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Volume 16, Number 15,
Issue of August 1, 1996
pp. 4651-4661
Copyright ©1996 Society for Neuroscience
Functional NMDA Receptors Are Transiently Active and Support the
Survival of Purkinje Cells in Culture
Received March 7, 1996; revised May 10, 1996; accepted May 15, 1996.
Michisuke Yuzaki1,
Douglas Forrest2,
Lynne M. Verselis3,
Shaiu C. Sun4,
Tom Curran1, and
John A. Connor5
1 Department of Developmental Neurobiology, St. Jude
Children's Research Hospital, Memphis, Tennessee 38105, 2 Department of Human Genetics, Mount Sinai School of
Medicine, New York, New York 10029, 3 Hoffmann-La Roche,
Nutley, New Jersey 07110, 4 Department of Central Nervous
System Disorders, Wyeth-Ayerst Research, Princeton, New Jersey 08543, and 5 Lovelace Institute, Albuquerque, New Mexico 87108
Conflicting evidence exists concerning the activity of NMDA
receptors (NMDARs) in cerebellar Purkinje cells and their possible
functions. To investigate the activity of NMDARs, we used whole-cell
recording on immunocytochemically identified Purkinje cells in primary
culture. In addition, we used mice with a disrupted NMDAR1 gene that
lack functional NMDARs (NR1 /) to assess the physiological role of
NMDARs. In cultures from normal mice, NMDA-mediated currents were
detected in all identified Purkinje cells at 4 d in
vitro (div). After 14 d, however, NMDA responses were reduced
in amplitude, whereas the responses to kainate and glutamate increased
steadily in amplitude. In addition, the NMDA-induced current displayed
a pronounced desensitization at these later stages; peak current
declined to zero during steady application of NMDA. At 7 div, the
number of surviving Purkinje cells was less in cultures treated with
NMDA antagonists, and their survival was dose-dependent. Purkinje cell
survival was correspondingly poorer in cultures from the NR1/ mice
than in wild-type controls, suggesting that NMDAR activity enhances the
survival of Purkinje cells in vitro. The addition of
moderate doses of NMDA promoted the survival of wild-type Purkinje
cells in the presence of tetrodotoxin. Feeder layers of cerebellar
granule cells derived from wild-type or NR1/ mice promoted survival
of Purkinje cells to a similar degree, suggesting that the NMDAR in
Purkinje cells, but not in other cells, is directly involved in
Purkinje cell viability. The results demonstrate that NMDARs
transiently produce membrane current in Purkinje cells and may serve as
one of the epigenetic factors that support the survival of Purkinje
cells in vitro.
Key words:
Purkinje cells;
cerebellum;
NMDA receptors;
excitatory
amino acids;
dissociated cell culture;
patch clamp
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