Age- and sex-dependent alterations in primary somatosensory cortex neuronal calcium network dynamics during locomotion

Over the past 30 years, the calcium (Ca²⁺) hypothesis of brain aging has provided clear evidence that hippocampal neuronal Ca²⁺ dysregulation is a key biomarker of aging. Age-dependent Ca²⁺-mediated changes in intrinsic excitability, synaptic plasticity, and activity have helped identify some of the mechanisms engaged in memory and cognitive decline based on work done mostly at the single-cell level and in the slice preparation. Recently, our lab identified age- and Ca²⁺-related neuronal network dysregulation in the cortex of the anesthetized animal. Still, investigations in the awake animal are needed to test the generalizability of the Ca²⁺ hypothesis of brain aging. Here, we used in vigilo two-photon imaging in ambulating mice, to image GCaMP8f in the primary somatosensory cortex (S1), during ambulation and at rest. We investigated aging- and sex-related changes in neuronal networks in the C56BL/6J mouse. Following imaging, gait behavior was characterized to test for changes in locomotor stability. During ambulation, in both young adult and aged mice, an increase in network connectivity and synchronicity was noted. An age-dependent increase in synchronicity was seen in ambulating aged males only. Additionally, females displayed increases in the number of active neurons, Ca²⁺ transients, and neuronal activity compared to males, particularly during ambulation. These results suggest S1 Ca²⁺ dynamics and network synchronicity are likely contributors of locomotor stability. We believe this work raises awareness of age- and sex-dependent alterations in S1 neuronal networks, perhaps underlying the increase in falls with age.     

Modulation of Intestinal Microbiota by the Probiotic VSL#3 Resets Brain Gene Expression and Ameliorates the Age-Related Deficit in LTP

The intestinal microbiota is increasingly recognized as a complex signaling network that impacts on many systems beyond the enteric system modulating, among others, cognitive functions including learning, memory and decision-making processes. This has led to the concept of a microbiota-driven gut–brain axis, reflecting a bidirectional interaction between the central nervous system and the intestine. A deficit in synaptic plasticity is one of the many changes that occurs with age. Specifically, the archetypal model of plasticity, long-term potentiation (LTP), is reduced in hippocampus of middle-aged and aged rats. Because the intestinal microbiota might change with age, we have investigated whether the age-related deficit in LTP might be attenuated by changing the composition of intestinal microbiota with VSL#3, a probiotic mixture comprising 8 Gram-positive bacterial strains. Here, we report that treatment of aged rats with VSL#3 induced a robust change in the composition of intestinal microbiota with an increase in the abundance of Actinobacteria and Bacterioidetes, which was reduced in control-treated aged rats. VSL#3 administration modulated the expression of a large group of genes in brain tissue as assessed by whole gene expression, with evidence of a change in genes that impact on inflammatory and neuronal plasticity processes. The age-related deficit in LTP was attenuated in VSL#3-treated aged rats and this was accompanied by a modest decrease in markers of microglial activation and an increase in expression of BDNF and synapsin. The data support the notion that intestinal microbiota can be manipulated to positively impact on neuronal function.     

Ablation of CaV2.1 Voltage-Gated Ca2+ Channels in Mouse Forebrain Generates Multiple Cognitive Impairments

Voltage-gated Ca_V2.1 (P/Q-type) Ca²⁺ channels located at the presynaptic membrane are known to control a multitude of Ca²⁺-dependent cellular processes such as neurotransmitter release and synaptic plasticity. Our knowledge about their contributions to complex cognitive functions, however, is restricted by the limited adequacy of existing transgenic Ca_V2.1 mouse models. Global Ca_V2.1 knock-out mice lacking the α1 subunit Cacna1a gene product exhibit early postnatal lethality which makes them unsuitable to analyse the relevance of Ca_V2.1 Ca²⁺ channels for complex behaviour in adult mice. Consequently we established a forebrain specific Ca_V2.1 knock-out model by crossing mice with a floxed Cacna1a gene with mice expressing Cre-recombinase under the control of the NEX promoter. This novel mouse model enabled us to investigate the contribution of Ca_V2.1 to complex cognitive functions, particularly learning and memory. Electrophysiological analysis allowed us to test the specificity of our conditional knock-out model and revealed an impaired synaptic transmission at hippocampal glutamatergic synapses. At the behavioural level, the forebrain-specific Ca_V2.1 knock-out resulted in deficits in spatial learning and reference memory, reduced recognition memory, increased exploratory behaviour and a strong attenuation of circadian rhythmicity. In summary, we present a novel conditional Ca_V2.1 knock-out model that is most suitable for analysing the in vivo functions of Ca_V2.1 in the adult murine forebrain.     

