Pyk2 is essential for astrocytes mobility following brain lesion.

Proline-rich tyrosine kinase 2 (Pyk2) is a calcium-dependent, non-receptor protein-tyrosine kinase of the focal adhesion kinase (FAK) family. Pyk2 is enriched in the brain, especially the forebrain. Pyk2 is highly expressed in neurons but is also present in astrocytes, where its role is not known. We used Pyk2 knockout mice (Pyk2(-/-) ) developed in our laboratory to investigate the function of Pyk2 in astrocytes. Morphology and basic properties of astrocytes in vivo and in culture were not altered in the absence of Pyk2. However, following stab lesions in the motor cortex, astrocytes-mediated wound filling was slower in Pyk2(-/-) than in wild-type littermates. In an in vitro wound healing model, Pyk2(-/-) astrocytes migrated slower than Pyk2(+/+) astrocytes. The role of Pyk2 in actin dynamics was investigated by treating astrocytic cultures with the actin-depolymerizing drug latrunculin B. Actin filaments re-polymerization after latrunculin B treatment was delayed in Pyk2(-/-) astrocytes as compared with wild-type astrocytes. We mimicked wound-induced activation by treating astrocytes in culture with tumor-necrosis factor alpha (TNFα), which increased Pyk2 phosphorylation at Tyr402. TNFα increased PKC activity, and Rac1 phosphorylation at Ser71 similarly in wild-type and Pyk2-deficient astrocytes. Conversely, we found that gelsolin, an actin-capping protein known to interact with Pyk2 in other cell types, was less enriched at the leading edge of migrating Pyk2(-/-) astrocytes, suggesting that its lack of recruitment mediated in part the effects of the mutation. This work shows the critical role of Pyk2 in astrocytes migration during wound healing.

Integrating neurotransmission in striatal medium spiny neurons.

The striatum is a major entry structure of the basal ganglia. Its role in information processing in close interaction with the cerebral cortex and thalamus has various behavioral consequences depending on the regions concerned, including control of body movements and motivation. A general feature of striatal information processing is the control by reward-related dopamine signals of glutamatergic striatal inputs and of their plasticity. This relies on specific sets of receptors and signaling proteins in medium-sized spiny neurons which belong to two groups, striatonigral and striatopallidal neurons. Some signaling pathways are activated only by dopamine or glutamate, but many provide multiple levels of interactions. For example, the cAMP pathway is mostly regulated by dopamine D1 receptors in striatonigral neurons, whereas the ERK pathway detects a combination of glutamate and dopamine signals and is essential for long-lasting modifications. These adaptations require changes in gene expression, and the signaling pathways linking synaptic activity to nuclear function and epigenetic changes are beginning to be deciphered. Their alteration underlies many aspects of striatal dysfunction in pathological conditions which include a decrease or an increase in dopamine transmission, as encountered in Parkinson's disease or exposure to addictive drugs, respectively.