Biomedical subjects
Publications and source records attributed to C M Regan.
Sodium valproate (VPA) inhibited the mitotic index of neuroblastoma (Neuro-2A) and glioma (C6) cells with an IC50 of 0.5 and 1.0 mM, respectively. Continued exposure of these cell lines to 1 mM VPA induced differentiation and increased adhesiveness. These observations are characteristic of putative teratogens and this implication for VPA is discussed.
The expression of the neurone-specific D2 protein changes both quantitatively and qualitatively during development in vivo and in cultures of cerebellar nerve cells. The total D2 content per unit protein shows a two-fold increase in vivo from birth to postnatal day 6, after which it declines progressively to about 50% of the maximal value. This increase can be accounted for by an immature form of the protein anodic D2 being preferentially expressed at the early stages of cerebellar development. After postnatal day 9 this form gradually switches to a mature form cathodic D2. This switch can be mimicked by neuraminidase treatment, suggesting a developmental loss of sialic acid from the D2 protein. In freshly isolated cells the total D2 content per unit protein is only 30% of that in the corresponding intact tissue from 8-day-old cerebella, but it increases rapidly during the first 8 days of culture to levels similar to those of the equivalent age in vivo. The switch from anodic D2 to cathodic D2 also occurs at a faster rate in culture, probably reflecting the culture conditions that favour differentiation. The changes in the expression of D2 during development of cerebellar nerve cells in culture suggest that anodic D2 is preferentially expressed on nerve cells that are proliferating, migrating, or in the initial stages of differentiation, whereas cathodic D2 is associated with differentiated neurones. The transition between the two forms appears to occur during the formation of interneuronal contacts.
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The fundamental concept that synapse growth and change are associated with learning is considered a "replay" of early neurodevelopmental principles that instruct neural connectivity pattern. Common mechanisms suggested to link the process of memory formation through synaptic elaboration are exemplified by the activity of cell adhesion molecules following learning and that center on waves of glycoprotein synthesis occurring in the 6- to 8-h and 10- to 12-h posttraining periods of consolidation. These are associated with spatially clustered granule cells in the adult rat hippocampus that show a transient time-dependent increase in ribosome production and greater microtubular complexity and dendritic spine number 6 to 8 h following training. The elimination and/or selection of the synapses to be retained in the memory trace is proposed to be dependent on cell adhesion molecule glycosylation events in the 10- to 12-h posttraining period. The existence of similar cell adhesion molecule glycosylation mechanisms within a corticohippocampal pathway is used to contribute to a model of memory in which sensory representations are eventually consolidated through relative change in synaptic weightings.
Exposure of rat pups to lead (less than 45 micrograms/dl blood) caused no alterations in the rate of cerebellar cell acquisition, migration or final number when compared with age-matched controls. The rate of DNA biosynthesis was higher in the lead-exposed animals compared to controls and remained elevated until postnatal day 10. This observation suggests lengthening of the cell cycle. The expected increase in DNA biosynthetic rate was delayed in neuron-enriched fractions obtained from lead-exposed pups. This may have been due to the isolation procedure specifically selecting internal granular layer cells which migrated precociously during a protracted G1 phase in a lead-impaired cell cycle. Morphometric studies revealed no difference in the number, viability and migration of cells within and from the external granular layer of the cerebellum of lead-exposed animals. It is concluded that chronic low level lead exposure has no significant effect on the early structuring of the developing cerebellum.
Mechanisms underlying the cognitive deficits arising from chronic low level lead exposure are viewed as a consequence of impaired neurodevelopmental events. These events are exemplified within the cerebellum which is formed completely after birth and, therefore, encompasses all major epochs of development. Further, the unique pharmacokinetic distribution of juvenile blood lead levels is developmentally regulated and can be correlated to the periods of impaired structuring and threshold values indicating no-effect levels established. Here, the endpoint value is related to lead-induced dysfunctioning of a morphoregulator--the neural cell adhesion molecule (NCAM). During final synaptic structuring its normal developmental sequence is perturbed when blood lead levels exceed 20 micrograms/dl. These events are similar, and compared to, those seen in the cerebellum of the staggerer mouse mutant (sg/sg) where the selection of circuits to be preserved from those transiently overproduced during development is impaired.
The major families of neural cell recognition molecules and the mechanisms by which they regulate neural development are described. The role of the neural cell adhesion molecule (NCAM) isoforms in organizing tissue structure and pattern is discussed in detail and their degree of sialylation is proposed to regulate the intimacy of cell-cell interaction, including that of synapse formation. The ability of chronic low level lead to impair normal NCAM sialylation pattern during postnatal development is discussed and this is suggested to perturb synapse selection procedures in a manner which may account for subsequent learning deficits in the adult rodent. In support of this proposal, change in hippocampal NCAM sialylation is demonstrated to occur in the synapse-specific isoform during the acquisition and consolidation of a passive avoidance response in the adult rat.