Biomedical subjects

Zao C Xu

Publications and source records attributed to Zao C Xu.

14 recordsLinked to original sources

PubMed2007

Chronic alcohol drinking alters neuronal dendritic spines in the brain reward center nucleus accumbens.

Alcohol is known to affect glutamate transmission. However, how chronic alcohol affects the synaptic structure mediating glutamate transmission is unknown. Repeated alcohol exposure in a subject with familial alcoholic history often leads to alcohol addiction. The current study adopts alcohol-preferring rats, which are known to develop high drinking. Two-photon microscopy analysis indicates that chronic alcohol of 14 weeks either, under continuous alcohol (C-Alc) or with repeated deprivation (RD-Alc), causes dysmorphology--thickened, beaded, and disoriented dendrites that are reminiscent of reactive astrocytes--in a subpopulation of medium spiny neurons. The density of dendritic spines was found differentially lower in the nucleus accumbens of RD-Alc and C-Alc groups as compared with those of Water groups. Large-sized spines and multiple-headed spines were increased in the RD-Alc group. The NMDA receptor subunit NR1 proteins, as analyzed with Western blot, were upregulated in C-Alc, but not in RD-Alc. The upregulated NMDA receptor subunits of NR1 however, are predominantly a splice variant isoform with truncated exon 21, which is required for membrane-bound trafficking or anchoring into a spine synaptic site. These maladaptations may contribute to the transformation of spines. The changes, in density and head-size of spines and the corresponding NMDA receptors, demonstrated an alteration of microcircuitry for glutamate reception. The current study demonstrates for the first time that chronic alcohol exposure causes structural alteration of dendrites and their spines in the key reward brain region in animals that have a genetic background leading to alcohol addiction.

Alcohol-Induced Disorders, Nervous System↗

PubMed2007

Morphological heterogeneity of CA1 pyramidal neurons in response to ischemia.

We have found, based on the electrophysiological properties, two subtypes of CA1 pyramidal neurons in the CA1 region of the normal hippocampus, late postsynaptic potential (L-PSP) neurons and non-L-PSP neurons. In addition, our previous study has shown that the electrophysiological properties of these two subtypes of pyramidal neurons were differentially modified after ischemia. In the present study, we hypothesized that ischemia might also induce different morphological alterations in these two subtypes of neuron. To test the hypothesis, we compared the changes in the dendritic arborization and soma volume of these two subtypes of neurons in rats subjected to transient global ischemia. We found a significant decrease in the basal dendritic length of L-PSP neurons at 12 hr after reperfusion, resulting mainly from a significant decrease in the dendrite terminal length. The apical dendritic length of L-PSP neurons markedly increased at 24 hr after ischemia, resulting mainly from an increase in the number of branching arbors in the middle part of the apical dendritic trees. The soma size of L-PSP neurons was significantly reduced at 12 hr, but they became slightly larger at 24 hr and 48 hr after reperfusion. In contrast to L-PSP neurons, non-L-PSP neurons showed slight modifications in the dendritic arborization but had persistent swelling of their soma after ischemia. These results indicate that pathological changes in these two subtypes of neurons are different after ischemia.

Animals↗

PubMed2006

Recent advances in basic neurosciences and brain disease: from synapses to behavior.

Understanding basic neuronal mechanisms hold the hope for future treatment of brain disease. The 1st international conference on synapse, memory, drug addiction and pain was held in beautiful downtown Toronto, Canada on August 21-23, 2006. Unlike other traditional conferences, this new meeting focused on three major aims: (1) to promote new and cutting edge research in neuroscience; (2) to encourage international information exchange and scientific collaborations; and (3) to provide a platform for active scientists to discuss new findings. Up to 64 investigators presented their recent discoveries, from basic synaptic mechanisms to genes related to human brain disease. This meeting was in part sponsored by Molecular Pain, together with University of Toronto (Faculty of Medicine, Department of Physiology as well as Center for the Study of Pain). Our goal for this meeting is to promote future active scientific collaborations and improve human health through fundamental basic neuroscience researches. The second international meeting on Neurons and Brain Disease will be held in Toronto (August 29-31, 2007).

