ABSTRACT
Pharmaceutical treatments are being developed to correct specific behavioural and morphological aspects of neurodevelopmental disorders such as mental retardation. Fragile X syndrome is an X-linked mental retardation with abnormal dendritic protrusions from neurons in the brain. Increased signalling via excitatory metabotropic glutamate receptor (mGluR) pathways is hypothesised to contribute to this disorder. Targeting these receptors has shown improvements in both behaviour and morphology with the Fmr1-KO mouse model for the syndrome. It is not known whether similar changes occur in excitatory synaptic activity following treatment with mGluR antagonists. We tested the effects of prolonged mGluR blockade on excitatory synaptic activity at three developmental time points in hippocampal slices. We observed a rescue effect of the antagonist MPEP upon spontaneous EPSC amplitude and charge at 2 weeks but not 1 week or 8-10 weeks of development. These data support the role of mGluR antagonist treatment for functional synaptic correction at an early developmental stage in a model for fragile X syndrome.
Subject(s)
Excitatory Amino Acid Antagonists/pharmacology , Fragile X Mental Retardation Protein/genetics , Fragile X Syndrome/drug therapy , Hippocampus/drug effects , Hippocampus/growth & development , Receptors, Metabotropic Glutamate/antagonists & inhibitors , Synaptic Transmission/drug effects , Animals , Animals, Newborn , Disease Models, Animal , Excitatory Amino Acid Antagonists/therapeutic use , Female , Fragile X Syndrome/metabolism , Fragile X Syndrome/physiopathology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Organ Culture Techniques , Pyridines/pharmacology , Pyridines/therapeutic use , Receptors, Metabotropic Glutamate/physiology , Synaptic Transmission/geneticsABSTRACT
Chondrocyte 'dedifferentiation' involves the switching of the cell phenotype to one that no longer secretes extracellular matrix found in normal cartilage and occurs frequently during chondrocyte expansion in culture. It is also characterized by the differential expression of receptors and intracellular proteins that are involved in signal transduction pathways, including those associated with cell shape and actin microfilament organization. The objective of this study was to examine the modulation of chondrocyte phenotype by cultivation on polymer substrates containing poly(ethylene glycol) (PEG). We observed differential arrangement of actin organization in articular chondrocytes, depending on PEG length. When cultivated on 300 g/mol PEG substrates at day 19, chondrocytes had lost intracellular markers characteristic of the differentiated phenotype, including type II collagen and protein kinase C (PKC). On these surfaces, chondrocytes also expressed focal adhesion and signaling proteins indicative of cell attachment, spreading, and FA turnover, including RhoA, focal adhesion kinase, and vinculin. The switch to a dedifferentiated chondrocyte phenotype correlated with integrin expression. Conversely, the expression of CD44 receptors coincided with chondrogenic characteristics, suggesting that binding via these receptors could play a role in maintaining the differentiated phenotype on such substrates. These effects can be similar to those of compounds that interfere in intracellular signaling pathways and can be utilized to engineer cellular response.