Donna L. Gruol

Scripps Research Institute

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Jeffrey G. Netzeband

Scripps Research Institute

Amanda J. Roberts

Scripps Research Institute

Kathy L. Parsons

Scripps Research Institute

Thomas E. Nelson

Wake Forest University

T. E. Nelson

Janssen Scientific Affairs (United States)

Mario Manto

University of Mons

Jeremy D. Schmahmann

Massachusetts General Hospital

C. L. Ur

Scripps Research Institute

Noriyuki Koibuchi

Gunma University

Salvador Huitrón‐Reséndiz

Scripps Research Institute

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Centre National de la Recherche Scientifique

Inserm

Salk Institute for Biological Studies

University of California, San Diego

Sorbonne Université

Erasmus MC

Universitat Autònoma de Barcelona

Erasmus University Rotterdam

National Institutes of Health

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Developmental changes in Ca²⁺‐regulated functions of early postnatal Purkinje neurons

Journal of Neuroscience Research (2006)

Donna L. Gruol Lely A. Quina Jeffrey G. Netzeband Duy Linh Nguyen C. E. Gullette

Abstract Ca 2+ influx through L‐type Ca 2+ channels regulates several different cellular processes in developing Purkinje neurons, including activation of transcription factors and expression of cellular proteins. In the current studies, we examined the age dependence of these actions of Ca 2+ during the early developmental period. Purkinje neurons acutely isolated from postnatal day 4–8 rat pups were studied. We also examined the sensitivity of the Ca 2+ ‐regulated processes to a toxic environmental factor (ethanol) known to show age‐dependent actions on developing Purkinje neurons. Results show that Ca 2+ activation of the transcription factor cAMP‐responsive element binding protein (CREB) and Ca 2+ ‐induced alterations in the level of the apoptotic enzyme caspase 3 show both dose and age dependence in the early‐developing Purkinje neurons. Interestingly, the age dependence was opposite for the two proteins. Ca 2+ regulation of calbindin, a Ca 2+ binding protein, was dose dependent but showed little age dependence. Exposure to ethanol altered Ca 2+ activation of pCREB in an age‐dependent manner but did not alter Ca 2+ regulation of caspase 3 or calbindin levels. Taken together, these results show that the downstream effects of Ca 2+ signaling have age‐dependent components during early Purkinje neuron development. This age dependence may play an important role in the normal developmental program and could contribute to the critical window of sensitivity observed for certain toxic agents during early development. © 2006 Wiley‐Liss, Inc.

10.1002/jnr.20844

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Citations (3)

The transient depression of hippocampal CA1 LTP induced by chronic intermittent ethanol exposure is associated with an inhibition of the MAP kinase pathway

European Journal of Neuroscience (2003)

Marisa Roberto T. E. Nelson C. L. Ur Marcello Brunelli Pietro Paolo Sanna

Abstract Using electrophysiological and biochemical approaches, we investigated the effects of chronic, intermittent ethanol (CIE) treatment on activation of the mitogen activated protein kinase (MAPK), also known as extracellular signal regulated protein kinase 1 and 2. In hippocampal slices taken from control rats, brief high‐frequency stimulation to Schaffer collateral fibers induced a large post‐tetanic potentiation (PTP) in the CA1 region that decayed to stable long‐term potentiation (LTP) of field extracellular postsynaptic potentials. Western blot analyses showed that phosphorylation of MAPK was increased during PTP and returned to baseline levels during LTP. In slices from the rats removed immediately from CIE treatment, PTP and MAPK activation during the PTP was significantly less than that observed in control slices and LTP was absent. In slices from rats subjected to 1 day withdrawal from CIE treatment, both the reduction in MAPK phosphorylation during PTP and the impairment of PTP and LTP were still evident. Recovery of PTP and partial recovery of LTP was observed in slices obtained from 5‐day withdrawn rats. However, MAPK activation during PTP was still attenuated significantly. Interestingly, MAPK activation was enhanced significantly during LTP in 5‐day withdrawn rats as well as the sensitivity to MAPK inhibitor PD 098059. In addition to these changes in HFS‐induced MAPK activation, we also observed a significant reduction in the basal phosphorylation of MAPK in slices removed from rats immediately after CIE treatment. These results implicate the MAPK signal transduction pathway as a potential cellular target of ethanol. Alterations in MAPKs could play an important role in the alcohol‐induced changes in synaptic plasticity associated with the effects of alcohol abuse on learning and memory processes.