Behavior↗

PubMed2006

NMDA receptor mediated dendritic plasticity in cortical cultures after oxygen-glucose deprivation.

Dendrites and spines undergo dynamic changes in physiological and pathological conditions. Dendritic outgrowth has been observed in surviving neurons months after ischemia, which is associated with the functional compensation. It remains unclear how dendrites in surviving neurons are altered shortly after ischemia, which might reveal the mechanisms underlying neuronal survival. Using primary cortical cultures, we monitored the dendritic changes in individual neurons after oxygen-glucose deprivation (OGD). Two to four hours of OGD induced approximately 30-50% cell death in 24 h. However, the total dendritic length in surviving neurons was significantly increased after OGD with a peak at 6 h after re-oxygenation. The increase of dendritic length after OGD was mainly due to the sprouting rather than the extension of the dendrites. The dendritic outgrowth after 2 h of OGD was greater than that after 4 h of OGD. Application of NMDA receptor blocker MK-801 abolished OGD-induced dendritic outgrowth, whereas application of AMPA receptor antagonist CNQX had no significant effects. These results demonstrate a NMDA receptor-dependent dendritic plasticity shortly after OGD, which provides insights into the early response of surviving neurons after ischemia.

Animals↗

PubMed2006

Enhanced presynaptic neurotransmitter release in the anterior cingulate cortex of mice with chronic pain.

The anterior cingulate cortex (ACC) is a forebrain structure known for its roles in learning and memory. Recent studies show that painful stimuli activate the prefrontal cortex and that brain chemistry is altered in this area in patients with chronic pain. Components of the CNS that are involved in pain transmission and modulation, from the spinal cord to the ACC, are very plastic and undergo rapid and long-term changes after injury. Patients suffering from chronic pain often complain of memory and concentration difficulties, but little is known about the neural circuitry underlying these deficits. To address this question, we analyzed synaptic transmission in the ACC from mice with chronic pain induced by hindpaw injection of complete Freund's adjuvant (CFA). In vitro whole-cell patch-clamp recordings revealed a significant enhancement in neurotransmitter release probability in ACC synapses from mice with chronic pain. Trace fear memory, which requires sustained attention and the activity of the ACC, was impaired in CFA-injected mice. Using knock-out mice, we found that calmodulin-stimulated adenylyl cyclases, AC1 and/or AC8, were crucial in mediating the long-lasting enhanced presynaptic transmitter release in the ACC of mice with chronic pain. Our findings provide strong evidence that presynaptic alterations caused by peripheral inflammation contribute to memory impairments after injury.

Adenylyl Cyclases↗

PubMed2005

Enhancement of excitatory synaptic transmission in spiny neurons after transient forebrain ischemia.

Spiny neurons in the neostriatum are highly vulnerable to ischemia. Enhancement of excitatory synaptic transmissions has been implicated in ischemia-induced excitotoxic neuronal death. Here we report that evoked excitatory postsynaptic currents in spiny neurons were potentiated after transient forebrain ischemia. The ischemia-induced potentiation in synaptic efficacy was associated with an enhancement of presynaptic release as demonstrated by an increase in the frequency of miniature excitatory postsynaptic currents (mEPSCs) and a decrease in the paired-pulse ratio. The amplitude of inward currents evoked by exogenous application of glutamate did not show significant changes after ischemia, suggesting that postsynaptic mechanism is not involved. The ischemia-induced increase in mEPSCs frequency was not affected by blockade of voltage-gated calcium channels, but it was eliminated in the absence of extracellular calcium. Bath application of ATP P2X receptor antagonist pyridoxal-phosphate-6-azophenyl-2',4'-disulfonic acid (PPADS) significantly reduced mEPSC frequency in ischemic neurons but had no effects on the control ones. Furthermore, the inhibitory effect of PPADS on ischemic neurons was abolished in Ca2+-free external solution. These results indicate that excitatory synaptic transmissions in spiny neurons are potentiated after ischemia via presynaptic mechanisms. Activation of P2X receptors and the consequent Ca2+ influx might contribute to the ischemia-induced facilitation of glutamate release.

