Thomas C. Foster

Calcium homeostasis and modulation of synaptic plasticity in the aged brain.

The level of intracellular Ca2+ plays a central role in normal and pathological signaling within and between neurons. These processes involve a cascade of events for locally raising and lowering cytosolic Ca2+. As the mechanisms for age‐related alteration in Ca2+ dysregulation have been illuminated, hypotheses concerning Ca2+ homeostasis and brain aging have been modified. The idea that senescence is due to pervasive cell loss associated with elevated resting Ca2+ has been replaced by concepts concerning changes in local Ca2+ levels associated with neural activity. This article reviews evidence for a shift in the sources of intracellular Ca2+ characterized by a diminished role for N‐methyl‐D‐aspartate receptors and an increased role for intracellular stores and voltage‐dependent Ca2+ channels. Physiological and biological models are outlined, which relate a shift in Ca2+ regulation with changes in cell excitability and synaptic plasticity, resulting in a functional lesion of the hippocampus.

Curcumin reverses impaired hippocampal neurogenesis and increases serotonin receptor 1A mRNA and brain-derived neurotrophic factor expression in chronically stressed rats

Curcuma longa is a major constituent of Xiaoyao-san, the traditional Chinese medicine, which has been used to effectively manage stress and depression-related disorders in China. As the active component of curcuma longa, curcumin possesses many therapeutic properties; we have previously described its antidepressant activity in our earlier studies using the chronic unpredictable stress model of depression in rats. Recent studies show that stress-induced damage to hippocampal neurons may contribute to the phathophysiology of depression. The aim of this study was to investigate the effects of curcumin on hippocampal neurogenesis in chronically stressed rats. We used an unpredictable chronic stress paradigm (20 days) to determine whether chronic curcumin treatment with the effective doses for behavioral responses (5, 10 and 20 mg/kg, p.o.), could alleviate or reverse the effects of stress on adult hippocampal neurogenesis. Our results suggested that curcumin administration (10 and 20 mg/kg, p.o.) increased hippocampal neurogenesis in chronically stressed rats, similar to classic antidepressant imipramine treatment (10 mg/kg, i.p.). Our results further demonstrated that these new cells mature and become neurons, as determined by triple labeling for BrdU and neuronal- or glial-specific markers. In addition, curcumin significantly prevented the stress-induced decrease in 5-HT(1A) mRNA and BDNF protein levels in the hippocampal subfields, two molecules involved in hippocampal neurogenesis. These results raise the possibility that increased cell proliferation and neuronal populations may be a mechanism by which curcumin treatment overcomes the stress-induced behavioral abnormalities and hippocampal neuronal damage. Moreover, curcumin treatment, via up-regulation of 5-HT(1A) receptors and BDNF, may reverse or protect hippocampal neurons from further damage in response to chronic stress, which may underlie the therapeutic actions of curcumin.

Muscleblind-like 2-Mediated Alternative Splicing in the Developing Brain and Dysregulation in Myotonic Dystrophy

The RNA-mediated disease model for myotonic dystrophy (DM) proposes that microsatellite C(C)TG expansions express toxic RNAs that disrupt splicing regulation by altering MBNL1 and CELF1 activities. While this model explains DM manifestations in muscle, less is known about the effects of C(C)UG expression on the brain. Here, we report that Mbnl2 knockout mice develop several DM-associated central nervous system (CNS) features including abnormal REM sleep propensity and deficits in spatial memory. Mbnl2 is prominently expressed in the hippocampus and Mbnl2 knockouts show a decrease in NMDA receptor (NMDAR) synaptic transmission and impaired hippocampal synaptic plasticity. While Mbnl2 loss did not significantly alter target transcript levels in the hippocampus, misregulated splicing of hundreds of exons was detected using splicing microarrays, RNA-seq, and HITS-CLIP. Importantly, the majority of the Mbnl2-regulated exons examined were similarly misregulated in DM. We propose that major pathological features of the DM brain result from disruption of the MBNL2-mediated developmental splicing program.

Calcium Dysregulation in the Aging Brain

The idea that age-related cognitive decline is associated with disruption of calcium (Ca2+) homeostasis has been investigated over the past two decades. Much of this work has focused on the hippocampus because hippocampal-dependent memory is age sensitive. It is now well established that Ca2+-dependent processes such as susceptibility to neurotoxicity, the afterhyperpolarization amplitude, induction of synaptic plasticity, and long-term potentiation and long-term depression are altered with age. Recent work has identified changes in Ca2+signaling pathways that may underlie the development of these biological markers of aging. This review considers recent findings concerning interactions between the various Ca2+-dependent processes, with special emphasis on the role of altered Ca2+ regulation and disruption of Ca2+ signaling pathways in mediating the expression of biological and behavioral markers of brain aging.

