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PubMed1998

Basic fibroblast growth factor promotes the generation and differentiation of calretinin neurons in the rat cerebral cortex in vitro.

Calretinin-expressing neurons are some of the earliest postmitotic cells to appear in the developing cerebral cortex. Lineage studies have shown that the expression of this calcium-binding protein in cortical neurons is not genetically programmed and is likely to be induced by external factors. A number of studies have clearly shown that basic fibroblast growth factor (bFGF) and a number of neurotrophins promote the proliferation and differentiation of cortical progenitor cells to a particular lineage. Here, using a culture system of dissociated rat cortical cells, we found that brain-derived neurotrophic factor and neurotrophin-3 promoted the morphological differentiation of one of the calretinin-containing neuronal subpopulations, the Cajal-Retzius cells. Another subpopulation of calretinin-expressing cells of smaller size and bipolar form was generated when cultures were treated with bFGF. The progenitors of these neurons were stimulated by bFGF to divide a number of times before initiating their differentiation programme. The number of calretinin-expressing neurons increased further when cultures were treated with a combination of bFGF and retinoic acid.

Animals↗
PubMed1998

AMPA receptor subunits are differentially expressed in parvalbumin- and calretinin-positive neurons of the rat hippocampus.

Recent studies suggest a functional diversity of native alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate-type glutamate receptor channels (AMPARs). In several types of interneurons, AMPARs are characterized by higher Ca2+ permeability and faster kinetics than AMPARs in principal cells. We studied the expression profile of AMPAR subunits in the hippocampal parvalbumin (PV)- and calretinin (CR)-positive cells, which represent different populations of non-principal cells. To this end, non-radioactive in situ hybridization with AMPAR subunit specific cRNAs was combined with immunocytochemistry for PV or CR. Double-immunolabelling using antibodies against AMPAR subunits and PV or CR was also performed. PV-containing neurons represent a fairly homogeneous population of cells expressing high levels of GluR-A and GluR-D mRNAs, moderate levels of GluR-C and low levels of GluR-B mRNAs in all the examined regions of hippocampus. The vast majority of CR-containing cells have a much lower expression of GluR-A, -C and -D mRNA than PV-positive neurons, although similarly featuring low levels of GluR-B mRNA. Only a subpopulation of CR-containing cells, the spiny neurons of the dentate gyrus and CA3 region of the hippocampus were characterized by a strong expression of GluR-A and -D subunit mRNAs. The differential pattern found for the AMPAR subunit mRNA expression was confirmed by immunocytochemistry at protein level. Despite the common feature of low GluR-B subunit expression, PV- and CR-containing interneurons differ with respect to the density and combination of their expressed AMPAR subunits. The different combination of subunits might subserve different properties of the AMPA channels featured by these cell types, with implications for the functioning of the hippocampal network.

Animals↗
PubMed1998

Transient features of the thalamic reticular nucleus in the human foetal brain.

The architectonic organization and neuronal types of the human foetal reticular nucleus (RN)--with special reference to transient characteristics--have been investigated using antisera against calretinin, parvalbumin and neurofilament epitopes of somata and dendrites (SMI 311). The RN consists of four subdivisions (clearly distinguishable in the 6/7th gestational month): The main portion appears as a prominent structure on account of its extension and high packing density of neurons which coexpress calretinin and parvalbumin. These two calcium-binding proteins are also expressed by the perireticular nucleus forming a conspicuous grey within the internal capsule. Perireticular cells form clusters which are in continuity with the main portion, globus pallidus, ganglionic eminence and pregeniculate nucleus. In double-labellings, a medial subnucleus stands out distinctly as it only expresses calretinin. SMI 311-immunopreparations show neurons revealing a high degree of diversification and elaborated dendritic trees. Several transient characteristics become obvious: the perireticular nucleus, not visible in the adult, represents a distinct entity in the human foetal brain. The main portion and the pregeniculate nucleus appearing as prominent greys are dramatically reduced in size later on. The percentage of RN-neurons expressing calretinin, the diversity of neuronal types and elaborated dendritic trees are reduced. The transient features can be correlated with the RN's putative functional roles in development: early RN-afferents to the dorsal thalamus may represent pioneer fibres providing guiding cues for outgrowing axons from or into the thalamus. Moreover, the RN may serve as an intermediate target for growing axons which are sorted and directed towards different final targets.