Action Potentials↗

PubMed2005

Asymmetrical changes of dopamine receptors in the striatum after unilateral dopamine depletion.

Dopamine plays an important role in modulating synaptic transmission in the striatum and has great influence on the function of the basal ganglia. Degeneration of dopamine neurons in the substantia nigra (SN) is the major cause of many neurological disorders, and the reduction of dopamine innervation results in alterations of dopamine receptors in the striatum. It has been shown that the nigrostriatal dopamine system has functional and neurochemical asymmetry. To investigate the lateralization of dopamine receptors in the striatum after dopamine denervation, the present study used quantitative autoradiography to compare the changes in dopamine receptor binding in the left and right striatum in rats after unilateral dopamine depletion. In comparison to control levels, dopamine D1)-like receptor binding, labeled with [3H]-SCH23390, in the dorsal striatum was reduced 2 weeks after unilateral lesions of the SN with 6-hydroxydopamine. D1-like receptor binding was decreased in the ipsilateral striatum following unilateral lesions of either the left or right SN. The left and right striatum responded similarly to unilateral SN lesions, as there were no significant differences in the percent decrease in D1-like binding in the two striata. In contrast, D2-like receptor binding, labeled with [3H]-spiroperidol, was significantly increased in the dorsal striatum following an ipsilateral SN lesion. Furthermore, the up-regulation of D2-like receptors in the right striatum was significantly greater than that in the left striatum after an ipsilateral lesion. The asymmetrical up-regulation of striatal D2 receptors after extensive dopamine depletion might contribute to the lateralization of the nigrostriatal system observed in some pathological conditions.

Animals↗

PubMed2005

Alterations of potassium currents in ischemia-vulnerable and ischemia-resistant neurons in the hippocampus after ischemia.

CA1 pyramidal neurons in the hippocampus die 2-3 days following transient forebrain ischemia, whereas CA3 pyramidal neurons and granule cells in the dentate gyrus remain viable. Excitotoxicity is the major cause of ischemic cell death, and potassium currents play important roles in regulating the neuronal excitability. The present study compared the changes of potassium currents in acutely dissociated hippocampal neurons at different intervals after ischemia. In CA1 neurons, the amplitude of rapid inactivating potassium currents (I(A)) was significantly increased at 14 h and returned to control levels at 38 h after ischemia; the rising slope and decay time constant of I(A) were accordingly increased after ischemia. The activation curve of I(A) in CA1 neurons shifted to the depolarizing direction at 38 h after ischemia. In granule cells, the amplitude and rising slope of I(A) were significantly increased at 38 h after ischemia; the inactivation curves of I(A) shifted toward the depolarizing direction accordingly at 38 h after ischemia. The I(A) remained unchanged in CA3 neurons after ischemia. The amplitudes of delayed rectifier potassium currents (I(Kd)) in CA1 neurons were progressively increased after ischemia. No significant difference in I(Kd) was detected in CA3 and granule cells at any time points after reperfusion. These results indicated that the voltage dependent potassium currents in hippocampal neurons were differentially altered after cerebral ischemia. The up-regulation of I(A) in dentate granule cells might have protective effects. The increase of I(Kd) in CA1 neurons might be associated with the neuronal damage after ischemia.

Animals↗

PubMed2004

Developmental changes of transient potassium currents in large aspiny neurons in the neostriatum.

Developmental regulation of the potassium conductance is important for the maturation of neuronal excitability and the formation of functional circuitry in the central nervous system (CNS). The rapidly inactivating A-type current is a major component of the voltage-dependent outward potassium currents in the large aspiny (LA) neurons in the neostriatum. The large aspiny neurons play important roles in the function of neostriatum in physiological and pathological conditions. Whole-cell patch-clamp recording was performed on acutely dissociated neurons and brain slices to investigate the postnatal development of A-type current in the large aspiny neurons. The current density of A-type current in large aspiny neurons was the highest at postnatal 1-3 days and gradually decreased during the development with the lowest levels in adult animals. In comparison to postnatal 1-3 days, the steady-state inactivation curve shifted in depolarizing direction in mature neurons. No significant changes in the voltage dependence of steady-state activation were observed during development. Consistent with the decrease in the current density of A-type current during development, the latency to the first spike was dramatically shortened in mature large aspiny neurons. These results suggest that the decrease of rapidly inactivating A-type potassium current during development might contribute, at least in part, to the maturation of the membrane excitability of large aspiny neurons in the neostriatum.