Single-Channel Resolution of the Interaction between C-Terminal CaV1.3 Isoforms and Calmodulin

Voltage-dependent calcium (Ca_V) 1.3 channels are involved in the control of cellular excitability and pacemaking in neuronal, cardiac, and sensory cells. Various proteins interact with the alternatively spliced channel C-terminus regulating gating of Ca_V1.3 channels. Binding of a regulatory calcium-binding protein calmodulin (CaM) to the proximal C-terminus leads to the boosting of channel activity and promotes calcium-dependent inactivation (CDI). The C-terminal modulator domain (CTM) of Ca_V1.3 channels can interfere with the CaM binding, thereby inhibiting channel activity and CDI. Here, we compared single-channel gating behavior of two natural Ca_V1.3 splice isoforms: the long Ca_V1.3₄₂ with the full-length CTM and the short Ca_V1.3_42A with the C-terminus truncated before the CTM. We found that CaM regulation of Ca_V1.3 channels is dynamic on a minute timescale. We observed that at equilibrium, single Ca_V1.3₄₂ channels occasionally switched from low to high open probability, which perhaps reflects occasional binding of CaM despite the presence of CTM. Similarly, when the amount of the available CaM in the cell was reduced, the short Ca_V1.3_42A isoform showed patterns of the low channel activity. CDI also underwent periodic changes with corresponding kinetics in both isoforms. Our results suggest that the competition between CTM and CaM is influenced by calcium, allowing further fine-tuning of Ca_V1.3 channel activity for particular cellular needs.     

The role of L-type voltage-gated calcium channels Cav1.2 and Cav1.3 in normal and pathological brain function

The use of specific activators and inhibitors that penetrate the central nervous system has suggested an essential functional role of L-type calcium channels (LTCC) in several important physiological processes of the brain, including the modulation of the mesoaccumbal dopamine signalling pathway, synaptic transmission of auditory stimuli and synaptic plasticity of neutral and aversive learning and memory processes. However, the lack of selectivity of available pharmacological agents towards the most prominent LTCC isoforms in the brain, namely Ca_v1.2 and Ca_v1.3, has hampered the elucidation of the precise contribution made by each specific channel isoform within these specific physiological processes. Modern genetic approaches, both in rodents and in human, have recently enhanced our understanding of the selective functional roles of Ca_v1.2 and Ca_v1.3 channels. In rodents, the characterisation of global and conditional isoform-specific knockouts suggests a contribution of Ca_v1.2 channels in spatial memory formation, whereas Ca_v1.3 channels seem to be involved in the consolidation of fear memories and in neurodegenerative mechanisms associated with the development of Parkinson’s disease. With regard to the molecular mechanisms underlying drug addiction, Ca_v1.3 channels are necessary for the development and Ca_v1.2 channels for the expression of cocaine and amphetamine behavioural sensitisation. In humans, both the identification of naturally occurring LTCC variants (“channelopathies”) and unbiased genome-wide association studies have linked LTCCs to working memory performance in healthy individuals and schizophrenic patients. Individually, CACNA1C polymorphisms and CACNA1D variants have been linked to a variety of psychiatric diseases and to congenital deafness, respectively. However, the contribution of individual LTCCs and their polymorphisms to human brain function and diseases remains unclear, necessitating the use of isoform-specific pharmacological agents.     

