Biomedical subjects

Jeannie Chin

Publications and source records attributed to Jeannie Chin.

10 recordsLinked to original sources

PubMed2006

A network dysfunction perspective on neurodegenerative diseases.

Patients with Alzheimer's disease or other neurodegenerative disorders show remarkable fluctuations in neurological functions, even during the same day. These fluctuations cannot be caused by sudden loss or gain of nerve cells. Instead, it is likely that they reflect variations in the activity of neural networks and, perhaps, chronic intoxication by abnormal proteins that the brain is temporarily able to overcome. These ideas have far-reaching therapeutic implications.

Alzheimer Disease↗

PubMed2006

AMPA receptors regulate transcription of the plasticity-related immediate-early gene Arc.

Learning and memory depend critically on long-term synaptic plasticity, which requires neuronal gene expression. In the prevailing view, AMPA receptors mediate fast excitatory synaptic transmission and effect short-term plasticity, but they do not directly regulate neuronal gene expression. By studying regulation of Arc, a gene required for long-term plasticity, we uncovered a new role for AMPA receptors in neuronal gene expression. Spontaneous synaptic activity or activity induced by brain-derived neurotrophic factor (BDNF) elicited Arc expression in cultures of rat cortical neurons and in organotypic brain slices. Notably, inhibiting AMPA receptors strongly potentiated activity-dependent Arc expression. We found that AMPA receptors negatively regulate Arc transcription, but not translation or stability, through a mechanism involving a pertussis toxin-sensitive G protein. These results provide insights into the activity-dependent mechanisms of Arc expression and suggest that, in addition to effecting short-term plasticity, AMPA receptors regulate genes involved in long-term plasticity.

Animals↗

PubMed2006

TGF-beta1-induced long-term changes in neuronal excitability in aplysia sensory neurons depend on MAPK.

Transforming growth factor beta-1 (TGF-beta1) plays important roles in the early development of the nervous system and has been implicated in neuronal plasticity in adult organisms. It induces long-term increases in sensory neuron excitability in Aplysia as well as a long-term enhancement of synaptic efficacy at sensorimotor synapses. In addition, TGF-beta1 acutely regulates synapsin phosphorylation and reduces synaptic depression induced by low-frequency stimuli. Because of the critical role of MAPK in other forms of long-term plasticity in Aplysia, we examined the role of MAPK in TGF-beta1-induced long-term changes in neuronal excitability. Prolonged (6 h) exposure to TGF-beta1 induced long-term increases in excitability. We confirmed this finding and now report that exposure to TGF-beta1 was sufficient to activate MAPK and increase nuclear levels of active MAPK. Moreover, TGF-beta1 enhanced phosphorylation of the Aplysia transcriptional activator cAMP response element binding protein (CREB)1, a homologue to vertebrate CREB. Both the TGF-beta1-induced long-term changes in neuronal excitability and the phosphorylation of CREB1 were blocked in the presence of an inhibitor of the MAPK cascade, confirming a role for MAPK in long-term modulation of sensory neuron function.

Action Potentials↗

PubMed2005

Vulnerability of dentate granule cells to disruption of arc expression in human amyloid precursor protein transgenic mice.

Activity-induced expression of Arc is necessary for maintenance of long-term potentiation and for memory consolidation. In transgenic (TG) mice with neuronal production of human amyloid precursor protein (hAPP) and hAPP-derived amyloid-beta (Abeta) peptides, basal Arc expression was reduced primarily in granule cells of the dentate gyrus. After exploration of a novel environment, Arc expression in these neurons was unaltered in hAPP mice but increased markedly in nontransgenic controls. Other TG neuronal populations showed no or only minor deficits in Arc expression, indicating a special vulnerability of dentate granule cells. The phosphorylation states of NR2B and ERK1/2 were reduced in the dentate gyrus of hAPP mice, suggesting attenuated activity in NMDA-dependent signaling pathways that regulate synaptic plasticity as well as Arc expression. Arc reductions in hAPP mice correlated with reductions in the actin-binding protein alpha-actinin-2, which is located in dendritic spines and, like Arc, fulfills important functions in excitatory synaptic activity. Reductions in Arc and alpha-actinin-2 correlated tightly with reductions in Fos and calbindin, shown previously to reflect learning deficits in hAPP mice. None of these alterations correlated with the extent of plaque formation, suggesting a plaque-independent mechanism of hAPP/Abeta-induced neuronal deficits. The brain region-specific depletion of factors that participate in activity-dependent modification of synapses may critically contribute to cognitive deficits in hAPP mice and possibly in humans with Alzheimer's disease.