Age Factors↗

PubMed2004

In vivo demonstration of a late depolarizing postsynaptic potential in CA1 pyramidal neurons.

Previous studies have shown that GABA can have a depolarizing and excitatory action through GABA(A) receptors in mature CNS neurons in vitro. However, it remains unknown whether this occurs under physiological conditions. In this study, using intracellular recording and staining in vivo technique, we show a late depolarizing postsynaptic potential (L-PSP) in CA1 pyramidal neurons of adult Wistar rats under halothane anesthesia. This L-PSP was elicited in approximately 70% of the recorded neurons on stimulation of the Schaffer collaterals or the contralateral commissural path. The size of L-PSP was linearly correlated to the decay time constant but not the rising slope of the initial excitatory PSP (EPSP). Intravenous administration of the N-methyl-D-aspartate (NMDA) receptor blocker MK-801 and the GABA(A) receptor blocker picrotoxin significantly reduced the size of the L-PSP. The spine density and apical dendritic branching length of the neurons that displayed L-PSPs was significantly greater than those that do not. These results indicate that NMDA receptor and GABA(A) receptor-mediated depolarizing postsynaptic potentials can be revealed in CA1 pyramidal neurons of adult rats in vivo, supporting the physiological relevance of GABA(A)-mediated depolarization in normal neuronal information processing. The difference in electrophysiological properties and morphological features between neurons that display the L-PSP and the other neurons suggest that they might represent two different subtypes of CA1 pyramidal neurons.

Animals↗

PubMed2003

Apoptosis in the adult striatum after transient forebrain ischemia and the effects of ischemic severity.

The mechanisms of neuronal injury after cerebral ischemia have been under active investigation. The medium-size neurons in the dorsal striatum die within 24 h after transient cerebral ischemia. Using electron microscopy, the present study examined the nature of neuronal death in the striatum of adult rats following transient forebrain ischemia and tested the hypothesis that the ischemic severity might influence the nature of cell death. After severe ischemia (approximately 21 min ischemic depolarization), most neurons in the dorsal striatum died with swollen organelles and small irregular chromatin clumps resembling necrosis. The tissue damage in the dorsomedial striatum was less severe than that in the dorsolateral striatum and approximately 5% of the neurons in this region died with large chromatin clumps and relatively intact organelles resembling apoptosis. Some neurons displayed a mixture of necrotic- and apoptotic-like appearance. In contrast, the neurons with large somata only exhibited mild ultrastructural changes. After moderate ischemia (approximately 15 min ischemic depolarization), the tissue damage was less severe and the process of necrosis was temporally prolonged compared with that after severe ischemia. The apoptotic-like neuronal death was observed not only in the dorsomedial (approximately 6%) but also in the dorsolateral striatum (approximately 7%). The neurons in the striatum showed transient reversible changes after mild ischemia (approximately 10 min ischemic depolarization). The present study demonstrates that both apoptosis and necrosis occur in the adult striatum following transient forebrain ischemia and apoptosis occurs in the regions with less severe ischemia. These results suggest that ischemic severity might be one of the contributing factors to necrosis or apoptosis following transient global ischemia.

Animals↗

PubMed2003

Neuropathologies in transgenic mice expressing human immunodeficiency virus type 1 Tat protein under the regulation of the astrocyte-specific glial fibrillary acidic protein promoter and doxycycline.