Antibodies, Monoclonal↗
PubMed1999

The paleocortical ventricle is the origin of reelin-expressing neurons in the marginal zone of the foetal human neocortex.

The subpial granular layer (SGL) is a transient cell layer in the cortical marginal zone during the period of neuronal migration into the cortical plate. The origin of the SGL has been studied by immunocytochemistry for calretinin (CR) and reelin in human foetuses from 11 to 40 gestational weeks (GW). At 11 GW, the paleocortical ventricle, a rostral dilatation of the lateral ventricle, gives rise to two fountainheads: a medial fountainhead provides neurons for the marginal zone (MZ) of the rostral cortex and rostral hippocampal rudiment, while multiple cell streams migrate from a lateral fountainhead into the MZ of the paleocortex and insula. The latero-medial gradient of neuronal packing density in the neocortical MZ indicates that migration extends farther into the neocortex. Neurons express CR already in the retrobulbar ventricular zone; they express reelin only as they approach the MZ of the paleocortex and rostral archicortex. At 16/17 GW, large numbers of CR-immunoreactive granule cells originate from the same fountainheads, and then direct medially, toward the surface of the anterior perforated substance, and laterally, into the paleocortical MZ, from where they continue into the neocortical SGL following a ventrolateral to dorsomedial gradient. From 13 to 18 GW, reelin is expressed by a subpopulation of granule cells and by Cajal-Retzius-like neurons. By 22 GW, the paleocortical ventricle undergoes regression and no longer supplies the SGL. Our results show that the paleocortical ventricle gives rise to a stream of neurons which extends over the cortical MZ as the subpial granular layer. The fact that SGL derivatives express reelin suggests that this transient cell layer may play a significant role in the establishment of the complex cytoarchitecture of the cerebral cortex.

Calbindin 2↗
PubMed1999

Hippocampal Cajal-Retzius cells project to the entorhinal cortex: retrograde tracing and intracellular labelling studies.

Cajal-Retzius (CR) cells are characteristic horizontally orientated, early-generated transient neurons in the marginal zones of the neocortex and hippocampus that synthesize the extracellular matrix protein reelin. They have been implicated in the pathfinding of entorhino-hippocampal axons, but their role in this process remained unclear. Here we have studied the axonal projection of hippocampal CR cells. Following injection of the carbocyanine dye DiI into the entorhinal cortex of aldehyde-fixed rat embryos and young postnatal rats, neurons in the outer molecular layer of the dentate gyrus and stratum lacunosum-moleculare of the hippocampus proper with morphological characteristics of CR cells were retrogradely labelled. In a time course analysis, the first retrogradely labelled CR cells were observed on embryonic day 17. This projection of hippocampal CR cells to the entorhinal cortex was confirmed by retrograde tracing with Fast Blue in new-born rats and by intracellular biocytin filling of CR cells in acute slices from young postnatal rat hippocampus/entorhinal cortex and in entorhino-hippocampal slice cocultures using infrared videomicroscopy in combination with the patch-clamp technique. In double-labelling experiments CR cells were identified by their immunocytochemical staining for reelin or calretinin, and their interaction with entorhino-hippocampal axons labelled by anterograde tracers was analysed. Future studies need to investigate whether this early transient projection of hippocampal CR cells to the entorhinal cortex is used as a template by the entorhinal axons growing to their target layers in the hippocampus.

Amidines↗
PubMed2000

The distribution and origin of the calretinin-containing innervation of the nucleus accumbens of the rat.

