Reducing excessive GABA-mediated tonic inhibition promotes functional recovery after stroke

Stroke is a leading cause of disability, but no pharmacological therapy is currently available for promoting recovery. The brain region adjacent to stroke damage-the peri-infarct zone-is critical for rehabilitation, as it shows heightened neuroplasticity, allowing sensorimotor functions to re-map from damaged areas. Thus, understanding the neuronal properties constraining this plasticity is important for the development of new treatments. Here we show that after a stroke in mice, tonic neuronal inhibition is increased in the peri-infarct zone. This increased tonic inhibition is mediated by extrasynaptic GABA(A) receptors and is caused by an impairment in GABA (γ-aminobutyric acid) transporter (GAT-3/GAT-4) function. To counteract the heightened inhibition, we administered in vivo a benzodiazepine inverse agonist specific for α5-subunit-containing extrasynaptic GABA(A) receptors at a delay after stroke. This treatment produced an early and sustained recovery of motor function. Genetically lowering the number of α5- or δ-subunit-containing GABA(A) receptors responsible for tonic inhibition also proved beneficial for recovery after stroke, consistent with the therapeutic potential of diminishing extrasynaptic GABA(A) receptor function. Together, our results identify new pharmacological targets and provide the rationale for a novel strategy to promote recovery after stroke and possibly other brain injuries.     

High-voltage electron microscopy of adrenal medulla: Direct connections between mitochondria and catecholamine-storage vesicles

Summary A high-voltage electron microscopic study of adrenal medullary cells from hypoglycemia-stressed rats revealed the existence of tubular channels which create a luminal continuity between the mitochondrial compartment and the catecholamine-storage vesicles. It is suggested that these channels allow for the transfer of materials such as high-energy nucleotides between the mitochondria and the catecholamine-storage vesicles without an intervening membrane.We thank Barbara Coalgate, Lin Cooper, Joann Cox, and the staff at the US Steel HVEM Laboratory for their assistance. This work was supported by NIH-DRR-70-4136, WVU Medical Corporation Research Grants, WVU Senate Research Grant, and West Virginia Heart Association Research Grant.     

Specific metal binding sites on calcified concretions in epithelial cells of the clam kidney

Summary Calcified granules (concretions) in the kidneys of bivalve molluscs are able to absorb metals from solution and this ability is the result of the existence of saturable, medium affinity metal binding sites on the concretions. In addition different metals may compete for the same sites so that some metals will be accumulated preferentially over others.