Amyloid beta-Protein Precursor↗

PubMed2005

Fyn kinase induces synaptic and cognitive impairments in a transgenic mouse model of Alzheimer's disease.

Human amyloid precursor protein (hAPP) transgenic mice with high levels of amyloid-beta (Abeta) develop behavioral deficits that correlate with the depletion of synaptic activity-related proteins in the dentate gyrus. The tyrosine kinase Fyn is altered in Alzheimer's disease brains and modulates premature mortality and synaptotoxicity in hAPP mice. To determine whether Fyn also modulates Abeta-induced behavioral deficits and depletions of synaptic activity-dependent proteins, we overexpressed Fyn in neurons of hAPP mice with moderate levels of Abeta production. Compared with nontransgenic controls and singly transgenic mice expressing hAPP or FYN alone, doubly transgenic FYN/hAPP mice had striking depletions of calbindin, Fos, and phosphorylated ERK (extracellular signal-regulated kinase), impaired neuronal induction of Arc, and impaired spatial memory retention. These deficits were qualitatively and quantitatively similar to those otherwise seen only in hAPP mice with higher Abeta levels. Surprisingly, levels of active Fyn were lower in high expresser hAPP mice than in NTG controls and lower in FYN/hAPP mice than in FYN mice. Suppression of Fyn activity may result from dephosphorylation by striatal-enriched phosphatase, which was upregulated in FYN/hAPP mice and in hAPP mice with high levels of Abeta. Thus, increased Fyn expression is sufficient to trigger prominent neuronal deficits in the context of even relatively moderate Abeta levels, and inhibition of Fyn activity may help counteract Abeta-induced impairments.

Alzheimer Disease↗

PubMed2004

Coregulation of glutamate uptake and long-term sensitization in Aplysia.

In Aplysia, long-term facilitation (LTF) at sensorimotor synapses of the pleural-pedal ganglia is mediated by an increase in the release of a neurotransmitter, which appears to be glutamate. Glutamate uptake also is increased in sensory neurons 24 hr after the induction of long-term sensitization (Levenson et al., 2000b). The present study investigated whether the same signaling pathways were involved in the long-term increase in glutamate uptake as in the induction of LTF. Thus, roles for cAMP, PKA (cAMP-dependent protein kinase), MAPK (mitogen-activated protein kinase), and tyrosine kinase in the regulation of glutamate uptake were tested. We found that 5-HT increased cAMP and activated PKA in sensory neurons. Exposure of pleural-pedal ganglia to analogs of cAMP or forskolin increased glutamate uptake 24 hr after treatments. Inhibitors of PKA (KT5720), MAPK (U0126 and PD98059), and tyrosine kinase (genistein) blocked the long-term increase in glutamate uptake produced by 5-HT. In addition, bpV, a tyrosine phosphatase inhibitor, facilitated the ability of subthreshold levels of 5-HT to increase glutamate uptake. Inhibition of PKC, which is not involved in LTF, had no effect on the long-term increase in glutamate uptake produced by 5-HT. Furthermore, activation of PKC by phorbol-12,13-dibutyrate did not produce long-term changes in glutamate uptake. The results demonstrate that the same constellation of second messengers and kinases is involved in the long-term regulation of both glutamate release and glutamate uptake. These similarities in signaling pathways suggest that regulation of glutamate release and uptake during formation of long-term memory are coordinated through coregulation of these two processes.

Animals↗

PubMed2004

Fyn kinase modulates synaptotoxicity, but not aberrant sprouting, in human amyloid precursor protein transgenic mice.

Alzheimer's disease (AD), the most common neurodegenerative disorder, results in progressive degeneration of synapses and aberrant sprouting of axon terminals. The mechanisms underlying these seemingly opposing cellular phenomena are unclear. We hypothesized that Fyn kinase may play a role in one or both of these processes because it is increased in AD brains and because it is involved in synaptic plasticity and axonal outgrowth. We investigated the effects of Fyn on AD-related synaptotoxicity and aberrant axonal sprouting by ablating or overexpressing Fyn in human amyloid precursor protein (hAPP) transgenic mice. On the fyn+/+ background, hAPP/amyloid beta peptide (Abeta) decreased hippocampal levels of synaptophysin-immunoreactive presynaptic terminals (SIPTs), consistent with previous findings. On the fyn-/- background, hAPP/Abeta did not affect SIPTs. SIPT reductions correlated with hippocampal Abeta levels in hAPP/fyn+/+, but not hAPP/fyn-/-, mice suggesting that Fyn provides a critical link between hAPP/Abeta and SIPTs. Furthermore, overexpression of Fyn exacerbated SIPT reductions in hAPP mice. We also found that the susceptibility of mice to hAPP/Abeta-induced premature mortality was decreased by Fyn ablation and increased by Fyn overexpression. In contrast, axonal sprouting in the hippocampus of hAPP mice was unaffected. We conclude that Fyn-dependent pathways are critical in AD-related synaptotoxicity and that the pathogenesis of hAPP/Abeta-induced neuronal alterations may be mechanistically heterogenous.