The nucleus accumbens of the rat consists of several subregions that can be distinguished on the basis of histochemical markers. For example, the calcium-binding protein calbindin D28k is a useful marker of the core compartment of the nucleus accumbens. Calretinin, another calcium-binding protein, is found in a dense fibre plexus in the accumbal shell and septal pole regions. The source of the accumbal calretinin innervation is not known. We examined the distribution of calretinin in the nucleus accumbens and used tract-tracing and lesion methods to determine the source of this calretinin innervation. Intense calretinin immunoreactivity was present in the medial shell, but the density of calretinin axons diminished sharply in the ventrolateral shell. Regions of dense calretinin immunostaining and those areas with calbindin-like immunoreactive cell bodies were generally segregated in the nucleus accumbens, although some overlap in the transition region between the core and shell was seen. Small clusters of calretinin-immunoreactive fibres were seen in the core, where they were restricted to calbindin-negative patches. Injections of the anterograde tracer biotinylated dextran amine into the paraventricular thalamic nucleus labelled fibres in calretinin-rich regions of the accumbens. Conversely, injections of Fluoro-gold into the accumbal shell retrogradely labelled numerous cells in the paraventricular thalamic nucleus that were calretinin-immunoreactive. Electrolytic lesions of the paraventricular thalamic nucleus reduced calretinin levels in the shell by approximately 80%. These data indicate that the calretinin innervation of the nucleus accumbens is derived primarily from the thalamic paraventricular nucleus, and marks accumbal territories that are largely complementary to those defined by calbindin.

Afferent Pathways↗
PubMed2002

Task-dependent and cell-type-specific Fos enhancement in rat sensory cortices during audio-visual discrimination.

Attention modulates neural activities in sensory cortices. Because cortical neurons are composed of many types of neurons, the activities of these different types of cells can exhibit different modifications depending on whether an animal pays attention to a particular sensory stimulus or not. In the present study, we examined which types of cortical neurons change their activities in rats during one of two types of audio-visual discrimination (AVD) tasks by using Fos immunohistochemistry. In the tasks, both auditory and visual stimuli were simultaneously presented but only one of the two modalities was task-relevant. Once the rats had learned one of the AVD tasks, presenting only relevant sensory stimuli was sufficient for them to perform the task correctly. These results suggest that the rats indeed attended to the relevant stimuli during the performance of the tasks. We found that Fos expression in the primary auditory and visual cortices was enhanced in a task-dependent manner during the performance of the AVD tasks. The enhancement of Fos expression depended on the behavioural significance of the stimulus in the tasks. Moreover, using double immunohistochemistry of Fos and a cell type-specific marker protein (phosphate-activated glutaminase, nonphosphorylated neurofilament protein, parvalbumin, calretinin or somatostatin), the task-dependent Fos expression was observed preferentially in excitatory neurons but not in inhibitory interneurons. These results suggest that modulation in cortical excitatory neurons might have critical roles in selecting and processing behaviourally relevant sensory stimuli.

Animals↗
PubMed2002

Molecular phenotype of rat striatal neurons expressing the dopamine D5 receptor subtype.

Dopamine is one of the principal neurotransmitters in the basal ganglia, where it plays a critical role in motor control and cognitive function through its interactions with the specific dopamine receptors D1 to D5. Although the activities mediated by most dopamine receptor subtypes have already been determined, the role of the D5 receptor subtype in the basal ganglia has still not been established. Furthermore, it is often difficult to distinguish between dopamine D5 and D1 receptors as they are stimulated by the same ligands, and they have a similar molecular structure and pharmacology. In an effort to understand the differences between these two receptor subtypes, we have studied the distribution of neurons containing D5 receptors in the striatum, and their molecular phenotype. As a result, we show that the D5 receptor subtype is present in two different populations of striatal neurons, projection neurons and interneurons. Overall, the abundance of this receptor subtype in the striatum is low, particularly in striatal projection neurons of both the direct and indirect projection pathways. In contrast, the expression of D5 receptors in striatal interneurons (cholinergic, somatostatin- or parvalbumin-positive neurons) is high, while low to moderate expression was observed in calretinin-positive neurons. Our results demonstrate the presence of D5 receptors in all the striatal cell populations so far described, although at different intensities in each. The fact that a large number of striatal neurons express the D5 receptor subtype suggests that this receptor fulfils an important function in the process of integrating information in the striatum.

