Astrocytic CD44 Deficiency Reduces the Severity of Kainate-Induced Epilepsy.

BACKGROUND: Epilepsy affects millions of people worldwide, yet we still lack a successful treatment for all epileptic patients. Most of the available drugs modulate neuronal activity. Astrocytes, the most abundant cells in the brain, may constitute alternative drug targets. A robust expansion of astrocytic cell bodies and processes occurs after seizures. Highly expressed in astrocytes, CD44 adhesion protein is upregulated during injury and is suggested to be one of the most important proteins associated with epilepsy. It connects the astrocytic cytoskeleton to hyaluronan in the extracellular matrix, influencing both structural and functional aspects of brain plasticity. METHODS: Herein, we used transgenic mice with an astrocyte CD44 knockout to evaluate the impact of the hippocampal CD44 absence on the development of epileptogenesis and ultrastructural changes at the tripartite synapse. RESULTS: We demonstrated that local, virally-induced CD44 deficiency in hippocampal astrocytes reduces reactive astrogliosis and decreases the progression of kainic acid-induced epileptogenesis. We also observed that CD44 deficiency resulted in structural changes evident in a higher dendritic spine number along with a lower percentage of astrocyte-synapse contacts, and decreased post-synaptic density size in the hippocampal molecular layer of the dentate gyrus. CONCLUSIONS: Overall, our study indicates that CD44 signaling may be important for astrocytic coverage of synapses in the hippocampus and that alterations of astrocytes translate to functional changes in the pathology of epilepsy.

S-Palmitoylation of Synaptic Proteins in Neuronal Plasticity in Normal and Pathological Brains.

Protein lipidation is a common post-translational modification of proteins that plays an important role in human physiology and pathology. One form of protein lipidation, S-palmitoylation, involves the addition of a 16-carbon fatty acid (palmitate) onto proteins. This reversible modification may affect the regulation of protein trafficking and stability in membranes. From multiple recent experimental studies, a picture emerges whereby protein S-palmitoylation is a ubiquitous yet discrete molecular switch enabling the expansion of protein functions and subcellular localization in minutes to hours. Neural tissue is particularly rich in proteins that are regulated by S-palmitoylation. A surge of novel methods of detection of protein lipidation at high resolution allowed us to get better insights into the roles of protein palmitoylation in brain physiology and pathophysiology. In this review, we specifically discuss experimental work devoted to understanding the impact of protein palmitoylation on functional changes in the excitatory and inhibitory synapses associated with neuronal activity and neuronal plasticity. The accumulated evidence also implies a crucial role of S-palmitoylation in learning and memory, and brain disorders associated with impaired cognitive functions.

The cell adhesion protein dystroglycan affects the structural remodeling of dendritic spines.

Dystroglycan (DG) is a cell membrane protein that binds to the extracellular matrix in various mammalian tissues. The function of DG has been well defined in embryonic development as well as in the proper migration of differentiated neuroblasts in the central nervous system (CNS). Although DG is known to be a target for matrix metalloproteinase-9 (MMP-9), cleaved in response to enhanced synaptic activity, the role of DG in the structural remodeling of dendritic spines is still unknown. Here, we report for the first time that the deletion of DG in rat hippocampal cell cultures causes pronounced changes in the density and morphology of dendritic spines. Furthermore, we noted a decrease in laminin, one of the major extracellular partners of DG. We have also observed that the lack of DG evokes alterations in the morphological complexity of astrocytes accompanied by a decrease in the level of aquaporin 4 (AQP4), a protein located within astrocyte endfeet surrounding neuronal dendrites and synapses. Regardless of all of these changes, we did not observe any effect of DG silencing on either excitatory or inhibitory synaptic transmission. Likewise, the knockdown of DG had no effect on Psd-95 protein expression. Our results indicate that DG is involved in dendritic spine remodeling that is not functionally reflected. This may suggest the existence of unknown mechanisms that maintain proper synaptic signaling despite impaired structure of dendritic spines. Presumably, astrocytes are involved in these processes.