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PubMed2005

Participation of autophagy in storage of lysosomes in neurons from mouse models of neuronal ceroid-lipofuscinoses (Batten disease).

In cathepsin D-deficient (CD-/-) and cathepsins B and L double-deficient (CB-/-CL-/-) mice, abnormal vacuolar structures accumulate in neurons of the brains. Many of these structures resemble autophagosomes in which part of the cytoplasm is retained but their precise nature and biogenesis remain unknown. We show here how autophagy contributes to the accumulation of these vacuolar structures in neurons deficient in cathepsin D or both cathepsins B and L by demonstrating an increased conversion of the molecular form of MAP1-LC3 for autophagosome formation from the cytosolic form (LC3-I) to the membrane-bound form (LC3-II). In both CD-/- and CB-/-CL-/- mouse brains, the membrane-bound LC3-II form predominated whereas MAP1-LC3 signals accumulated in granular structures located in neuronal perikarya and axons of these mutant brains and were localized to the membranes of autophagosomes, evidenced by immunofluorescence microscopy and freeze-fracture-replica immunoelectron microscopy. Moreover, as in CD-/- neurons, autofluorescence and subunit c of mitochondrial ATP synthase accumulated in CB-/-CL-/- neurons. This suggests that not only CD-/- but also CB-/-CL-/- mice could be useful animal models for neuronal ceroid-lipofuscinosis/Batten disease. These data strongly argue for a major involvement of autophagy in the pathogenesis of Batten disease/lysosomal storage disorders.

Animals↗
PubMed2002

Neuronal apoptosis inhibitory protein: Structural requirements for hippocalcin binding and effects on survival of NGF-dependent sympathetic neurons.

Neuronal apoptosis inhibitory protein (NAIP) has been linked to the inherited disease, spinal muscular atrophy (SMA), which occurs in children with degeneration of the motorneurons. In the nervous system, NAIP is expressed by specific classes of neurons including spinal motorneurons. Recently, NAIP was shown to interact with hippocalcin, which belongs to the neuronal calcium sensor (NCS) protein family. Here we have studied this interaction in more detail, using deletions and a mutagenesis of the third baculovirus inhibitory repeat (BIR) motif in NAIP, and functional assays for neuronal death. The results showed that specific amino acids and the zinc finger domain in BIR3 are needed for efficient interaction of NAIP with hippocalcin. Cotransfections of NAIP-BIR3 and hippocalcin resulted in translocation and colocalisation of the two proteins in neuroblastoma cells. This was accompanied by an enhanced resistance towards cell death induced by high levels of calcium. In contrast, expression of NAIP-BIR3 and hippocalcin in sympathetic neurons did not protect against death induced by nerve growth factor (NGF) withdrawal. The results demonstrate a functional interaction of hippocalcin with NAIP-BIR3, which in neuroblastoma cells leads to rescue of cells after high intracellular calcium, but which in sympathetic neurons had no significant effect. The results indicate that NAIP in conjunction with hippocalcin can affect the survival of some, but not all neural cells, and this interaction may play a role in the neurodegenerative processes in SMA, and possible other human disorders.

Animals↗
PubMed1994

The neuronal chondroitin sulfate proteoglycan neurocan binds to the neural cell adhesion molecules Ng-CAM/L1/NILE and N-CAM, and inhibits neuronal adhesion and neurite outgrowth.

