A Pharmacogenetic Inducible Approach to the Study of NMDA/αCaMKII Signaling in Synaptic Plasticity

We recently introduced an inducible pharmacogenetic approach where pharmacological manipulations can be used to reveal recessive mutant phenotypes in a temporally controlled manner [1]. This approach takes advantage of synergisms between pharmacological and genetic manipulations to alter the function of specific signaling pathways. For example, mice heterozygous for a point mutation (T286A) in the α-calcium/calmodulin-dependent kinase II (αCaMKII) gene show normal learning and memory. However, a concentration of an NMDA receptor antagonist (CPP) that does not affect learning in wild-type (WT) littermates, reveals learning deficits in this heterozygote (αCaMKIIT286A+/−) [1]. Here, we show that pretetanic application of a concentration of CPP (0.1 μM) ineffective in WT hippocampal slices induced deficits in αCaMKIIT286A+/− slices in hippocampal long-term potentiation (LTP), a mechanism thought to be involved in learning and memory. Importantly, posttetanic application of CPP (0.1 μM) had no effect on the expression or maintenance of LTP in hippocampal slices from αCaMKIIT286A+/− mice. Thus, this pharmacogenetic approach allowed us to demonstrate that NMDA receptor-dependent autophosphorylation of αCaMKII is required during the induction but not maintenance of LTP. This ability to temporally induce recessive mutant phenotypes could be applicable to a broad range of problems and genetic systems

Starting at the endophenotype: A role for alpha-CaMKII in schizophrenia?

Using an endophenotype-driven screen, a new study finds that α-calcium/calmodulin kinase II mutant mice exhibit a range of behavioral abnormalities related to schizophrenia. Perhaps most strikingly, this cluster of schizophrenia-related endophenotypes was associated with abnormal neurogenesis in the adult hippocampus, raising the possibility that disrupted adult neurogenesis lies at the core of this and other psychiatric disorders

Heroes of the engram

In 1904, Richard Semon introduced the term “engram” to describe the neural substrate responsible for (or at least important in) storing and recalling memories (i.e., a memory trace). The recent introduction of a vast array of powerful new tools to probe and manipulate memory function at the cell and neuronal circuit level has spurred an explosion of interest in studying the engram. However, the present “engram renaissance” was not borne in isolation but rather builds on a long tradition of memory research. We believe it is important to acknowledge the debts our current generation of scientists owes to those scientists who have offered key ideas, persevered through failed experiments and made important discoveries before us. Examining the past can also offer a fresh perspective on the present state and future promise of the field. Given the large amount of empirical advances made in recent years, it seems particularly timely to look back and review the scientists who introduced the seminal terminology, concepts, methodological approaches, and initial data pertaining to engrams. Rather than simply list their many accomplishments, here we color in some details of the lives and milestone contributions of our seven personal heroes of the engram (Richard Semon, Karl Lashley, Donald Hebb, Wilder Penfield, Brenda Milner, James McConnell, and Richard Thompson). In reviewing their historic role, we also illustrate how their work remains relevant to today’s studies

Development and Validation of a Sensitive Entropy-Based Measure for the Water Maze

In the water maze, mice are trained to navigate to an escape platform located below the water's surface, and spatial learning is most commonly evaluated in a probe test in which the platform is removed from the pool. While contemporary tracking software provides precise positional information of mice for the duration of the probe test, existing performance measures (e.g., percent quadrant time, platform crossings) fail to exploit fully the richness of this positional data. Using the concept of entropy (H), here we develop a new measure that considers both how focused the search is and the degree to which searching is centered on the former platform location. To evaluate how H performs compared to existing measures of water maze performance we compiled five separate databases, containing more than 1600 mouse probe tests. Random selection of individual trials from respective databases then allowed us to simulate experiments with varying sample and effect sizes. Using this Monte Carlo-based method, we found that H outperformed existing measures in its ability to detect group differences over a range of sample or effect sizes. Additionally, we validated the new measure using three models of experimentally induced hippocampal dysfunction: (1) complete hippocampal lesions, (2) genetic deletion of αCaMKII, a gene implicated in hippocampal behavioral and synaptic plasticity, and (3) a mouse model of Alzheimer's disease. Together, these data indicate that H offers greater sensitivity than existing measures, most likely because it exploits the richness of the precise positional information of the mouse throughout the probe test

What is the Most Sensitive Measure of Water Maze Probe Test Performance?