Spatial Cognition in Adult and Aged Mice Exposed to High-Fat Diet

Aging is associated with a decline in multiple aspects of cognitive function, with spatial cognition being particularly sensitive to age-related decline. Environmental stressors, such as high-fat diet (HFD) exposure, that produce a diabetic phenotype and metabolic dysfunction may indirectly lead to exacerbated brain aging and promote the development of cognitive deficits. The present work investigated whether exposure to HFD exacerbates age-related cognitive deficits in adult versus aged mice. Adult (5 months old) and aged (15 months old) mice were exposed to control diet or HFD for three months prior to, and throughout, behavioral testing. Anxiety-like behavior in the light-dark box test, discrimination learning and memory in the novel object/place recognition tests, and spatial learning and memory in the Barnes maze test were assessed. HFD resulted in significant gains in body weight and fat mass content with adult mice gaining significantly more weight and adipose tissue due to HFD than aged mice. Weight gain was attributed to food calories sourced from fat, but not total calorie intake. HFD increased fasting insulin levels in all mice, but adult mice showed a greater increase relative to aged mice. Behaviorally, HFD increased anxiety-like behavior in adult but not aged mice without significantly affecting spatial cognition. In contrast, aged mice fed either control or HFD diet displayed deficits in novel place discrimination and spatial learning. Our results suggest that adult mice are more susceptible to the physiological and anxiety-like effects of HFD consumption than aged mice, while aged mice displayed deficits in spatial cognition regardless of dietary influence. We conclude that although HFD induces systemic metabolic dysfunction in both adult and aged mice, overall cognitive function was not adversely affected under the current experimental conditions.     

Age-related alterations of Nestin-immunoreactive neurons in rat basal forebrain with aged memory deficit

Age-related and aged memory deficit changes in Nestin-immunoreactive (Nestin-IR) neurons were studied following recent evidence of distinct Nestin-IR neurons within adult rat basal forebrain. Morris water maze task assessed spatial learning capacity of 3- and 24-month rats (aged-impaired and aged-unimpaired groups). Nestin-IR neuron distributional and morphological features were investigated by immunohistochemistry and positive neuronal number calculation. Nestin-IR neuron number declined with aging, especially aged-impaired. Significant negative correlations existed between average escape latencies and Nestin-IR neuron number in medial septum-diagonal band of Broca (MS-DBB). Correlations of rostral portion [medial septum (MS) and vertical limb diagonal band (vDB)] were higher than caudal portion [horizontal limb diagonal band (hDB)]. Aged-impaired showed reduced complexity of Nestin-IR neuron dendrite arborization and dendritic length. Nestin-IR astrocyte-like cells appeared scattered among Nestin-IR neurons on some aged-impaired slices. In conclusion, aged-impaired rats showed worse cognitive spatial performance and less Nestin-IR neuronal number compared to aged-unimpaired. Nestin-IR neuronal loss and morphological changes are some pathological characteristics of rat aged basal forebrain and may be important in neurobiological mechanisms of brain aging and aged memory deficit.     

Age-related alterations of Nestin-immunoreactive neurons in rat basal forebrain with aged memory deficit

Age-related and aged memory deficit changes in Nestin-immunoreactive (Nestin-IR) neurons were studied following recent evidence of distinct Nestin-IR neurons within adult rat basal forebrain. Morris water maze task assessed spatial learning capacity of 3- and 24-month rats (aged-impaired and aged-unimpaired groups). Nestin-IR neuron distributional and morphological features were investigated by immunohistochemistry and positive neuronal number calculation. Nestin-IR neuron number declined with aging, especially aged-impaired. Significant negative correlations existed between average escape latencies and Nestin-IR neuron number in medial septum-diagonal band of Broca (MS-DBB). Correlations of rostral portion [medial septum (MS) and vertical limb diagonal band (vDB)] were higher than caudal portion [horizontal limb diagonal band (hDB)]. Aged-impaired showed reduced complexity of Nestin-IR neuron dendrite arborization and dendritic length. Nestin-IR astrocyte-like cells appeared scattered among Nestin-IR neurons on some aged-impaired slices. In conclusion, aged-impaired rats showed worse cognitive spatial performance and less Nestin-IR neuronal number compared to aged-unimpaired. Nestin-IR neuronal loss and morphological changes are some pathological characteristics of rat aged basal forebrain and may be important in neurobiological mechanisms of brain aging and aged memory deficit.     

