Cell Adhesion Molecule Polysialylation State Research Articles

Class I histone deacetylase inhibition ameliorates social cognition and cell adhesion molecule plasticity deficits in a rodent model of autism spectrum disorder

In utero exposure of rodents to valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, has been proposed to induce an adult phenotype with behavioural characteristics reminiscent of those observed in autism spectrum disorder (ASD). We have evaluated the face validity of this model in terms of social cognition deficits which are a major core symptom of ASD. We employed the social approach avoidance paradigm as a measure of social reciprocity, detection of biological motion that is crucial to social interactions, and spatial learning as an indicator of dorsal stream processing of social cognition and found each parameter to be significantly impaired in Wistar rats with prior in utero exposure to VPA. We found no significant change in the expression of neural cell adhesion molecule polysialylation state (NCAM PSA), a measure of construct validity, but a complete inability to increase its glycosylation state which is necessary to mount the neuroplastic response associated with effective spatial learning. Finally, in all cases, we found chronic HDAC inhibition, with either pan-specific or HDAC1-3 isoform-specific inhibitors, to significantly ameliorate deficits in both social cognition and its associated neuroplastic response. We conclude that in utero exposure to VPA provides a robust animal model for the social cognitive deficits of ASD and a potential screen for the development of novel therapeutics for this condition.

Low-Level Lead Exposure in the Early Postnatal Period Results in Persisting Neuroplastic Deficits Associated with Memory Consolidation

Prospective studies in humans and experimental investigations in animals have correlated elevated perinatal blood lead levels with enduring behavioural and cognitive perturbations. Although deficits in neuroplastic events necessary for long-term memory consolidation have been observed during the postnatal period, there is little evidence that these persist into adulthood in the absence of continued lead exposure. To address this issue, we exposed Wistar rat pups to 400 mg of PbCI2/L via their dams' drinking water from postnatal day 1 to 30. At postnatal day 80, the animals were trained in a one-trial, step-through, light-dark passive avoidance paradigm. Prior postnatal lead exposure resulted in a significant decline in recall latency on posttraining day 5, an effect that was specific to the learned response as no obvious behavioural alterations were apparent in open-field studies. As recall was unaffected in the immediate 48-h posttraining period, this suggested an enduring impairment in events associated with long-term memory storage. To investigate this further, we determined the influence of prior lead exposure on the transient modulations of hippocampal neural cell adhesion molecule polysialylation state that occur in the 10-12-h posttraining period, a neuroplastic event associated with memory consolidation. Direct quantification of polysialylated dentate neurons revealed prior lead exposure to have no effect on basal number but to significantly delay and blunt the transient increase observed in control animals at the 12-h posttraining time. These findings confirm that lead exposure in the postnatal period results in enduring neuroplastic deficits most likely associated with reordering of connections in pathways subservient to memory consolidation.

The selective 5-HT 6 receptor antagonists SB-271046 and SB-399885 potentiate NCAM PSA immunolabeling of dentate granule cells, but not neurogenesis, in the hippocampal formation of mature Wistar rats

While there is now substantial evidence that 5-HT 6 antagonism leads to significantly improved cognitive ability, the mechanism(s) and/or pathway(s) involved are poorly understood. We have evaluated the consequence of chronic administration of the 5-HT 6 receptor antagonists SB-271046 and SB-399885 on neural cell adhesion molecule polysialylation state (NCAM PSA), a neuroplastic mechanism necessary for memory consolidation. Quantitative analysis of NCAM PSA immunopositive neurons in the dentate gyrus of drug-treated animals revealed a dose-dependent increase in polysialylated cell frequency following treatment with both SB-271046 and SB-399885. These effects could not be attributed to increased neurogenesis, as no difference in the rate of bromodeoxyuridine incorporation was apparent between the control and drug-treated groups. A substantial increase in the frequency of polysialylated cells in layer II of the entorhinal and perirhinal cortices was also observed, brain regions not previously associated with neurogenesis. Chronic treatment with SB-271046 or SB-399885 also significantly increased the activation of dentate polysialylation that is specific to learning. This effect does not occur with other cognition-enhancing drugs, such as tacrine, and this action potentially differentiates 5-HT 6 receptor antagonism as an unique neuroplastic mechanism for cognitive processes which may slow or reverse age/neurodegenerative related memory deficits.

Protein kinase C delta regulates neural cell adhesion molecule polysialylation state in the rat brain.