Animals↗
PubMed1998

Innervation of intestinal arteries by axons with immunoreactivity for the vesicular acetylcholine transporter (VAChT).

The presence of a cholinergic innervation of arterioles within the gut wall is suggested by pharmacological studies of nerve mediated vasodilatation, but attempts to identify nerve cells that give rise to cholinergic vasodilator fibres have yielded discrepant results. In the present work, antibodies to the vesicular acetylcholine transporter protein (VAChT) were used to investigate the relationships of immunoreactive nerve fibres to submucosal arterioles. Comparison was made with cerebral arteries, which are known to be cholinergically innervated. Double labelling immunohistochemical techniques revealed separate VAChT and tyrosine hydroxylase (TH) immunoreactive (IR) fibres innervating all sizes of arteries of the submucosa of the stomach, ileum, proximal colon, distal colon and rectum as well as the cerebral arteries. Arterioles of all digestive tract regions had greater densities of TH-IR innervation than VAChT-IR innervation. In the ileum, double labelling for VAChT-IR and VIP-IR or calretinin-IR showed more VAChT-IR than either VIP-IR or calretinin-IR fibres. Calretinin-IR and VAChT-IR were colocalised in a majority of calretinin-IR axons, but VIP-IR and VAChT-IR were not colocalised. All calretinin-IR nerve cells in submucous ganglia were immunoreactive for choline acetyltransferase, but only 1-2% of VIP-IR nerve cells were immunoreactive. Extrinsic denervation of the ileum did not alter the distribution of VAChT-IR fibres, but it eliminated TH-IR fibres. Removal of myenteric ganglia (myectomy) did not alter the distribution of fibres with VAChT or TH-IR. This work thus provides evidence for cholinergic innervation of intrinsic arterioles throughout the digestive tract and indicates that the fibres in the small intestine originate from submucosal nerve cells.

Animals↗
PubMed2003

Differentiation of human retinal pigment epithelial cells into neuronal phenotype by N-(4-hydroxyphenyl)retinamide.

ARPE-19, a human retinal pigment epithelial (RPE) cell line, has been widely used in studies of RPE function as well as gene expression. Here, we report the novel finding that N-(4-hydroxyphenyl)retinamide (fenretinide), a synthetic retinoic acid derivative and a potential chemopreventive agent against cancer, induced the differentiation of ARPE-19 cells into a neuronal phenotype. The treated cells lost their epithelial phenotype and exhibited a typical neuronal shape with long processes (four to five times longer than the cell body). The onset of fenretinide-induced neuronal differentiation was dose and time dependent, started within 1-2 days, and lasted at least 4 weeks. Immunohistochemical studies indicated that the expression of neurofilament proteins (NF160 and NF200), calretinin and neural cell adhesion molecule was increased in these differentiated cells. Western blot analysis indicated that cellular retinaldehyde-binding protein, which is normally expressed in RPE cells, was decreased in treated cells. Protein analysis on a two-dimensional gel followed by matrix-assisted laser desorption ionization-time of flight mass spectrometric analysis demonstrated that heat-shock protein 70 was increased after fenretinide treatment. Thus, fenretinide, a synthetic retinoid, is able to induce neuronal differentiation of human RPE cells in culture.

Amino Acid Sequence↗
PubMed2003

Rat hippocampal GABAergic molecular markers are differentially affected by ageing.

