Although endoplasmic reticulum (ER) stress is a pathologic mechanism in a variety of chronic diseases, it is unclear what role it plays in chronic hypertension (HTN). Dysregulation of brain mechanisms controlling arterial pressure is strongly implicated in HTN, particularly in models involving angiotensin II (Ang II). We tested the hypothesis that ER stress in the brain is causally linked to Ang II-dependent HTN. Chronic systemic infusion of low-dose Ang II in C57BL/6 mice induced slowly developing HTN, which was abolished by co-infusion of the ER stress inhibitor tauroursodeoxycholic acid (TUDCA) into the lateral cerebroventricle. Investigations of the brain regions involved revealed robust increases in ER stress biomarkers and profound ER morphological abnormalities in the circumventricular subfornical organ (SFO), a region outside the blood-brain barrier and replete with Ang II receptors. Ang II-induced HTN could be prevented in this model by selective genetic supplementation of the ER chaperone 78-kDa glucose-regulated protein (GRP78) in the SFO. These data demonstrate that Ang II-dependent HTN is mediated by ER stress in the brain, particularly the SFO. To our knowledge, this is the first report that ER stress, notably brain ER stress, plays a key role in chronic HTN. Taken together, these findings may have broad implications for the pathophysiology of this disease.

Three physiologically characterized spindle (group Ia) afferents were labeled by the intracellular injection of HRP and were processed for light-level reconstruction. Thirty-five boutons in the ventral horn were then selected for analysis. They were serially thin sectioned and characterized in terms of volume, total surface area and the surface area of apposition to postsynaptic neurons (apposed surface area), mitochondrial volume, vesicle and active zone features, relation to presynaptic contacts, postsynaptic profile size, and position within the terminal arbor. Virtually all of these characteristics were widely variable, both within the entire population and in the endings of a single fiber. Apposed surface area, mitochondrial volume, vesicle number, active zone vesicle number, active zone number, and total active zone area were highly correlated in a positive linear manner with bouton volume. This suggests a type of ultrastructural "size principle," in which the morphological features associated with synaptic release scale directly in proportion to bouton size. This pattern also extends to local circuit interactions: the extent of an Ia bouton's input from axoaxonal contacts (86% receive at least one axoaxonal contact) was directly proportional to its size. In addition, the characteristics of an Ia bouton were related to its position on the postsynaptic element and within the terminal arbor. Vesicle density, percentage mitochondrial volume, and active zone size increased as the postsynaptic process decreased in size, while volume, apposed surface area, active zone number and area, and vesicle number all decreased as one moved downstream within a terminal branch, with the exception of the terminal bouton. Vesicle density also decreased as one moved away from the dorsal root entry zone.

The application of electron microscopic immunolabeling techniques to the identification and analysis of degenerating processes in neural tissue has greatly enhanced the ability of researchers to examine apoptosis and other degenerative disease mechanisms. This is particularly true for the early stages of such mechanisms. Traditionally, degenerating processes could only be identified at the ultrastructural level after significant cellular atrophy had occurred, when subcellular detail was obscured and synaptic relationships altered. Using immunocytochemical labeling procedures, degenerating neural and glial processes are first identified through the use of antibodies directed against a variety of degenerative markers, such as proapoptotic effectors (i.e., cytoplasmic cytochrome c), pathological components (i.e., beta amyloid deposits), or inflammatory agents (i.e., Iba1). Both the subcellular distribution of the marker within the process and the relationship of the labeled process to surrounding elements can then be carefully characterized. The information obtained can be further refined through the use of dual immunolabeling, which can provide additional data on the phenotype of the degenerating process and inputs to the process.

Long-term information storage within the brain requires the synthesis of new proteins and their use in synapse-specific modifications [1]. Recently, we demonstrated that translation sites for the local synthesis of integral membrane and secretory proteins occur within distal dendritic spines [2]. It remains unresolved, however, whether a complete secretory pathway, including Golgi and trans Golgi network-like membranes, exists near synapses for the local transport and processing of newly synthesized proteins. Here, we report evidence of a satellite secretory pathway in distal dendritic spines and distal dendrites of the mammalian brain. Membranes analogous to early (RER and ERGIC), middle (Golgi cisternae), and late (TGN) secretory pathway compartments are present within dendritic spines and in distal dendrites. Local synthesis, processing, and transport of newly translated integral membrane and secretory proteins may thus provide the molecular basis for synapse-specific modifications during long-term information storage in the brain.