Schaffer collateral

LTP induction

10.1046/j.1460-9568.2003.02614.x

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Citations (60)

Handbook of the Cerebellum and Cerebellar Disorders

Springer eBooks (2012)

Mario Manto Jeremy D. Schmahmann Ferdinando Rossi Donna L. Gruol Noriyuki Koibuchi

Cerebellar ataxia

10.1007/978-94-007-1333-8

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Citations (301)

Ca2+ signaling pathways linked to glutamate receptor activation in the somatic and dendritic regions of cultured cerebellar purkinje neurons

Journal of Neurophysiology (1996)

Donna L. Gruol Jeffrey G. Netzeband Kathy L. Parsons

1. Ca2+ signaling elicited by ionotropic alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate (iGluR) and metabotropic (mGluR) glutamate receptor agonists was studied in the somatic and dendritic regions of cultured cerebellar Purkinje neurons using microscopic video imaging and the Ca2+ sensitive dye fura-2. 2. iGluR and mGluR agonists and K+ depolarization applied by brief micropressure pulses evoked Ca2+ signals in both the somatic and dendritic regions of all Purkinje neurons studied. The Ca2+ signals were generated simultaneously in both cellular regions. The Ca+ signals to these stimulants were similar in general form, consisting of an initial peak and slow recovery phase, but differed in details of amplitude, time course, and complexity. 3. Removal of extracellular Ca2+ abolished the Ca2+ signal to the iGluR agonist AMPA, indicating that Ca2+ influx was essential to the generation of Ca2+ signals by iGluR agonists. The Ca2+ channel blocker lanthanum almost completely eliminated the Ca2+ signals to AMPA, indicating that Ca2+ influx through voltage-sensitive Ca2+ channels was the main pathway for Ca2+ influx. Omega-agatoxin IVA, a P-type Ca2+ channel blocker, significantly reduced the Ca2+ signals to AMPA suggesting that Ca2+ influx was predominately through P-type Ca2+ channels. 4. Pharmacological manipulation of intracellular Ca2+ stores significantly reduced the Ca2+ signals to AMPA, indicating that release of Ca2+ from intracellular Ca2+ stores also plays a prominent role in the generation of the Ca2+ signals to iGluR agonists. These manipulations included blocking Ca2+ release from intracellular stores with dantrolene, an antagonist at the ryanodine receptor that controls Ca2+ release from one pool of intracellular Ca2+ stores, and depletion of intracellular Ca2+ stores with caffeine or ryanodine. 5. Ca2+ influx through voltage-sensitive Ca2+ channels did not appear to be involved in the Ca2+ signals to mGluR activation, because neither lanthanum nor omega-agatoxin IVA altered Ca2+ signals to mGluR agonists. Manipulation of intracellular stores with Ca(2+)-ATPase inhibitors and dantrolene significantly reduced the Ca2+ signal to mGluR agonists, indicating that Ca2+ signals were derived from both the inositol trisphosphate (IP3) and the ryanodine receptor-controlled intracellular Ca2+ stores. 6. Ca2+ signals to the iGluR agonist AMPA correlated temporally with the prolonged, multiphasic membrane responses elicited by similar agonist application in parallel electrophysiological studies. Pharmacological manipulation of Ca2+ influx and release of Ca2+ from intracellular stores significantly influenced components of the membrane response to AMPA, indicating a potential modulator or mediator role for Ca2+ in the membrane response to iGluR activation.

Kainate receptor

Channel blocker

10.1152/jn.1996.76.5.3325

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Citations (49)

Chronic CXCL10 alters the level of activated ERK1/2 and transcriptional factors CREB and NF-κB in hippocampal neuronal cell culture

Journal of Neuroimmunology (2008)

Hilda Bajova Thomas E. Nelson Donna L. Gruol

10.1016/j.jneuroim.2008.01.003

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Citations (19)

Metabotropic Glutamate Receptor Agonists Alter Neuronal Excitability and Ca²⁺Levels via the Phospholipase C Transduction Pathway in Cultured Purkinje Neurons

Journal of Neurophysiology (1997)