We have previously shown that aggregation of microbeads coated with N-CAM and Ng-CAM is inhibited by incubation with soluble neurocan, a chondroitin sulfate proteoglycan of brain, suggesting that neurocan binds to these cell adhesion molecules (Grumet, M., A. Flaccus, and R. U. Margolis. 1993. J. Cell Biol. 120:815). To investigate these interactions more directly, we have tested binding of soluble 125I-neurocan to microwells coated with different glycoproteins. Neurocan bound at high levels to Ng-CAM and N-CAM, but little or no binding was detected to myelin-associated glycoprotein, EGF receptor, fibronectin, laminin, and collagen IV. The binding to Ng-CAM and N-CAM was saturable and in each case Scatchard plots indicated a high affinity binding site with a dissociation constant of approximately 1 nM. Binding was significantly reduced after treatment of neurocan with chondroitinase, and free chondroitin sulfate inhibited binding of neurocan to Ng-CAM and N-CAM. These results indicate a role for chondroitin sulfate in this process, although the core glycoprotein also has binding activity. The COOH-terminal half of neurocan was shown to have binding properties essentially identical to those of the full-length proteoglycan. To study the potential biological functions of neurocan, its effects on neuronal adhesion and neurite growth were analyzed. When neurons were incubated on dishes coated with different combinations of neurocan and Ng-CAM, neuronal adhesion and neurite extension were inhibited. Experiments using anti-Ng-CAM antibodies as a substrate also indicate that neurocan has a direct inhibitory effect on neuronal adhesion and neurite growth. Immunoperoxidase staining of tissue sections showed that neurocan, Ng-CAM, and N-CAM are all present at highest concentration in the molecular layer and fiber tracts of developing cerebellum. The overlapping localization in vivo, the molecular binding studies, and the striking effects on neuronal adhesion and neurite growth support the view that neurocan may modulate neuronal adhesion and neurite growth during development by binding to neural cell adhesion molecules.

Aggrecans↗
PubMed2001

Differential regulation of GABA release and neuronal excitability mediated by neuropeptide Y1 and Y2 receptors in rat thalamic neurons.

1. Neuropeptide Y (NPY) produced inhibitory effects on neurons of the thalamic reticular nucleus (RT; n = 18) and adjacent ventral basal complex (VB; n = 22), which included hyperpolarization (approximately 4 mV), a reduction in rebound and regular spikes and an increased membrane conductance. These effects were mediated predominantly via NPY1 receptor activation of G-protein-activated, inwardly rectifying K+ (GIRK) channels. 2. NPY reduced the frequency of spontaneous GABAA receptor-mediated inhibitory postsynaptic currents (sIPSCs) in RT (by 60 +/- 7 %, n = 14) and VB neurons (by 25 +/- 11 %, n = 16), but had no effect on the kinetic properties of sIPSCs. After removal of the RT nucleus, the inhibitory effects of NPY on sIPSCs in VB neurons remained (29 +/- 7 %, n = 5). The synaptic effects were mediated via NPY2 receptors. 3. NPY inhibited the frequency of miniature IPSCs (mIPSCs) in RT and VB neurons (by 63 +/- 7 %, n = 5, and 37 +/- 8 %, n = 10, respectively) in the presence of tetrodotoxin (TTX) (1 microM) but not TTX (1 microM) and Cd2+ (200 microM). 4. NPY inhibited evoked IPSCs in both RT (by 18 +/- 3 %, n = 6) and VB (by 5 +/- 4 %, n = 6) neurons without change in short-term synaptic plasticity. 5. We conclude that NPY1 and NPY2 receptors are functionally segregated in the thalamus: NPY1 receptors are predominantly expressed at the somata and dendrites and directly reduce the excitability of neurons in both the RT and VB nuclei by activating GIRK channels. NPY2 receptors are located at recurrent (RT) and feed-forward GABAergic terminals (VB) and downregulate GABA release via inhibition of Ca2+ influx from voltage-gated Ca2+ channels.

Animals↗
PubMed2005

Loss of ALS2 function is insufficient to trigger motor neuron degeneration in knock-out mice but predisposes neurons to oxidative stress.

Amyotrophic lateral sclerosis (ALS), the most common motor neuron disease, is caused by a selective loss of motor neurons in the CNS. Mutations in the ALS2 gene have been linked to one form of autosomal recessive juvenile onset ALS (ALS2). To investigate the pathogenic mechanisms of ALS2, we generated ALS2 knock-out (ALS2(-/-)) mice. Although ALS2(-/-) mice lacked obvious developmental abnormalities, they exhibited age-dependent deficits in motor coordination and motor learning. Moreover, ALS2(-/-) mice showed a higher anxiety response in the open-field and elevated plus-maze tasks. Although they failed to recapitulate clinical or neuropathological phenotypes consistent with motor neuron disease by 20 months of age, ALS2(-/-) mice or primary cultured neurons derived from these mice were more susceptible to oxidative stress compared with wild-type controls. These observations suggest that loss of ALS2 function is insufficient to cause major motor deficits or motor neuron degeneration in a mouse model but predisposes neurons to oxidative stress.

