This Week in The Journal

Cellular/Molecular

InsP₃-Mediated Calcium Domains

Simon N. Jacob, Chi-Un Choe, Per Uhlen, Brenda DeGray, Mark F. Yeckel, and Barbara E. Ehrlich

The local calcium microdomains created around voltage-gated calcium channels are a well described feature of nerve terminals. Now Jacob et al. extend the evidence for localized calcium microdomains to inositol 1,4,5-trisphosphate (InsP₃)-mediated signals in the cytoplasm. InsP₃ generates calcium transients by activating calcium release channels in the endoplasmic reticulum. Using immunohistochemistry in cultured hippocampal neurons and pheochromocytoma (PC12) cells, the authors found localized domains of proteins that increase InsP₃ receptor activity, specifically phosphatidylinositol-4-phosphate kinase (PIPKIγ) and chromogranin B (CGB). For example PIPKIγ was concentrated at growth cones and at neurite branch points. Calcium pumps and buffers were distributed more uniformly. Pharmacological disruption of PIPKIγ or CGB altered the kinetics and site of initiation of the calcium transients. The results suggest that the distribution of PIPKIγ and CGB plays an important role in determining the site of fast, localized calcium signaling in the cytoplasm.

Development/Plasticity/Repair

When Tangential Is Right on Target

Irina Bystron, Zoltán Molnár, Vladimir Otellin, and Colin Blakemore

(see pages 2781-2792)

This week, Bystron et al. provide information on the earliest neurons that appear in the human telencephalon, well before the formation of the cortical plate or the onset of synaptogenesis. They identified the cells as neurons based on microtubule-associated protein 2 (MAP2) immunoreactivity in tissue available from embryonic forebrain 1-2 months after conception. Using dye-tracing methods in fixed tissue, the authors found that the nonaxonal processes of these cells formed tangential “guide wires” between the intermediate zones of brain subdivisions, including the thalamus, ganglionic eminence, hypothalamus, and cortical plate. Based on their monopolar or bipolar morphology and on the appearance of similar cells at the level of the ventricular angle and the intermediate zone of the basal telencephalon, the authors suggest that these pioneering neurons originate in the subcortical area. These cells may serve a role in guiding axons or transverse neuronal migration akin to the “pioneer” neurons in invertebrates or the transient early neurons in several mammalian species.

A precocious neuron in the human preplate is stained with an anti-MAP2 antibody. See the article by Bystron et al. for details.

Behavioral/Systems/Cognitive

Goals and Habits in the Overtrained Rat

Alexis Faure, Ulrike Haberland, Françoise Condé, and Nicole El Massioui

(see pages 2771-2780)

While learning a task, goal-directed performance is dictated by associations between an action and the outcome. If the outcome or reward is reduced, the behavior changes as well. However after many repetitions, reward-motivated actions become a matter of habit and essentially continue regardless of the outcome: stimulus-response, stimulus-response, stimulus-response. This week, Faure et al. examine the turning point between action-outcome and stimulus-response associations in the rat nigrostriatal dopaminergic pathway. They selectively destroyed dopaminergic neurons with 6-hydroxydopamine (6-OHDA). Rats were overtrained to either press a lever or pull a chain to receive a food or sugar pellet in response to a tone or light. With goal devaluation, control rats continued to press the lever (i.e., it had become habit). However, the more difficult chain-pulling task was sensitive to devaluation, suggesting that the complexity of a motor task affects habit formation. After 6-OHDA lesions, both tasks were sensitive to devaluation, confirming a role for striatal dopamine transmission in habit formation.

Neurobiology of Disease

A FLIM Analysis of PS1 Conformations

Oksana Berezovska, Alberto Lleo, Lauren D. Herl, Matthew P. Frosch, Edward A. Stern, Brian J. Bacskai, and Bradley T. Hyman

(see pages 3009-3017)

Familial Alzheimer's disease (AD) is associated with autosomal dominant mutations in presenilin 1 (PS1), one of the components of the γ-secretase complex that cleaves amyloid β (Aβ) from the amyloid precursor protein. Each mutation increases the ratio of Aβ₄₂ to Aβ₄₀ and causes plaque buildup and early disease onset. Berezovska et al. hypothesized that the common pathology arises from an abnormal conformation of PS1. Presenilin 1 normally undergoes processing to function as a heterodimeric complex of N- and C-terminal fragments. The authors labeled various domain pairs in PS1 and then used fluorescence lifetime imaging microscopy (FLIM) to assay intermolecular distances in intact cells. The C and N termini were closer together in PS1 mutations, whereas nonsteroidal anti-inflammatory drugs (NSAIDs) levered the domains apart. Accordingly, NSAID treatment offset the conformational change caused by a PS1 mutation. The authors suggest that the observed conformation is shared by PS1 mutations and represents an AD-causing phenotype.