automatically the eccentricity of a newly developed area of fixation in fundus images with macular lesions.

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