Amyotrophic Lateral Sclerosis↗
PubMed1996

Mitochondrial- and nuclear-encoded subunits of cytochrome oxidase in neurons: differences in compartmental distribution, correlation with enzyme activity, and regulation by neuronal activity.

Cytochrome oxidase (CO), a mitochondrial energy-generating enzyme, contains both mitochondrial- and nuclear-encoded subunits. In neurons, local levels of CO activity vary among different neuronal compartments, reflecting local demands for energy. The goals of the present study were to determine if compartmental distribution of CO subunit proteins from the two genomes was correlated with local CO activity, and if their expression was regulated proportionately in neurons. The subcellular distributions of mitochondrial-encoded CO III and nuclear-encoded CO Vb proteins were quantitatively analyzed in mouse cerebellar sections subjected to postembedding immunocytochemistry. Local levels of subunit proteins were also compared to local CO activity, as revealed by CO cytochemistry. In order to study the regulation of subunit protein expression, we assessed changes in immunoreactivity of the two CO subunits as well as changes in CO activity in mouse superior colliculus after 1 to 7 days of monocular enucleation. We found that immunoreaction product for both CO III and CO Vb existed almost exclusively in mitochondria, but their compartmental distributions were different. CO III was nonhomogeneously distributed among different neuronal compartments, where its local level was positively correlated with that of CO activity. In contrast, the subcellular distribution of CO Vb was relatively uniform and did not bear a direct relationship with that of CO activity. Moreover, the two subunit proteins were disproportionately regulated by neuronal activity. CO III and CO activity exhibited parallel decreases after the deprivation of afferent input, and their changes were earlier and to a greater degree than that of CO Vb proteins. Thus, the present findings indicate that the local expression and/or distribution of CO subunit proteins from the two genomes may involve different regulatory mechanisms in neurons. Our data also suggest that the activity-dependent regulation of mitochondrial-encoded CO subunits is likely to play a major role in controlling the local levels of CO content and its activity.

Amino Acid Sequence↗
PubMed1996

Distinct effects of recombinant tenascin-C domains on neuronal cell adhesion, growth cone guidance, and neuronal polarity.

Using a set of recombinantly expressed proteins, distinct domains of the mouse extracellular matrix glycoprotein tenascin-C, hereafter called tenascin, have been identified to confer adhesion, anti-adhesion, and changes in morphology of neuronal cells. In short-term adhesion assays (1 hr), cerebellar and hippocampal neurons adhered to several domains, encompassing the fibronectin type III-like (FN III) repeats 1-2 and 6-8, as well as to the alternatively spliced FN III repeats and to tenascin itself. Although no short-term adhesion to the EGF repeats containing fragment could be detected under the conditions used, it was anti-adhesive for neuronal cell bodies and repellent for growth cone advance and neuritogenesis. FN III repeats 3-5 were repellent only for growth cones but not for neuronal cell bodies. Neurite outgrowth promoting activities at early stages and induction of a polarized neuronal morphology at later stages of differentiation were associated with the EGF repeats and the FN III repeats 6-8. These observations suggest differential effects of particular domains of the tenascin molecule on distinct cellular compartments, i.e., cell body, axon and dendrite, and existence of multiple neuronal receptors with distinct intracellular signaling features.

Animals↗
PubMed1997

Expression of DA11, a neuronal-injury-induced fatty acid binding protein, coincides with axon growth and neuronal differentiation during central nervous system development.