We previously reported that the pharmacological properties of the hippocampal GABAA receptor and the expression of several subunits are modified during normal ageing. However, correlation between these post-synaptic modifications and pre-synaptic deficits were not determined. To address this issue, we have analysed the mRNA levels of several GABAergic molecular markers in young and old rat hippocampus, including glutamic acid decarboxylase enzymes, parvalbumin, calretinin, somatostatin, neuropeptide Y and vasoactive intestinal peptide (VIP). There was a differential age-related decrease in these interneuronal mRNAs that was inversely correlated with up-regulation of the alpha1 GABA receptor subunit. Somatostatin and neuropeptide Y mRNAs were most frequently affected (75% of the animals), then calretinin and VIP mRNAs (50% of the animals), and parvalbumin mRNA (25% of the animals) in the aged hippocampus. This selective vulnerability was well correlated at the protein/cellular level as analysed by immunocytochemistry. Somatostatin interneurones, which mostly innervate principal cell distal dendrites, were more vulnerable than calretinin interneurones, which target other interneurones. Parvalbumin interneurones, which mostly innervate perisomatic domains of principal cells, were preserved. This age-dependent differential reduction of specific hippocampal inteneuronal subpopulations might produce functional alterations in the GABAergic tone which might be compensated, at the post-synaptic level, by up-regulation of the expression of the alpha1 GABAA receptor subunit.

Aging↗
PubMed2000

Vacuolated cell mesothelioma of the pericardium resembling liposarcoma: a case report.

We report a case of localized pericardial mesothelioma with unusual histological features in a 44-year-old woman. Her radiological imagings showed an 11-cm pericardial tumor, between the heart and aortic arch. Microscopically, the tumor was predominantly composed of vacuolated cells and vaguely reminiscent of well differentiated "lipoma-like" liposarcoma, but only small foci of the tumor showed the papillotubular configuration. Histochemically, the tumor cells contained hyaluronic acid in the vacuoles but no lipids. Immunohistochemically, they showed immunoreactivity for cytokeratin, calretinin, vimentin, and epithelial membrane antigen. Ultrastructural study showed that the vacuoles of the tumor cells were intracytoplasmic lumina. The intracytoplasmic lumina and the surface membranes of the tumor cells had many long and slender microvilli with focal bush-like appearance. Desmosomes between adjacent cells were occasionally observed. To our knowledge, this is the first case report of epithelial type mesothelioma predominantly composed of vacuolated tumor cells, microscopically mimicking liposarcoma.

Adult↗
PubMed2003

Expression of calretinin and other mesothelioma-related markers in thymic carcinoma and thymoma.

Thymic carcinoma and thymoma are primary neoplasms of the anterior mediastinum that can involve the lung and pleura in advanced stages or, in rare instances, occur as primary pleural tumors. Thus these tumors may be encountered in thoracic and pleural biopsy specimens. Recognizing the immunohistochemical patterns of calretinin and other mesothelioma-related markers in thymic carcinoma and thymoma may be helpful in avoiding confusion with malignant mesothelioma and pulmonary carcinoma, both of which are major differential diagnoses in this location. Accordingly, in the present study we examined the expression of calretinin, mesothelin, cytokeratin (CK) 5/6, thrombomodulin, HBME-1, Wilms' tumor-1 (WT-1), Ber-EP4, MOC-31, BG-8, B72.3, carcinoembryonic antigen (CEA), CD15, thyroid transcription factor-1 (TTF-1), p63, and CD5 in 22 thymic carcinomas and 35 thymomas, and compared the results with those of malignant mesothelioma and pulmonary adenocarcinoma. Around 1/3 of thymic carcinomas were positive for calretinin and/or mesothelin. Both thymic carcinomas and thymomas were frequently positive for CK 5/6. Immunoreactivity for HBME-1 was seen in 4 thymic carcinomas and 10 thymomas. Except for 1 thymic carcinoma being positive for WT-1, all other thymic carcinomas and thymomas were negative for WT-1 and thrombomodulin. None of the thymic carcinomas and thymomas expressed TTF-1. More than 70% of the thymic carcinomas were positive for Ber-EP4, BG-8, and CD15. The positive rates of MOC-31, B72.3, and CEA in thymic carcinomas were in the middle between those in mesothelioma and pulmonary adenocarcinoma. All thymic epithelial tumors revealed nuclear immunoreactivity for p63. Nine thymic carcinomas (41%) expressed CD5. We found that a panel of positive p63, negative thrombomodulin, WT-1, and TTF-1 is most discriminatory for thymic epithelial tumors. Other mesothelial (calretinin and mesothelin) and epithelial (Ber-EP4, BG-8, and CD15) markers are less contributory in discerning thymic epithelial tumors due to their overlapping expression with malignant mesothelioma and pulmonary adenocarcinoma. Given the complexity of the staining patterns among the different entities, proper immunohistochemical stainings should be selected and interpreted with caution, and correlated with clinicopathologic findings in the differential diagnoses of thoracic biopsy specimens.