The human immunodeficiency virus type 1 (HIV-1) Tat protein is a key pathogenic factor in a variety of acquired immune deficiency syndrome (AIDS)-associated disorders. A number of studies have documented the neurotoxic property of Tat protein, and Tat has therefore been proposed to contribute to AIDS-associated neurological diseases. Nevertheless, the bulk of these studies are performed in in vitro neuronal cultures without taking into account the intricate cell-cell interaction in the brain, or by injection of recombinant Tat protein into the brain, which may cause secondary stress or damage to the brain. To gain a better understanding of the roles of Tat protein in HIV-1 neuropathogenesis, we attempted to establish a transgenic mouse model in which Tat expression was regulated by both the astrocyte-specific glial fibrillary acidic protein promoter and a doxycycline (Dox)-inducible promoter. In the present study, we characterized the phenotypic and neuropathogenic features of these mice. Both in vitro and in vivo assays confirmed that Tat expression occurred exclusively in astrocytes and was Dox-dependent. Tat expression in the brain caused failure to thrive, hunched gesture, tremor, ataxia, and slow cognitive and motor movement, seizures, and premature death. Neuropathologies of these mice were characterized by breakdown of cerebellum and cortex, brain edema, astrocytosis, degeneration of neuronal dendrites, neuronal apoptosis, and increased infiltration of activated monocytes and T lymphocytes. These results together demonstrate that Tat expression in the absence of HIV-1 infection is sufficient to cause neuropathologies similar to most of those noted in the brain of AIDS patients, and provide the first evidence in the context of a whole organism to support a critical role of Tat protein in HIV-1 neuropathogenesis. More importantly, our data suggest that the Dox inducible, brain-targeted Tat transgenic mice offer an in vivo model for delineating the molecular mechanisms of Tat neurotoxicity and for developing therapeutic strategies for treating HIV-associated neurological disorders.

Acquired Immunodeficiency Syndrome↗

PubMed2002

Depression of fast excitatory synaptic transmission in large aspiny neurons of the neostriatum after transient forebrain ischemia.

Spiny neurons in the neostriatum die within 24 hr after transient global ischemia, whereas large aspiny (LA) neurons remain intact. To reveal the mechanisms of such selective cell death after ischemia, excitatory neurotransmission was studied in LA neurons before and after ischemia. The intrastriatally evoked fast EPSCs in LA neurons were depressed < or =24 hr after ischemia. The concentration-response curves generated by application of exogenous glutamate in these neurons were approximately the same before and after ischemia. A train of five stimuli (100 Hz) induced progressively smaller EPSCs, but the proportion of decrease in EPSC amplitude at 4 hr after ischemia was significantly smaller compared with control and at 24 hr after ischemia. Parallel depression of NMDA receptor and AMPA receptor-mediated EPSCs was also observed after ischemia, supporting the involvement of presynaptic mechanisms. The adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine blocked the inhibition of evoked EPSCs at 4 hr after ischemia but not at 24 hr after ischemia. Electron microscopic studies demonstrated that the most presynaptic terminals in the striatum had a normal appearance at 4 hr after ischemia but showed degenerating signs at 24 hr after ischemia. These results indicated that the excitatory neurotransmission in LA neurons was depressed after ischemia via presynaptic mechanisms. The depression of EPSCs shortly after ischemia might be attributable to the enhanced adenosine A1 receptor function on synaptic transmission, and the depression at late time points might result from the degeneration of presynaptic terminals.

Animals↗

PubMed2002

Involvement of the calcium-independent receptor for alpha-latrotoxin in brain ischemia.

Cerebral ischemia is caused by a reduced blood supply to neurons, and vulnerability to neurodegeneration varies considerably among neuronal types. In hippocampus, neurons in the CA1 region are more susceptible to ischemia-induced neuronal death than neurons in the CA3 region, and in response to transient forebrain ischemia a family of calcium-dependent receptors for alpha-latrotoxin is differentially expressed in the two regions. Here, we report that an ischemic insult up-regulated a family of calcium-independent receptors for alpha-latrotoxin (CIRL) mRNAs in CA1 neurons and down-regulated their mRNAs in CA3 neurons. Furthermore, antisense oligonucleotides complementary to CIRL-1 mRNA or CIRL-3 mRNA suppressed neuronal death associated with hypoxia in hippocampal and cortical cell cultures. The observed region-specific CIRL mRNA expression in hippocampus and an in vitro rescue experiment by antisense oligonucleotides against CIRL mRNAs suggest a functional importance of CIRL in neurodegeneration.

Animals↗