DA11 is the first fatty acid binding protein (FABP) for which gene expression has been shown to be upregulated following neuronal injury in the adult peripheral nervous system. To understand better the potential regulatory role(s) of this unique FABP in axonal growth and neuronal differentiation, we undertook a temporal and spatial study of DA11 gene expression in the developing rat central nervous system (CNS). Transient upregulation of DA11 mRNA and protein levels in CNS tissues were quantified by Northern blot hybridization and Western immunoblot analyses at different developmental ages. Homogenates of embryonic and neonatal cerebral cortex, cerebellum, brain stem, and hippocampal tissues contained 100-fold more DA11 mRNA and protein than corresponding adult tissues. Significant increase in DA11 mRNA was observed as early as embryonic day (E) 14 in cerebral cortex and cerebellum and E19 in brain stem and hippocampus. Postnatal levels of DA11 remained elevated through postnatal day (P) 10 in cerebral cortex, P14 in brain stem and hippocampus, and P20 in cerebellum. Localization of DA11-like immunoreactivity to specific CNS tissues, cell types, and intracellular compartments at P9 revealed a spatial pattern of neuronal expression different than that reported for other FABPs. DA11 protein was detected in the nucleus, cytoplasm, axons, and dendrites of differentiating neurons in cerebral cortex, hippocampus, cerebellum, brain stem, spinal cord, and olfactory bulb. The strong association of DA11 gene expression with development throughout the CNS suggests that this unique FABP plays an important role in axonal growth and neuronal differentiation in many different neuronal populations.

Animals↗
PubMed2005

Neuronal pentraxin with chromo domain (NPCD) is a novel class of protein expressed in multiple neuronal domains.

The receptor tyrosine phosphatase PTPRO is involved in axon guidance, but its intracellular signaling mechanisms are unknown. Signals generated through PTPRO must involve interaction of the intracellular domain with substrates and/or signaling proteins. By screening for proteins interacting with PTPRO's intracellular domain, we have identified a new class of cytoplasmic protein. This novel protein, NPCD (Neuronal Pentraxin with Chromo Domain), has multiple cytoplasmic isoforms generated by alternative splicing that are selectively expressed in neurons. These cytoplasmic NPCD isoforms are composed of a neuronal pentraxin domain (formerly thought exclusively extracellular) linked to a chromo domain (formerly thought exclusively nuclear); this protein motif organization is unprecedented. NPCD isoforms are expressed in numerous regions of the central nervous system, where they are present in distinct subcellular arrangements in different brain regions. NPCD isoforms are mainly associated with the inner side of the plasma membrane in brain neurons and rat PC12 cells in vitro; they are present in cell bodies, processes, and growth cones. The biochemical complexity and neuronal expression pattern of NPCD, together with its interaction with PTPRO, suggests involvement in multiple neuronal processes.

Animals↗
PubMed2006

Reevaluation of Drosophila melanogaster's neuronal circadian pacemakers reveals new neuronal classes.

In the brain of the fly Drosophila melanogaster, approximately 150 clock-neurons are organized to synchronize and maintain behavioral rhythms, but the physiological and neurochemical bases of their interactions are largely unknown. Here we reevaluate the cellular properties of these pacemakers by application of a novel genetic reporter and several phenotypic markers. First, we describe an enhancer trap marker called R32 that specifically reveals several previously undescribed aspects of the fly's central neuronal pacemakers. We find evidence for a previously unappreciated class of neuronal pacemakers, the lateral posterior neurons (LPNs), and establish anatomical, molecular, and developmental criteria to establish a subclass within the dorsal neuron 1 (DN1) group of pacemakers. Furthermore, we show that the neuropeptide IPNamide is specifically expressed by this DN1 subclass. These observations implicate IPNamide as a second candidate circadian transmitter in the Drosophila brain. Finally, we present molecular and anatomical evidence for unrecognized phenotypic diversity within each of four established classes of clock neurons.

Animals↗
PubMed1981

Neuronal types in the deep dorsal cochlear nucleus of the cat: I. Giant neurons.