Kelch-like 1 protein up-regulates T-type currents by an actin-F dependent increase in α1H channels via the recycling endosome

The neuronal protein Kelch-like 1 (KLHL1) is a novel actin-binding protein that modulates neuronal structure and function. KLHL1 knockout mice exhibit dendritic atrophy in cerebellar Purkinje neurons and motor dysfunction. Interestingly, KLHL1 up-regulates high and low voltage-gated calcium currents (Ca_V2.1 and Ca_V3.2) and interacts with their respective principal subunits, α1A and α1H. We reported the mechanism of enhanced Ca_V3.2 (α1H) current density (and calcium influx) by KLHL1 is due to an increase in channel number (N) that requires the binding of actin. In this report we further elucidate the role of the actin cytoskeleton in this process using pharmacological tools to disrupt or stabilize actin filaments and to prevent protein trafficking and vesicle recycling. Disruption of the cytoskeleton did not affect the basal activity of α1H, but did eliminate its modulation by KLHL1. In contrast, actin-F stabilization on its own increased basal α1H activity similar to KLHL1 but without synergy in its presence, suggesting KLHL1 requires actin-polymerization to increase α1H currents. Noise analysis revealed that actin polymerization induced an increase in N and Po, in contrast to increased N in the presence of KLHL1. Interestingly, pharmacological or genetic disruption of endosomal recycling eliminated the increase in channel number by KLHL1 demonstrating this effect occurs via enhanced α1H re-insertion through the recycling endosome. Our findings afford insight on a novel mechanism of T-type channel modulation that could have overall functional implications for T-type channel function in the brain.     

Increased CaVβ1a expression with aging contributes to skeletal muscle weakness

Ca²⁺ release from the sarcoplasmic reticulum (SR) into the cytosol is a crucial part of excitation–contraction (E‐C) coupling. Excitation–contraction uncoupling, a deficit in Ca²⁺ release from the SR, is thought to be responsible for at least some of the loss in specific force observed in aging skeletal muscle. Excitation–contraction uncoupling may be caused by alterations in expression of the voltage‐dependent calcium channel α_1s (Ca_V1.1) and β_1a (Ca_Vβ_1a) subunits, both of which are necessary for E‐C coupling to occur. While previous studies have found Ca_V1.1 expression declines in old rodents, Ca_Vβ_1a expression has not been previously examined in aging models. Western blot analysis shows a substantial increase of Ca_Vβ_1a expression over the full lifespan of Friend Virus B (FVB) mice. To examine the specific effects of Ca_Vβ_1a overexpression, a Ca_Vβ_1a‐YFP plasmid was electroporated in vivo into young animals. The resulting increase in expression of Ca_Vβ_1a corresponded to decline of Ca_V1.1 over the same time period. YFP fluorescence, used as a measure of Ca_Vβ_1a‐YFP expression in individual fibers, also showed an inverse relationship with charge movement, measured using the whole‐cell patch‐clamp technique. Specific force was significantly reduced in young Ca_Vβ_1a‐YFP electroporated muscle fibers compared with sham‐electroporated, age‐matched controls. siRNA interference of Ca_Vβ_1a in young muscles reduced charge movement, while charge movement in old was restored to young control levels. These studies imply Ca_Vβ_1a serves as both a positive and negative regulator Ca_V1.1 expression, and that endogenous overexpression of Ca_Vβ_1a during old age may play a role in the loss of specific force.     

