Exaggerated cyclic AMP accumulation and glial cell reaction in the cerebellum during Purkinje cell degeneration in pcd mutant mice

The Purkinje cell degeneration mutant (pcd) is characterized by a complete loss of cerebellar Purkinje cells. Norepinephrine causes an accumulation of cyclic AMP in the cerebellum of pcd that is far greater than in normal mice. Experiments were conducted (1) to correlate changes in the cyclic‐nucleotide response with a histologic examination of the cerebellum during neuronal loss and (2) to examine the role of cyclic AMP catabolism and adenosine receptor interactions in the phenomenon. The greatest elevation in cyclic AMP occurred between 30 and 128 days of age when a severe astrocytic response was demonstrated throughout the cerebellar cortex. Purkinje cells had degenerated by 45 days of age. Norepinephrine elicited a smaller increase in cyclic AMP from 155‐day‐old mice than at earlier ages, and the response continued to decrease with age; at 270 days, equal accumulation, and at 365 days, lower accumulation of cyclic AMP was detected in pcd cerebella. During this time, the Purkinje cell debris had been removed, the granule cell layer was depleted of granule cells, and the molecular layer was deprived of a large number of parallel fibers. However, although phagocytosis of neuronal debris was completed, large numbers of astrocytic processes were still seen in the neuropil.

[1]  P. Molinoff,et al.  Ontogeny of β1- and β2-adrenergic receptors in rat cerebellum and cerebral cortex , 1980, Brain Research.

[2]  H. Maeno,et al.  Characterization of beta-adrenergic receptor and adenylate cyclase in canine cerebellum. , 1979, Archives of biochemistry and biophysics.

[3]  R. Sidman,et al.  Neurochemical and morphological consequences of axon terminal degeneration in cerebellar deep nuclei of mice with inherited purkinje cell degeneration , 1979, Brain Research.

[4]  J. de Vellis,et al.  Cellular interactions uncouple beta-adrenergic receptors from adenylate cyclase. , 1978, Science.

[5]  B. Ghetti,et al.  STUDIES ON THE PURKINJE CELL DEGENERATION (pcd) MUTANT: PRIMARY PATHOLOGY AND TRANSNEURONAL CHANGES , 1978 .

[6]  R. Sidman,et al.  Concentrations of glutamic acid in cerebellar cortex and deep nuclei of normal mice and weaver, staggerer and nervous mutants , 1978, Brain Research.

[7]  W. Mcbride,et al.  Contents of serotonin, norepinephrine and dopamine in the cerebrum of the ‘staggerer’, ‘weaver’ and ‘nervous’ neurologically mutant mice , 1977, Journal of neurochemistry.

[8]  J. Daly,et al.  The role of calcium ions in accumulation of cyclic adenosine monophosphate elicited by alpha and beta adrenergic agonists in rat brain slices. , 1977, The Journal of pharmacology and experimental therapeutics.

[9]  E. Rubin,et al.  DISTRIBUTION AND REGULATION OF CYCLIC NUCLEOTIDE LEVELS IN CEREBELLUM, IN VIVO 1 , 1977, Journal of neurochemistry.

[10]  M. Schmidt,et al.  CYCLIC NUCLEOTIDE ACCUMULATION IN VITRO IN THE CEREBELLUM OF ‘NERVOUS’ NEUROLOGICALLY MUTANT MICE , 1977, Journal of neurochemistry.

[11]  A. Gilman,et al.  Adenylate cyclase permanently uncoupled from hormone receptors in a novel variant of S49 mouse lymphoma cells. , 1977, Proceedings of the National Academy of Sciences of the United States of America.

[12]  M. Schmidt,et al.  Effects of kainic acid, a cyclic analogue of glutamic acid, on cyclic nucleotide accumulation in slices of rat cerebellum , 1976, Brain Research.

[13]  W. Mcbride,et al.  CONTENTS OF SEVERAL AMINO ACIDS IN THE CEREBELLUM, BRAIN STEM AND CEREBRUM OF THE ‘STAGGERER’, ‘WEAVER’ AND ‘NERVOUS’ NEUROLOGICALLY MUTANT MICE 1 , 1976, Journal of neurochemistry.

[14]  J. Changeux,et al.  Anatomical, physiological and biochemical studies on the cerebellum from mutant mice. III. Protein differences associated with the weaver, staggerer and nervous mutations , 1976, Brain Research.

[15]  J. Hadden,et al.  Effects of levamisole and imidazole on lymphocyte proliferation and cyclic nucleotide levels. , 1975, Cellular immunology.

[16]  A. Guidotti,et al.  Cyclic GMP: reduction of cerebellar concentrations in ‘nervous’ mutant mice , 1975, Brain Research.

[17]  R. Gross,et al.  Regulation of adenosine 3':5'-monophosphate content in human astrocytoma cells by adenosine and the adenine nucleotides. , 1974, The Journal of biological chemistry.

[18]  S. Landis.  ULTRASTRUCTURAL CHANGES IN THE MITOCHONDRIA OF CEREBELLAR PURKINJE CELLS OF NERVOUS MUTANT MICE , 1973, The Journal of cell biology.

[19]  M. Nirenberg,et al.  Effect of catecholamines on the adenosine 3':5'-cyclic monophosphate concentrations of clonal satellite cells of neurons. , 1971, Proceedings of the National Academy of Sciences of the United States of America.

[20]  S. Hess,et al.  Alpha- and beta-adrenergic receptors as mediators of accumulation of cyclic adenosine 3',5'-monophosphate in specific areas of guinea pig brain. , 1971, The Journal of biological chemistry.

[21]  F. Bloom,et al.  Cyclic Adenosine Monophosphate: Possible Mediator for Norepinephrine Effects on Cerebellar Purkinje Cells , 1969, Science.

[22]  Oliver H. Lowry,et al.  Protein measurement with the Folin phenol reagent. , 1951, The Journal of biological chemistry.

[23]  D. Burk,et al.  The Determination of Enzyme Dissociation Constants , 1934 .

[24]  P. Epstein,et al.  Assay of cyclic nucleotide phosphodiesterase and resolution of multiple molecular forms of the enzyme. , 1979, Advances in cyclic nucleotide research.

[25]  R. J. Mullen,et al.  The development and degeneration of Purkinje cells in pcd mutant mice , 1978, The Journal of comparative neurology.

[26]  K. McCarthy,et al.  Alpah-adrenergic receptor modulation of beta-adrenergic, adenosine and prostaglandin E1 increased adenosine 3':5'-cyclic monophosphate levels in primary cultures of glia. , 1978, Journal of cyclic nucleotide research.

[27]  R. J. Mullen,et al.  Purkinje cell degeneration, a new neurological mutation in the mouse. , 1976, Proceedings of the National Academy of Sciences of the United States of America.

[28]  A Sattin,et al.  The effect of adenosine and adenine nucleotides on the cyclic adenosine 3', 5'-phosphate content of guinea pig cerebral cortex slices. , 1970, Molecular pharmacology.

[29]  R. Sidman,et al.  'nervous', A new mutant mouse with cerebellar disease. Les mutants pathologiques chez l'animal (colloq. Internat. Cnrs no. , 1969 .