Large or "giant" neurons (average somatic diameter greater than 22 micron) of the dorsal cochlear nucleus (DCN) have been carefully described in this light (LM) and electron (EM) microscopic study of normal Nissl-stained and Golgi-impregnated cat brain stems. These neurons can be roughly classed by somatic shape (width:length ratio = r) as elongate (r less than 0.65), ovoid (0.65 less than or equal to r less than 0.75), or spherical (0.75 less than or equal to r less than or equal to 1.0) in Nissl-stained sections. However, orientation and location of somata, size, number, and distribution of basal dendrites and other cytological features seen in Nissl material provided five, easily recognized classes of large neurons: elongate bipolar, elongate multipolar, globular, radiate, and oriented multipolar giant cells. Further cytological details of the dendritic tree and axonal morphology of these neurons, observed in rapid Golgi impregnations of cat and kitten brain stems, extended these descriptive categories of giant neurons. These same deep DCN giant cells were identified in thick plastic sections and in subsequent thin sections. Thin sections showed further neuronal distinctions by relative density of somatic and dendritic synaptic inputs. All giant cells have dense synaptic inputs to basal and primary dendrites but only elongate multipolar and radiate giant cell somata have nearly continuous synaptic coverage of somata. Many axodendritic terminals and some axosomatic endings resemble cochlear endings as identified on fusiform cells of the DCN. Nauta preparations after ipsilateral cochlear ablations have confirmed (1) cochlear input to all giant cell types and (2) different patterns of input to each type. Hence, each giant cell type must process incoming auditory signals, but each cell must receive slightly different primary information. Since some giant cells of each type had observable axons heading into the dorsal acoustic stria, they must all carry encoded primary information to higher auditory centers.

Animals↗
PubMed1985

Degeneration of thalamic neurons in "Purkinje cell degeneration" mutant mice. I. Distribution of neuron loss.

The Purkinje cell degeneration (pcd) mutation of the mouse is an autosomal recessive allele which previous studies have shown to be the cause of rapid degeneration of nearly all cerebellar Purkinje cells between 18 and 30 postnatal days of age (P18-P30), and slowly developing, progressive losses of retinal photoreceptor cells and mitral cells of the olfactory bulb. Through examination of serial frozen sections alternately stained for Nissl substance and for degenerating neuronal processes, we have found that discrete populations of thalamic neurons degenerate rapidly between P50 and P60. Severely affected nuclei, in which a majority of neurons degenerate, include the central division of the mediodorsal nucleus, the ventral medial geniculate, posterior, posterior ventromedial, and submedial nuclei, and those portions of the ventrolateral and posteromedial nuclei which immediately surround the medial division of the ventrobasal complex. More subtle cell losses occur during the same time period in restricted portions of the lateral ventrobasal, dorsal lateral geniculate, and lateral posterior nuclei, but even at P180 these nuclei are not markedly atrophic. No common denominator among target cell populations has been established. The pcd allele affects a diverse assortment of specific relay nuclei; degeneration has not been recognized in thalamic nuclei characterized primarily or exclusively by subcortical projections or by cortical projections directed relatively selectively to superficial or deep cortical laminae. The neuronal degenerations in the thalamus are not precipitated by prior or concurrent degeneration of cortical targets or afferent sources, though striking transneuronal changes, including cell death, do develop following thalamic neuronal degeneration in this mutant. No previously described murine mutant phenotype includes the rapid degeneration of highly restricted neuronal populations beginning at these relatively advanced ages.

Aging↗
PubMed1985

Distribution of central cholinergic neurons in the baboon (Papio papio). II. A topographic atlas correlated with catecholamine neurons.

The topographic distribution of central cholinergic and catecholaminergic neurons has been investigated in the baboon (Papio papio). The perikarya were mapped on an atlas through the brain and spinal cord employing sections processed for acetylcholinesterase (AChE) pharmacohistochemistry coupled with choline acetyltransferase (ChAT) immunohistochemistry or aqueous catecholamine-fluorescence histochemistry. Compared with subprimates, there is a remarkable increase in the volume occupied by and the number of cholinergic cells contained in the nucleus basalis and nucleus tegmenti pedunculopontinus (subnucleus compacta). The elaboration of these parts of the cholinergic system is accompanied by a large extension of catecholaminergic cell groups in the midbrain (groups A8-A10), particularly the substantia nigra (pars compacta), and in the dorsolateral pontine tegmentum (A5-A7 complex). Although cholinergic and catecholaminergic soma generally occupy distinctly different regions of the brain, a close apposition of cholinergic and noradrenergic neurons occurs in the dorsolateral pontine tegmentum. In the peripeduncular region ChAT-positive cells and green fluorescent neurons of the A6-A7 complex form parallel lines and do not intermingle as has previously been demonstrated in the cat. Two distribution patterns, aggregated or disseminated, are another common feature of central cholinergic and catecholaminergic perikarya. The cholinergic neurons in the nucleus tegmenti pedunculopontinus and the catecholaminergic neurons in A6-A7 complex display both patterns. This comparative study of three transmitter systems in the baboon suggests that the cholinergic as well as the catecholaminergic neurons that give rise to ascending telencephalic and dorsal diencephalic projections undergo phylogenetic development in terms of cell number and nuclear volume.