Intracellular Redox State Alters NMDA Receptor Response during Aging through Ca2+/Calmodulin-Dependent Protein Kinase II

The contribution of the NMDA receptors (NMDARs) to synaptic plasticity declines during aging, and the decline is thought to contribute to memory deficits. Here, we demonstrate that an age-related shift in intracellular redox state contributes to the decline in NMDAR responses through Ca2+/calmodulin-dependent protein kinase II (CaMKII). The oxidizing agent xanthine/xanthine oxidase (X/XO) decreased the NMDAR-mediated synaptic responses at hippocampal CA3–CA1 synapses in slices from young (3–8 months) but not aged (20–25 months) rats. Conversely, the reducing agent dithiothreitol (DTT) selectively enhanced NMDAR response to a greater extent in aged hippocampal slices. The enhancement of NMDAR responses facilitated induction of long-term potentiation in aged but not young animals. The DTT-mediated growth in the NMDAR response was not observed for the AMPA receptor-mediated synaptic responses. A similar increase was observed by intracellular application of the membrane-impermeable reducing agent, l-glutathione (l-GSH), through the intracellular recording pipette, indicating that the increased NMDAR response was dependent on intracellular redox state. DTT enhancement of the NMDAR response was dependent on CaMKII activity and was blocked by the CaMKII inhibitor—myristoylated autocamtide-2-related inhibitory peptide (myr-AIP)—but not by inhibition of the activity of protein phosphatases—PP1 and calcineurin (CaN/PP2B) or protein kinase C. CaMKII activity assays established that DTT increased CaMKII activity in CA1 cytosolic extracts in aged but not in young animals. These findings indicate a link between oxidation of CaMKII during aging, a decline in NMDAR responses, and altered synaptic plasticity.

Role of Estrogen Receptor Alpha and Beta Expression and Signaling on Cognitive Function During Aging

This review presents evidence for the idea that the expression of estrogen receptor alpha and beta (ERα and ERβ) interacts with the level of estradiol (E2) to influence the etiology of age‐related cognitive decline and responsiveness to E2 treatments. There is a nonmonotonic dose response curve for E2 influences on behavior and transcription. Evidence is mounting to indicate that the dose response curve is shifted according to the relative expression of ERα and ERβ. Recent work characterizing age‐related changes in the expression of ERα and ERβ in the hippocampus, as well as studies using mutant mice, and viral mediated delivery of estrogen receptors indicate that an age‐related shift in ERα/ERβ expression, combined with declining gonadal E2 can impact transcription, cell signaling, neuroprotection, and neuronal growth. Finally, the role of ERα/ERβ on rapid E2 signaling and synaptogenesis as it relates to hippocampal aging is discussed.

AAV-Mediated Gene Therapy for Retinal Degeneration in the rd10 Mouse Containing a Recessive PDEβ Mutation

PURPOSE To test AAV-mediated gene therapy in the rd10 mouse, a natural model of recessive RP caused by mutation of the beta-subunit of rod photoreceptor cGMP phosphodiesterase. METHODS One eye of a cohort of rd10 mice kept in a dark environment was subretinally injected at postnatal day (P) 14 with 1 microL AAV5-smCBA-PDEbeta. The contralateral eye was not injected. The animals were then maintained for 2 weeks in the dark before they were moved to a normal 12-hour light/12-hour dark cycling light environment for visually guided behavioral training. Three weeks after injection, treated rd10 mice were examined by scotopic and photopic electroretinography and then killed for biochemical and morphologic examination. RESULTS Substantial scotopic ERG signals were maintained in treated rd10 eyes, whereas untreated eyes in the same animals showed minimal signals. Treated eyes showed photopic ERG b-wave amplitudes similar to those of the normal eyes; in untreated partner eyes, only half the normal amplitudes remained. Strong PDEbeta expression was observed in photoreceptor outer segments only in treated eyes. Light microscopy showed a substantial preservation of the outer nuclear layer in most parts of the treated retina only. Electron microscopy showed good outer segment preservation only in treated eyes. A visually guided water maze behavioral test under dim light showed significantly improved performance in one eye-treated rd10 mice compared with untreated mice. CONCLUSIONS These data demonstrate that P14 administration of AAV5-smCBA-PDEbeta can prevent retinal degeneration in rd10 mice, as reflected by significant structural, biochemical, electrophysiological, and behavioral preservation/restoration. These results serve as a baseline for studying long-term retinal rescue in rd10 mice.