Adenocarcinoma↗
PubMed2003

Calretinin expression in human normal and neoplastic tissues: a tissue microarray analysis on 5233 tissue samples.

Calretinin is a calcium-binding protein expressed in different normal and neoplastic tissues. Early studies suggested that calretinin is a useful marker to differentiate adenocarcinomas from malignant mesotheliomas of the lung, but subsequent work has shown that calretinin can be expressed in several other tumor types. To systematically investigate the epidemiology of calretinin expression in normal and neoplastic tissues, we used tissue microarrays (TMAs) to analyze the immunohistochemically detectable expression of calretinin in 5233 tissue samples from 128 different tumor categories and 76 different normal tissue types. At least 1 case with weak expression could be found in 74 of 128 (58%) different tumor types and 46 entities (36%) had at least 1 tumor with strong positivity. In normal tissues, a particularly strong expression was found in Leydig cells of the testis, neurons of the brain, theca-lutein and theca interna cells of the ovary, and mesothelium. In tumors, strong calretinin expression was most frequently found in malignant mesotheliomas (6 of 7), Leydig cell tumors of the testis (5 of 5), adenomas of adrenal gland (5 of 9), and adenomatoid tumors (4 of 9). In summary, calretinin is frequently expressed in many different tumor types. Metastases of various different origins must be included in the differential diagnosis of calretinin-positive pleura tumors.

Biomarkers↗
PubMed2006

Estrogen receptor beta expression in the embryonic brain regulates development of calretinin-immunoreactive GABAergic interneurons.

Our previous studies with estrogen receptor beta knockout (ERbeta(-/-)) mice demonstrated that ERbeta is necessary for embryonic development of the brain as early as embryonic day 14.5 (E14.5) and is involved in neuronal migration. Such early effects of ER were unexpected because estradiol synthesis and action in the brain occur at E18.5. In the present study, we examined the distribution of ERbeta in the developing brain and identified a population of ERbeta-regulated interneurons. ERbeta appears in the brain at E12.5, mainly localized in the wall of the midbrain, neuromere, hypothalamus, thalamus, and basal plate of pons. At E15.5 and E16.5, ERbeta expression increased in the hypothalamus, thalamus, and midbrain and appeared in the limbic forebrain. At E18.5, ERbeta expression was strongly expressed throughout the brain, including the cerebellum and striatum, whereas there were very few positive cells in the ventricular region. In the paraventricular thalamic nucleus and parafascicular nucleus, most of the calretinin-immunopositive interneurons expressed ERbeta. In ERbeta(-/-) mice, calretinin expression was markedly lower than in WT mice in the hippocampus, thalamus, and amygdala both at E16.5 and at E18.5. Epidermal growth factor receptor expression was lower in the cortex of ERbeta(-/-) than in WT mice at E15.5 and, unlike WT mice, was absent from the superficial marginal zone. These findings suggest that ERbeta in the embryonic brain is necessary for the development of calretinin-immunoreactive GABAergic interneurons and for neuronal migration in the cortex through modulating epidermal growth factor receptor expression at middle and later embryonic stages.