Acetylcholinesterase↗
PubMed1988

GABAergic basal forebrain neurons project to the neocortex: the localization of glutamic acid decarboxylase and choline acetyltransferase in feline corticopetal neurons.

Our objective was to determine whether GABAergic and cholinergic basal forebrain neurons project to the neocortex. The retrograde connectivity marker wheat germ agglutinin lectin-bound horseradish peroxidase was injected into the neocortex of adult cats. Histo- and immunohistochemical methods were combined to label sequentially connectivity and transmitter markers (glutamic acid decarboxylase; choline acetyltransferase) in forebrain neurons. The labels of each marker were identified by correlative light and electron microscopy. Two principal types of doubly labeled neurons were demonstrated. The connectivity marker was colocalized with glutamic acid decarboxylase or choline acetyltransferase. The neurons were located in the basal forebrain. Their ultrastructural, cellular, and regional organization supported 2 conclusions. (1) GABAergic basal forebrain neurons project to the neocortex. This is important new morphological evidence for the origin of inhibitory neocortical afferents from a subcortical brain site. (2) The GABAergic and cholinergic basal forebrain neurons projecting to the neocortex exhibit remarkable structural similarities. The transmitter diversity of these intertwined neocortical afferents may be significant for the pathology and treatment of human neurological disorders such as Alzheimer's disease.

Animals↗
PubMed1990

Galanin immunoreactive neurons in the human hypothalamus: colocalization with vasopressin-containing neurons.

Galanin (GA) is a recently described neuropeptide that has been demonstrated to be widely distributed in the hypothalamus of experimental animals. So far there is no immunohistochemical description of GA in the human hypothalamus and, in particular, no studies of the colocalization of this neuropeptide with other transmitter candidates in the human hypothalamus. We have now investigated this question immunohistochemically by using human brains fixed by vascular perfusion within 24 hours of death. Nerve cell bodies and fibers stained for GA were observed throughout the hypothalamus. Major populations of GA-ir cell bodies were found in the suprachiasmatic, intermediate, supraoptic, paraventricular, arcuate, tuberomammillary, and supramammillary nuclei. Scattered positive neurons were found in the periventricular preoptic area, the posterior hypothalamic nucleus, the lateral hypothalamic area, and zona incerta. A few positive cells were located in the dorsomedial and ventromedial hypothalamic nuclei. The number of GA-ir neurons estimated from three brains was 11,100 +/- 2,400 for the intermediate nucleus, 57,800 +/- 9,100 for the supraoptic nucleus and 47,400 +/- 13,900 for the paraventricular nucleus. GA-ir fibers were widely distributed in the hypothalamus. They were more dense in the periventricular and medial hypothalamic zones, whereas the lateral tuberal nuclei and the dorsolateral part of the supraoptic nucleus contained sparse positive fibers. The mammillary complex contained almost no GA-ir fibers. In the ventromedial tuberal region, GA-ir axons formed bundles travelling down in the infundibular stem. In the median eminence the vascular plexus was wrapped by GA-ir fiber networks. The coexistence of GA with arginine vasopressin (AVP), oxytocin (OXY), and tyrosine hydroxylase (TH) was examined in the supraoptic, paraventricular, and suprachiasmatic nuclei in adjacent paraffin sections. Neurons containing both GA and AVP were very common in the supraoptic nucleus and also occurred in the paraventricular and suprachiasmatic nuclei. The supraoptic and paraventricular nuclei also contained some neurons immunoreactive for both GA and OXY. Neurons positive for GA and TH were rare. The topographic distribution of GA-ir neuronal structures in the hypothalamus and the colocalization of GA, principally with AVP and to a lesser extent with OXY, in some hypothalamic nuclei constitute anatomical evidence that this neuropeptide may be involved in the regulation of endocrine, autonomic, and behavioural homeostatic responses.