Activity-dependent modulation of neuronal KV channels by retinoic acid enhances CaV channel activity

The metabolite of vitamin A, retinoic acid (RA), is known to affect synaptic plasticity in the nervous system and to play an important role in learning and memory. A ubiquitous mechanism by which neuronal plasticity develops in the nervous system is through modulation of voltage-gated Ca²⁺ (Ca_V) and voltage-gated K⁺ channels. However, how retinoids might regulate the activity of these channels has not been determined. Here, we show that RA modulates neuronal firing by inducing spike broadening and complex spiking in a dose-dependent manner in peptidergic and dopaminergic cell types. Using patch-clamp electrophysiology, we show that RA-induced complex spiking is activity dependent and involves enhanced inactivation of delayed rectifier voltage-gated K⁺ channels. The prolonged depolarizations observed during RA-modulated spiking lead to an increase in Ca²⁺ influx through Ca_V channels, though we also show an opposing effect of RA on the same neurons to inhibit Ca²⁺ influx. At physiological levels of Ca²⁺, this inhibition is specific to Ca_V2 (not Ca_V1) channels. Examining the interaction between the spike-modulating effects of RA and its inhibition of Ca_V channels, we found that inhibition of Ca_V2 channels limits the Ca²⁺ influx resulting from spike modulation. Our data thus provide novel evidence to suggest that retinoid signaling affects both delayed rectifier K⁺ channels and Ca_V channels to fine-tune Ca²⁺ influx through Ca_V2 channels. As these channels play important roles in synaptic function, we propose that these modulatory effects of retinoids likely contribute to synaptic plasticity in the nervous system.     

Neuroactive steroids: new biomarkers of cognitive aging

Intensive studies in animals established that neuroactive steroids display neuronal actions and influence behavioral functions. We describe here investigations on the role of neuroactive steroids in learning and memory processes during aging and suggest their role as biomarkers of cognitive aging. Our work demonstrated the role of the steroid pregnenolone (PREG) sulfate as a factor underlying an individual’s age-related cognitive decline in animals. As new perspectives of research we argue that knowing whether neuroactive steroids exist as endogenous neuromodulators and modulate physiologically behavioral functions is essential. To this end, a new approach using the sensitive, specific, and accurate quantitative determination of neuroactive steroids by mass spectrometry seems to have potential for examining the role of each steroid in discrete brain areas in learning and memory alterations, as observed during aging.     

Increased neuronal excitability, synaptic plasticity, and learning in aged Kvbeta1.1 knockout mice

BACKGROUND: Advancing age is typically accompanied by deficits in learning and memory. These deficits occur independently of overt pathology and are often considered to be a part of "normal aging." At the neuronal level, normal aging is known to be associated with numerous cellular and molecular changes, which include a pronounced decrease in neuronal excitability and an altered induction in the threshold for synaptic plasticity. Because both of these mechanisms (neuronal excitability and synaptic plasticity) have been implicated as putative cellular substrates for learning and memory, it is reasonable to propose that age-related changes in these mechanisms may contribute to the general cognitive decline that occurs during aging. RESULTS: To further investigate the relationship between aging, learning and memory, neuronal excitability, and synaptic plasticity, we have carried out experiments with aged mice that lack the auxiliary potassium channel subunit Kvbeta1.1. In aged mice, the deletion of the auxiliary potassium channel subunit Kvbeta1.1 resulted in increased neuronal excitability, as measured by a decrease in the post-burst afterhyperpolarization. In addition, long-term potentiation (LTP) was more readily induced in aged Kvbeta1.1 knockout mice. Finally, the aged Kvbeta1.1 mutants outperformed age-matched controls in the hidden-platform version of the Morris water maze. Interestingly, the enhancements in excitability and learning were both sensitive to genetic background: The enhanced learning was only observed in a genetic background in which the mutants exhibited increased neuronal excitability. CONCLUSIONS: Neuronal excitability is an important determinant of both synaptic plasticity and learning in aged subjects.     