Jeffrey G. Netzeband Kathy L. Parsons Dan D. Sweeney Donna L. Gruol

Netzeband, Jeffrey G., Kathy L. Parsons, Dan D. Sweeney, and Donna L. Gruol. Metabotropic glutamate receptor agonists alter neuronal excitability and Ca 2+ levels via the phospholipase C transduction pathway in cultured Purkinje neurons. J. Neurophysiol. 78: 63–75, 1997. Selective agonists for metabotropic glutamate receptor (mGluR) subtypes were tested on mature, cultured rat cerebellar Purkinje neurons (≥21 days in vitro) to identify functionally relevant mGluRs expressed by these neurons and to investigate the transduction pathways associated with mGluR-mediated changes in membrane excitability. Current-clamp recordings (nystatin/perforated-patch method) were used to measure the membrane response of Purkinje neurons to brief microperfusion pulses (1.5 s) of the group I (mGluR1/mGluR5) agonists (1 S,3 R)-1-aminocyclopentane-1,3-dicarboxylic acid (300 μM), quisqualate (5 μM), and ( R,S)-3,5-dihydroxyphenylglycine (50–500 μM). All group I mGluR agonists elicited biphasic membrane responses and burst activity in the Purkinje neurons. In addition, the group I mGluR agonists produced alterations in the active membrane properties of the Purkinje neurons and depressed the off response after hyperpolarizing current injection. In parallel microscopic Ca 2+ imaging experiments, application of the group I mGluR agonists to fura-2-loaded cells elicited increases in intracellular Ca 2+ in both the somatic and dendritic regions. The group II (mGluR2/mGluR3) agonist (2 S,3 S,4 S)-α-(carboxycyclopropyl)-glycine (10 μM) and the group III (mGluR4/mGluR6/mGluR7/mGluR8) agonists l(+)-2-amino-4-phosphonobutyric acid (1 mM) and O-phospho-l-serine (200 μM) had no effect on the membrane potential or intracellular Ca 2+ levels of the Purkinje neurons. The cultured Purkinje neurons, but not granule neurons or interneurons, showed immunostaining for mGluR1α in both the somatic and dendritic regions. All effects of the group I mGluR agonists were blocked by (+)-α-methyl-4-carboxyphenylglycine (1 mM), an mGluR antagonist. Furthermore, the phospholipase C inhibitor 1-[6-((17β-3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl]-1H-pyrrole-2,5-dione (2 μM) blocked the group I mGluR agonist-mediated electrophysiological response and greatly attenuated the Ca 2+ signal elicited by group I mGluR agonists, particularly in the dendrites. The inactive analogue1-[6-((17β-3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl]2,5-pyrrolidine-dione (2 μM) was relatively ineffective against the electrophysiological response and Ca 2+ signal. These results indicate that functional group I mGluRs (but not group II or III mGluRs) can be activated on mature Purkinje neurons in culture and result in changes in neuronal excitability and intracellular Ca 2+ mediated through phospholipase C. These data obtained from a defined neuronal type, the Purkinje neuron, confirm biochemical and molecular studies on the transduction mechanisms of group I mGluRs and show that this transduction pathway is linked to neuronal excitability and intracellular Ca 2+ release in the Purkinje neurons.

10.1152/jn.1997.78.1.63

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Citations (63)

The chemokine CCL2 modulates Ca²⁺ dynamics and electrophysiological properties of cultured cerebellar Purkinje neurons

European Journal of Neuroscience (2005)

Koen L.I. van Gassen Jeffrey G. Netzeband P.N.E. de Graan Donna L. Gruol

Abstract The chemokine CCL2 is produced at high levels in the central nervous system (CNS) during infection, injury, neuroinflammation and other pathological conditions. Cells of the CNS including neurons and glia express receptors for CCL2 and these receptors may contribute to a signaling system through which pathologic conditions in the CNS are communicated. However, our understanding of the consequences of activation of chemokine signaling in the CNS is limited, especially for neurons. In many cell types, chemokine signaling alters intracellular Ca 2+ dynamics. Therefore, we investigated the potential involvement of this mechanism in neuronal signaling activated by CCL2. In addition, we examined the effects of CCL2 on neuronal excitability. The studies focused on the rat cerebellar Purkinje neuron, an identified CNS neuronal type reported to express both CCL2 and its receptor, CCR2. Immunohistochemical studies of Purkinje neurons in situ confirmed that they express CCR2 and CCL2. The effect of exogenous application on Purkinje neurons was studied in a cerebellar culture preparation. CCL2 was tested by micropressure or bath application, at high concentrations (13–100 n m ) to simulate conditions during a pathologic state. Results show that Purkinje neurons express receptors for CCL2 and that activation of these receptors alters several neuronal properties. CCL2 increased resting Ca 2+ levels, enhanced the Ca 2+ response evoked by activation of metabotropic glutamate receptor 1 and depressed action potential generation in the cultured Purkinje neurons. Passive membrane properties were unaltered. These modulatory effects of CCL2 on neuronal properties are likely to contribute to the altered CNS function associated with CNS disease and injury.

10.1111/j.1460-9568.2005.04113.x

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Citations (52)

Acute alcohol blocks neurosteroid modulation of synaptic transmission and long-term potentiation in the rat hippocampal slice

Brain Research (1995)

R. D. Randall S.Y. Lee J. Harlan Meyer George F. Wittenberg Donna L. Gruol

Schaffer collateral

LTP induction

10.1016/0006-8993(95)01007-9

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Citations (31)

Multiple voltage-sensitive K+ channels regulate dendritic excitability in cerebellar Purkinje neurons