Animals↗
PubMed1997

Impaired long-term potentiation induction in dentate gyrus of calretinin-deficient mice.

Calretinin (Cr) is a Ca2+ binding protein present in various populations of neurons distributed in the central and peripheral nervous systems. We have generated Cr-deficient (Cr-/-) mice by gene targeting and have investigated the associated phenotype. Cr-/- mice were viable, and a large number of morphological, biochemical, and behavioral parameters were found unaffected. In the normal mouse hippocampus, Cr is expressed in a widely distributed subset of GABAergic interneurons and in hilar mossy cells of the dentate gyrus. Because both types of cells are part of local pathways innervating dentate granule cells and/or pyramidal neurons, we have explored in Cr-/- mice the synaptic transmission between the perforant pathway and granule cells and at the Schaffer commissural input to CA1 pyramidal neurons. Cr-/- mice showed no alteration in basal synaptic transmission, but long-term potentiation (LTP) was impaired in the dentate gyrus. Normal LTP could be restored in the presence of the GABAA receptor antagonist bicuculline, suggesting that in Cr-/- dentate gyrus an excess of gamma-aminobutyric acid (GABA) release interferes with LTP induction. Synaptic transmission and LTP were normal in CA1 area, which contains only few Cr-positive GABAergic interneurons. Cr-/- mice performed normally in spatial memory task. These results suggest that expression of Cr contributes to the control of synaptic plasticity in mouse dentate gyrus by indirectly regulating the activity of GABAergic interneurons, and that Cr-/- mice represent a useful tool to understand the role of dentate LTP in learning and memory.

Animals↗
PubMed1999

Impaired motor coordination and Purkinje cell excitability in mice lacking calretinin.

In the cerebellum, the parallel fiber-Purkinje cell synapse can undergo long-term synaptic plasticity suggested to underlie motor learning and resulting from variations in intracellular calcium concentration ([Ca2+]i). Ca2+ binding proteins are enriched in the cerebellum, but their role in information processing is not clear. Here, we show that mice deficient in calretinin (Cr-/-) are impaired in tests of motor coordination. An impairment in Ca2+ homeostasis in Cr-/- Purkinje cells was supported by the high Ca2+-saturation of calbindin-D28k in these cells. The firing behavior of Purkinje cells is severely affected in Cr-/- alert mice, with alterations of simple spike firing rate, complex spike duration, and simple spike pause. In contrast, in slices, transmission at parallel fiber- or climbing fiber-Purkinje cell synapses is unaltered, indicating that marked modifications of the firing behavior in vivo can be undetectable in slice. Thus, these results show that calretinin plays a major role at the network level in cerebellar physiology.

Aging↗
PubMed2003

Impaired electroretinogram (ERG) response in apolipoprotein E-deficient mice.

PURPOSE: We investigated the effects of 35 weeks of a cholesterol diet in apolipoprotein E (apoE)-deficient mice on their ERG response. METHODS: C57BL/6J and apoE-deficient mice were fed regular mouse chow (C57-R and ApoE-R, respectively) or a cholesterol-containing diet (C57-C and ApoE-C, respectively). Retinal function was assessed by dark-adapted electroretinography (ERG). Retina tissue was also analyzed by immunohistochemical staining and nucleic acid array expression analysis performed by gene array technology. RESULTS: ApoE-C mice had diminished a- and b-wave amplitudes (60.7% +/- 8.4% (p < 0.005) and 44.8% +/- 10% (p < 0.005) of control values, respectively). Gene expression profiling revealed upregulation of several pro-apoptotic genes. Furthermore, immunohistochemistry showed increased Bax immunoreactivity. CONCLUSIONS: In the hypercholesterolemic mice, we demonstrated a loss of ERG response and induction of apoptotic activity at the gene and protein levels. Our current and previous findings suggest that cholesterol metabolism plays an important role in retinal function.

Animals↗