Daily exercise improves memory, stimulates hippocampal neurogenesis and modulates immune and neuroimmune cytokines in aging rats

We tested whether daily exercise modulates immune and neuroimmune cytokines, hippocampus-dependent behavior and hippocampal neurogenesis in aging male F344 rats (18mo upon arrival). Twelve weeks after conditioned running or control group assignment, the rats were trained and tested in a rapid water maze followed by an inhibitory avoidance task. The rats were BrdU-injected beginning 12days after behavioral testing and killed 3weeks later to quantify cytokines and neurogenesis. Daily exercise increased neurogenesis and improved immediate and 24h water maze discrimination index (DI) scores and 24h inhibitory avoidance retention latencies. Daily exercise decreased cortical VEGF, hippocampal IL-1β and serum MCP-1, GRO-KC and leptin levels but increased hippocampal GRO-KC and IL-18 concentrations. Serum leptin concentration correlated negatively with new neuron number and both DI scores while hippocampal IL-1β concentration correlated negatively with memory scores in both tasks. Cortical VEGF, serum GRO-KC and serum MCP-1 levels correlated negatively with immediate DI score and we found novel positive correlations between hippocampal IL-18 and GRO-KC levels and new neuron number. Pathway analyses revealed distinct serum, hippocampal and cortical compartment cytokine relationships. Our results suggest that daily exercise potentially improves cognition in aging rats by modulating hippocampal neurogenesis and immune and neuroimmune cytokine signaling. Our correlational data begin to provide a framework for systematically manipulating these immune and neuroimmune signaling molecules to test their effects on cognition and neurogenesis across lifespan in future experiments.

Dissecting the age-related decline on spatial learning and memory tasks in rodent models: N-methyl-D-aspartate receptors and voltage-dependent Ca2+ channels in senescent synaptic plasticity

In humans, heterogeneity in the decline of hippocampal-dependent episodic memory is observed during aging. Rodents have been employed as models of age-related cognitive decline and the spatial water maze has been used to show variability in the emergence and extent of impaired hippocampal-dependent memory. Impairment in the consolidation of intermediate-term memory for rapidly acquired and flexible spatial information emerges early, in middle-age. As aging proceeds, deficits may broaden to include impaired incremental learning of a spatial reference memory. The extent and time course of impairment has been be linked to senescence of calcium (Ca²⁺) regulation and Ca²⁺-dependent synaptic plasticity mechanisms in region CA1. Specifically, aging is associated with altered function of N-methyl-D-aspartate receptors (NMDARs), voltage-dependent Ca²⁺ channels (VDCCs), and ryanodine receptors (RyRs) linked to intracellular Ca²⁺ stores (ICS). In young animals, NMDAR activation induces long-term potentiation of synaptic transmission (NMDAR-LTP), which is thought to mediate the rapid consolidation of intermediate-term memory. Oxidative stress, starting in middle-age, reduces NMDAR function. In addition, VDCCs and ICS can actively inhibit NMDAR-dependent LTP and oxidative stress enhances the role of VDCC and RyR-ICS in regulating synaptic plasticity. Blockade of L-type VDCCs promotes NMDAR-LTP and memory in older animals. Interestingly, pharmacological or genetic manipulations to reduce hippocampal NMDAR function readily impair memory consolidation or rapid learning, generally leaving incremental learning intact. Finally, evidence is mounting to indicate a role for VDCC-dependent synaptic plasticity in associative learning and the consolidation of remote memories. Thus, VDCC-dependent synaptic plasticity and extrahippocampal systems may contribute to incremental learning deficits observed with advanced aging.

Biological markers of age-related memory deficits: treatment of senescent physiology.

In humans, age-related memory impairments begin in mid-life and cognitive weakening continues with advancing age. An important aspect of defining memory decline is the distinction between dementia as a result of neurological diseases, such as Alzheimer’s disease, and memory loss not specifically associated with disease. Within the population of elderly without dementia, there is considerable variability in memory. This variability is likely to be a result of the interaction of genetic make-up and environment, which influences several processes for cell maintenance and repair including oxidative damage and cholesterol metabolism, leading to disruption of Ca2+ homeostasis, and ultimately Ca2+-dependent processes that underlie memory. In humans, several methods have been employed to distinguish biological markers of aging that may predict cognitive decline.Memory deficits associated with normal aging and Alzheimer’s disease have been linked to a decrease in the volume of brain structures, such as the hippocampus and to genetic markers, such as apolipoprotein E. In this regard, examination of CSF for biomarkers of disease can help in differentiating normal aging from Alzheimer’s disease. Measures of oxidative stress and cholesterol in plasma correlate with memory deficits; research suggests that treatments that reduce oxidative stress or cholesterol through exercise, diet or the use of antioxidant vitamins may delay cognitive decline.Nevertheless, to date, very little treatment is available to reverse memory deficits in later life. In this regard it is important to identify individuals at risk for memory deficits in order to discriminate different mechanisms of brain aging and develop treatments.Considerable effort is driving research to develop accurate biological markers of brain aging. In turn, these markers will provide information on mechanisms of aging and cognitive decline and point to potential treatments. Accordingly, the effectiveness of treatment needs to be verified for both cognitive changes and biological markers that are specific for age-related memory deficits.