Polysialylation of neural cell adhesion molecule (NCAM PSA) modulates cell-cell homophilic binding and signalling during brain development and the remodelling of discrete brain regions in the adult. Following learning, a transient increase in the frequency of polysialylated neurones occurs in the dentate gyrus of the hippocampal formation, and this has been correlated with the selective retention and/or elimination of synapses that are transiently overproduced during memory consolidation. We now demonstrate that protein kinase C delta (PKCdelta) negatively regulates polysialyltransferase activity in the rat brain during development and also in the hippocampus during memory consolidation, where its down-regulation in the Golgi membrane fraction coincides with the transient increase in NCAM PSA expression. Decreased expression of PKCdelta was also observed in the hippocampus of rats reared in a complex environment and this directly contrasted the significant increase in frequency of hippocampal polysialylated neurones observed in these animals. These effects were isoform-specific as no change in total PKC enzyme activity was detected during memory consolidation and complex environment rearing had no effect on the hippocampal expression of PKCalpha, beta, gamma or epsilon. By sequential immunoprecipitation and immunoblot analysis, phosphorylation of polysialyltransferase protein(s) was (were) demonstrated to occur on both serine and tyrosine residues and this was associated with decreased enzyme activity. Moreover, a similar experimental approach revealed the degree of PKCdelta co-precipitation with polysialyltransferase protein(s) to be inversely correlated with polysialyltransferase activity. These findings support in vitro evidence indicating PKCdelta to regulate polysialyltransferase activity and NCAM polysialylation state.

Regulation of neural cell adhesion molecule polysialylation state by cell‐cell contact and protein kinase C delta

Regulation of neural cell adhesion molecule polysialylation state by cell‐cell contact and protein kinase C delta

Regulation of neural cell adhesion molecule polysialylation state by cell-cell contact and protein kinase C delta.

Post-translational modification of neural cell adhesion molecule (NCAM) with alpha2,8-linked polysialic acid, which regulates homophilic adhesion and/or signal transduction events, is crucial to synaptic plasticity in the developing and adult brain. Evidence from in vitro models has implicated polysialylation in the regulation of cell growth, migration, and differentiation. Here, using two in vitro models, we demonstrate that polysialylation is downregulated by cell-cell contact and correlated with a state of neuronal differentiation. Furthermore, we report a role for protein kinase C delta (PKCdelta) in the regulation of NCAM polysialylation. Pharmacological studies using the PKC activator, phorbol myristate acetate, and inhibitors, calphostin-C, and staurosporine, demonstrated PKC activity to be inversely related to NCAM polysialylation in the mouse neuro-2A cell line. Isoform-specific immunoblot studies indicated this effect to be mediated by the calcium-independent PKCdelta isozyme, as its expression was inversely related to NCAM polysialylation state in both neuro-2A and rat PC-12 cell lines. Isoform specificity was further confirmed using the PKCdelta-selective inhibitor rottlerin, which produced a marked increase in PSA expression (36.9+/-5.25 a.u. vs. 24.7+/-0.80 arbitrary units control) coupled with a neuritogenic response. Likewise, decreased expression of PKCdelta was seen in nerve growth factor (NGF)-differentiated PC-12 cells. These findings suggest that the neuronal differentiation process may involve inhibition of PKCdelta, resulting in enhanced morphological plasticity, as evidenced by activation of NCAM polysialylation.

Kv1.1 channel antisense attenuates learning and modulation of dentate polysialylated NCAM.

The distribution and modulation of neural cell adhesion molecule polysialylation state (NCAM PSA) and the consequence of antisense inactivation of the Kv1.1 potassium channel was investigated following avoidance learning in mice. PSA immunoreactivity was most notable on cells at the inner denate border and in cortical layer II. Task acquisition resulted in a significant 30% transient increase in the frequency of dentate polysialylated neurons at the 12 h post-training time. In contrast, animals pretreated with the Kv1.1 antisense oligonucleotide exhibited both attenuated recall avoidance latencies and polysialylated cell frequency. As Kv1.1 is enriched on the dendrites of these granule-like cells, the attenuated polysialylation response is considered secondary to NCAM-mediated events during their transient synapse production in the 6-8 h post-training period.

Repetitive and transient increases in hippocampal neural cell adhesion molecule polysialylation state following multitrial spatial training.

Polysialylated neurons, located at the inner border of the dentate granule cell layer, have been demonstrated to exhibit time-dependent change in their frequency at 10-12 h following training in the Morris water maze, a spatial learning paradigm. Such a change was not observed in animals required to locate a visible platform or in those rendered amnesic with scopolamine. This frequency response was capable of rapid reactivation following further training stimuli in a manner that was independent of circadian influence. These learning-associated modulations in neural cell adhesion molecule (NCAM) polysialylation state did not increase in magnitude despite improved performance, suggesting their activation is required for processing information rather than contributing to previously stored, task-associated memory. An increase in NCAM polysialylation appears to be a universal learning response to both spatial and nonspatial paradigms as similar time-dependent changes occurred following training in a one-trial, step-through, passive avoidance response subsequent to water maze training.