The water maze is commonly used to assay spatial cognition, or, more generally, learning and memory in experimental rodent models. In the water maze, mice or rats are trained to navigate to a platform located below the water's surface. Spatial learning is then typically assessed in a probe test, where the platform is removed from the pool and the mouse or rat is allowed to search for it. Performance in the probe test may then be evaluated using either occupancy-based (percent time in a virtual quadrant [Q] or zone [Z] centered on former platform location), error-based (mean proximity to former platform location [P]) or counting-based (platform crossings [X]) measures. While these measures differ in their popularity, whether they differ in their ability to detect group differences is not known. To address this question we compiled five separate databases, containing more than 1600 mouse probe tests. Random selection of individual trials from respective databases then allowed us to simulate experiments with varying sample and effect sizes. Using this Monte Carlo-based method, we found that the P measure consistently outperformed the Q, Z and X measures in its ability to detect group differences. This was the case regardless of sample or effect size, and using both parametric and non-parametric statistical analyses. The relative superiority of P over other commonly used measures suggests that it is the most appropriate measure to employ in both low- and high-throughput water maze screens

Neurogenesis-mediated forgetting minimizes proactive interference.

Established memories may interfere with the encoding of new memories, particularly when existing and new memories overlap in content. By manipulating levels of hippocampal neurogenesis, here we show that neurogenesis regulates this form of proactive interference. Increasing hippocampal neurogenesis weakens existing memories and, in doing so, facilitates the encoding of new, conflicting (but not non-conflicting) information in mice. Conversely, decreasing neurogenesis stabilizes existing memories, and impedes the encoding of new, conflicting information. These results suggest that reduced proactive interference is an adaptive benefit of neurogenesis-induced forgetting

Impaired spatial and contextual memory formation in galectin-1 deficient mice

Galectins are a 15 member family of carbohydrate-binding proteins that have been implicated in cancer, immunity, inflammation and development. While galectins are expressed in the central nervous system, little is known about their function in the adult brain. Previously we have shown that galectin-1 (gal-1) is expressed in the adult hippocampus, and, in particular, in putative neural stem cells in the subgranular zone. To evaluate how gal-1 might contribute to hippocampal memory function here we studied galectin-1 null mutant (gal-1-/-) mice. Compared to their wildtype littermate controls, gal-1-/- mice exhibited impaired spatial learning in the water maze and contextual fear learning. Interestingly, tone fear conditioning was normal in gal-1-/- mice suggesting that loss of gal-1 might especially impact hippocampal learning and memory. Furthermore, gal-1-/- mice exhibited normal motor function, emotion and sensory processing in a battery of other behavioral tests, suggesting that non-mnemonic performance deficits are unlikely to account for the spatial and contextual learning deficits. Together, these data reveal a role for galectin-carbohydrate signalling in hippocampal memory function

Fetal alcohol exposure leads to abnormal olfactory bulb development and impaired odor discrimination in adult mice

Background: Children whose mothers consumed alcohol during pregnancy exhibit widespread brain abnormalities and a complex array of behavioral disturbances. Here, we used a mouse model of fetal alcohol exposure to investigate relationships between brain abnormalities and specific behavioral alterations during adulthood. Results: Mice drank a 10% ethanol so

Metformin Activates an Atypical PKC-CBP Pathway to Promote Neurogenesis and Enhance Spatial Memory Formation

SummaryAlthough endogenous recruitment of adult neural stem cells has been proposed as a therapeutic strategy, clinical approaches for achieving this are lacking. Here, we show that metformin, a widely used drug, promotes neurogenesis and enhances spatial memory formation. Specifically, we show that an atypical PKC-CBP pathway is essential for the normal genesis of neurons from neural precursors and that metformin activates this pathway to promote rodent and human neurogenesis in culture. Metformin also enhances neurogenesis in the adult mouse brain in a CBP-dependent fashion, and in so doing enhances spatial reversal learning in the water maze. Thus, metformin, by activating an aPKC-CBP pathway, recruits neural stem cells and enhances neural function, thereby providing a candidate pharmacological approach for nervous system therapy.Video Abstrac

p73 Regulates Neurodegeneration and Phospho-Tau Accumulation during Aging and Alzheimer's Disease

SummaryThe genetic mechanisms that regulate neurodegeneration are only poorly understood. We show that the loss of one allele of the p53 family member, p73, makes mice susceptible to neurodegeneration as a consequence of aging or Alzheimer's disease (AD). Behavioral analyses demonstrated that old, but not young, p73+/− mice displayed reduced motor and cognitive function, CNS atrophy, and neuronal degeneration. Unexpectedly, brains of aged p73+/− mice demonstrated dramatic accumulations of phospho-tau (P-tau)-positive filaments. Moreover, when crossed to a mouse model of AD expressing a mutant amyloid precursor protein, brains of these mice showed neuronal degeneration and early and robust formation of tangle-like structures containing P-tau. The increase in P-tau was likely mediated by JNK; in p73+/− neurons, the activity of the p73 target JNK was enhanced, and JNK regulated P-tau levels. Thus, p73 is essential for preventing neurodegeneration, and haploinsufficiency for p73 may be a susceptibility factor for AD and other neurodegenerative disorders