Alzheimer Disease↗

PubMed2003

Neuronal depletion of calcium-dependent proteins in the dentate gyrus is tightly linked to Alzheimer's disease-related cognitive deficits.

Transgenic mice expressing human amyloid precursor proteins (hAPP) and amyloid-beta peptides (Abeta) in neurons develop phenotypic alterations resembling Alzheimer's disease (AD). The mechanisms underlying cognitive deficits in AD and hAPP mice are largely unknown. We have identified two molecular alterations that accurately reflect AD-related cognitive impairments. Learning deficits in mice expressing familial AD-mutant hAPP correlated strongly with decreased levels of the calcium-binding protein calbindin-D28k (CB) and the calcium-dependent immediate early gene product c-Fos in granule cells of the dentate gyrus, a brain region critically involved in learning and memory. These molecular alterations were age-dependent and correlated with the relative abundance of Abeta1-42 but not with the amount of Abeta deposited in amyloid plaques. CB reductions in the dentate gyrus primarily reflected a decrease in neuronal CB levels rather than a loss of CB-producing neurons. CB levels were also markedly reduced in granule cells of humans with AD, even though these neurons are relatively resistant to AD-related cell death. Thus, neuronal populations resisting cell death in AD and hAPP mice can still be drastically altered at the molecular level. The tight link between Abeta-induced cognitive deficits and neuronal depletion of CB and c-Fos suggests an involvement of calcium-dependent pathways in AD-related cognitive decline and could facilitate the preclinical evaluation of novel AD treatments.

Aged↗

PubMed2002

Serotonin stimulates phosphorylation of Aplysia synapsin and alters its subcellular distribution in sensory neurons.

Only a small fraction of neurotransmitter-containing synaptic vesicles (SVs), the readily releasable pool, is available for fast Ca(2+)-induced release at any synapse. Most SVs are sequestered at sites away from the plasma membrane and cannot be exocytosed directly. Recruitment of SVs to the releasable pool is thought to be an important component of short-term synaptic facilitation by serotonin (5-HT) at Aplysia sensorimotor synapses. Synapsins are associated with SVs and hypothesized to play a central role in the regulation of SV mobilization in nerve terminals. Aplysia synapsin was cloned to examine its role in synaptic plasticity at the well characterized sensorimotor neuron synapse of this animal. Acute 5-HT treatment of ganglia induced synapsin phosphorylation. Immunohistochemical analyses of cultured Aplysia neurons revealed that synapsin is distributed in distinct puncta in the neurites. These puncta are rapidly dispersed after treatment of the neurons with 5-HT. The dispersion of synapsin puncta by 5-HT was fully reversible after washout of the modulator. Both 5-HT-induced phosphorylation and dispersion of synapsin were mediated, at least in part, by cAMP-dependent protein kinase and mitogen-activated protein kinase. These experiments indicate that synapsin and its regulation by 5-HT may play an important role in the modulation of SV trafficking in short-term synaptic plasticity.

Animals↗

PubMed2002

Inhibitor of glutamate transport alters synaptic transmission at sensorimotor synapses in Aplysia.

Aplysia sensory neurons possess high-affinity glutamate uptake activity that is regulated by serotonin. To gain insight into the physiological role of glutamate uptake in sensory neurons, we examined whether blockade of glutamate transport altered synaptic transmission. We also examined whether glutamate transport affected homosynaptic depression and posttetanic potentiation (PTP). In the presence of DL-threo-beta-hydroxyaspartic acid (THA), previously shown to block glutamate uptake in Aplysia, the duration of unitary excitatory postsynaptic potentials (EPSPs) was significantly increased and their amplitude was significantly reduced. Similar effects were observed in the properties of summated EPSPs. However, no effect on the induction of homosynaptic depression or PTP was observed. Although it is unclear whether THA exerted its effect by modulating neuronal and/or glial mechanisms, at least one target of THA was neuronal, as the duration of unitary EPSPs measured in cultured sensorimotor synapses was also increased in the presence of THA. These results support the hypotheses that glutamate is the transmitter released by the sensory neurons and that glutamate transport plays an important role in regulating features of synaptic transmission in Aplysia.

Action Potentials↗