Antagonism of L-type Ca2+ channels CaV1.3 and CaV1.2 by 1,4-dihydropyrimidines and 4H-pyrans as dihydropyridine mimics

The L-type calcium channel (LTCC) Ca_V1.3 is regarded as a new potential therapeutic target for Parkinson’s disease. Calcium influx through Ca_V1.3 LTCC during autonomous pacemaking in adult dopaminergic neurons of the substantia nigra pars compacta is related to the generation of mitochondrial oxidative stress in animal models. Development of a Ca_V1.3 antagonist selective over Ca_V1.2 is essential because Ca_V1.2 pore-forming subunits are the predominant form of LTCCs and are abundant in the central nervous and cardiovascular systems. We have explored 1,4-dihydropyrimidines and 4H-pyrans to identify potent and selective antagonists of Ca_V1.3 relative to Ca_V1.2 LTCCs. A library of 36 dihydropyridine (DHP)-mimic 1,4-dihydropyrimidines and 4H-pyrans was synthesized, and promising chiral compounds were resolved. The antagonism studies of Ca_V1.3 and Ca_V1.2 LTCCs using DHP mimic compounds showed that dihydropyrimidines and 4H-pyrans are effective antagonists of DHPs for Ca_V1.3 LTCCs. Some 1,4-dihydropyrimidines are more selective than isradipine for Ca_V1.3 over Ca_V1.2, shown here by both calcium flux and patch-clamp electrophysiology experiments, where the ratio of antagonism is around 2–3. These results support the hypothesis that the modified hydrogen bonding donor/acceptors in DHP-mimic dihydropyrimidines and 4H-pyrans can interact differently with DHP binding sites, but, in addition, the data suggest that the binding sites of DHP in Ca_V1.3 and Ca_V1.2 LTCCs are very similar.     

Impact of gating modulation in CaV1.3 L-type calcium channels

Ca_V1.3 L-type channels control inner hair cell (IHC) sensory and sinoatrial node (SAN) function, and excitability in central neurons by means of their low-voltage activation and inactivation properties. In SAN cells Ca_V1.3 inward calcium current (I_Ca) inactivates rapidly whereas in IHCs inactivation is slow. A candidate suggested in slowing Ca_V1.3 channel inactivation is the presynaptically located ribbon-synapse protein RIM that is expressed in immature IHCs in presynaptic compartments also expressing Ca_V1.3 channels. Ca_V1.3 channel gating is also modulated by an intramolecular C-terminal mechanism. This mechanism was elicited during analysis of human C-terminal splice variants that differ in the length of their C-terminus and that modulates the channel’s negative activation range and slows calcium-dependent inactivation.     

中枢神经系统钙稳态失调和老龄脑功能

脑的老化表现为记忆力的减退。脑老化的钙假说认为脑的老化与中枢神经系统「Ｃａ＾２＋」ｉ的调节机制紊乱有关,衰老可以通过多种因素导致「Ｃａ＾２＋」ｉ升高,影响突触传导,神经递质释放,信号转导等导致记忆障碍,本文综述了近年来的进展。     

Aging and surface expression of hippocampal NMDA receptors

Aging is known to alter many physiological processes within the brain including synaptic responses, long-term potentiation, learning, and memory. Aging has also been shown to alter the expression and distribution of N-methyl-d-aspartate (NMDA) receptors in many different brain regions, including the hippocampus. Additionally, we have recently reported that young adult rats show an activity-dependent increase in the surface expression of NMDA receptors. We have extended these observations in the present study in aged animals and have found that aged Fischer 344 rats fail to show activity-dependent changes in the surface distribution of NMDA receptors. In conjunction with this observation we have also noted that aged rats show an expression deficit in the C2 splice variant of the NR1 subunit. This subunit is preferentially shifted to the surface following stimulation in young adult animals. As the NMDA receptor is thought to play an important role in neuronal signaling, these observations suggest possible new areas of dysfunction in this receptor that might underlie age-related deficits in neuronal physiology.     