Aged↗
PubMed2006

Neuron-specific enolase-cre mouse line with cre activity in specific neuronal populations.

To establish genetic tools for conditional gene deletion in mouse neurons, we generated two independent neuron-specific enolase (Nse)-cre transgenic lines. The transgenic line termed Nse-cre(CK1) showed cre activity in most neuronal regions in the nervous system, while the Nse-cre(CK2) line exhibited a unique cre activity that has not been reported in other cre transgenic lines. Nse-cre(CK2) cre activity was detectable from embryogenesis and mostly restricted to neuronal regions. In postnatal brain, the Nse-cre(CK2) line exhibited cre activity limited to differentiated neurons in the cerebral cortex and hippocampus. Cre activity was assayed in several internal organs and sporadic activity was limited to the kidney and testis. We conclude that these cre lines will be useful for studying loss of gene function in specific neuronal populations.

Animals↗
PubMed2001

Alpha-cyano-4-hydroxycinnamate decreases both glucose and lactate metabolism in neurons and astrocytes: implications for lactate as an energy substrate for neurons.

The rates of uptake and oxidation of [U-(14)C]lactate and [U-(14)C]glucose were determined in primary cultures of astrocytes and neurons from rat brain, in the presence and absence of the monocarboxylic acid transport inhibitor alpha-cyano-4-hydroxycinnamate (4-CIN). The rates of uptake for 1 mM lactate and glucose were 7.45 +/- 1.35 and 8.80 +/- 1.0 nmol/30 sec/mg protein in astrocytes and 2.36 +/- 0.19 and 1.93 +/- 0.16 nmol/30 sec/mg protein in neuron cultures, respectively. Lactate transport into both astrocytes and neurons was significantly decreased by 0.25-1.0 mM 4-CIN; however, glucose uptake was not affected. The rates of (14)CO(2) formation from 1 mM lactate and glucose were 12.49 +/- 0.77 and 3.42 +/- 0.67 nmol/hr/mg protein in astrocytes and 29.32 +/- 2.81 and 10.04 +/- 1.79 nmol/hr/mg protein in neurons, respectively. Incubation with 0.25 mM 4-CIN decreased the oxidation of lactate and glucose to 57.1% and 54.1% of control values in astrocytes and to 13.2% and 41.6% of the control rates in neurons, respectively. Preincubation with 4-CIN further decreased the oxidation of both glucose and lactate. Studies with glucose specifically labeled in the one and six positions demonstrated that 4-CIN decreased mitochondrial glucose oxidation but did not impair the metabolism of glucose via the pentose phosphate pathway in the cytosol. The lack of effect of 4-CIN on glutamate oxidation demonstrated that overall mitochondrial metabolism was not impaired. These findings suggest that the impaired neuronal function and tissue damage in the presence of 4-CIN observed in other studies may be due in part to decreased uptake of lactate; however, the effects of 4-CIN on mitochondrial transport would significantly decrease the oxidative metabolism of pyruvate derived from both glucose and lactate.

Animals↗
PubMed1980

Neuron-specific enolase levels in primary cultures of neurons.

Primary neuronal cell cultures, derived by centrifugal elutriation of cells dissociated from embryonic rat cerebra, have been analyzed for their content of neuron-specific enolase (NSE) and non-neuronal enolase (NNE). Both immunocytochemical staining and radioimmunoassay establish that NSE is present in these cells. Furthermore, the observed increase in NSE and decrease in the NNE/NSE ratio with time in culture parallels that observed in vivo. It has recently been shown that during in vivo neurogenesis and maturation a "switch over" occurs from NNE to NSE which correlates with neuronal differentiation. The presence of a neuron-specific protein in these primary neuronal cultures and the changes observed during growth further support their use as a model system for the study of nervous tissue differentiation.

Animals↗