Proteomic analysis of specific brain proteins in aged SAMP8 mice treated with alpha-lipoic acid: implications for aging and age-related neurodegenerative disorders

Free radical-mediated damage to neuronal membrane components has been implicated in the etiology of Alzheimer's disease (AD) and aging. The senescence accelerated prone mouse strain 8 (SAMP8) exhibits age-related deterioration in memory and learning along with increased oxidative markers. Therefore, SAMP8 is a suitable model to study brain aging and, since aging is the major risk factor for AD and SAMP8 exhibits many of the biochemical findings of AD, perhaps as a model for and the early phase of AD. Our previous studies reported higher oxidative stress markers in brains of 12-month-old SAMP8 mice when compared to that of 4-month-old SAMP8 mice. Further, we have previously shown that injecting the mice with alpha-lipoic acid (LA) reversed brain lipid peroxidation, protein oxidation, as well as the learning and memory impairments in SAMP8 mice. Recently, we reported the use of proteomics to identify proteins that are expressed differently and/or modified oxidatively in aged SAMP8 brains. In order to understand how LA reverses the learning and memory deficits of aged SAMP8 mice, in the current study, we used proteomics to compare the expression levels and specific carbonyl levels of proteins in brains from 12-month-old SAMP8 mice treated or not treated with LA. We found that the expressions of the three brain proteins (neurofilament triplet L protein, alpha-enolase, and ubiquitous mitochondrial creatine kinase) were increased significantly and that the specific carbonyl levels of the three brain proteins (lactate dehydrogenase B, dihydropyrimidinase-like protein 2, and alpha-enolase) were significantly decreased in the aged SAMP8 mice treated with LA. These findings suggest that the improved learning and memory observed in LA-injected SAMP8 mice may be related to the restoration of the normal condition of specific proteins in aged SAMP8 mouse brain. Moreover, our current study implicates neurofilament triplet L protein, alpha-enolase, ubiquitous mitochondrial creatine kinase, lactate dehydrogenase B, and dihydropyrimidinase-like protein 2 in process associated with learning and memory of SAMP8 mice.     

Reversal of aging‐related emotional memory deficits by norepinephrine via regulating the stability of surface AMPA receptors

Aging‐related emotional memory deficit is a well‐known complication in Alzheimer's disease and normal aging. However, little is known about its molecular mechanism. To address this issue, we examined the role of norepinephrine (NE) and its relevant drug desipramine in the regulation of hippocampal long‐term potentiation (LTP), surface expression of AMPA receptor, and associative fear memory in rats. We found that there was a defective regulation of NE content and AMPA receptor trafficking during fear conditioning, which were accompanied by impaired emotional memory and LTP in aged rats. Furthermore, we also found that the exogenous upregulation of NE ameliorated the impairment of LTP and emotional memory via enhancing AMPA receptor trafficking in aged rats, and the downregulation of NE impaired LTP in adult rats. Finally, acute treatment with NE or desipramine rescued the impaired emotional memory in aged rats. These results imply a pivotal role for NE in synaptic plasticity and associative fear memory in aging rats and suggest that desipramine is a potential candidate for treating aging‐related emotional memory deficit.     

Age-related alteration of PKC, a key enzyme in memory processes

Brain aging is characterized by a progressive decline of the cognitive and memory functions. It is becoming increasingly clear that protein phosphorylation and, in particular, the activity of the calcium-phospholipid-dependent protein kinase C (PKC) may be one of the fundamental cellular changes associated with memory function. PKC is a multigene family of enzymes highly expressed in brain tissues. The activation of kinase C is coupled with its translocation from the cytosol to different intracellular sites and recent studies have demonstrated the key role played by several anchoring proteins in this mechanism. PKC-phosphorylating activity appears to be impaired during senescence at brain level in a strain-dependent fashion in rodents. Whereas the levels of the various isoforms do not show age-related alterations, the enzyme translocation upon phorbol-ester treatment is deficitary among all strains investigated. Anchoring proteins may contribute to this activation deficit. We discuss also modifications of the PKC system in Alzheimer's disease that may be related to pathological alterations in neurotransmission. A better insight of the different factors controlling brain-PKC activation may be important not only for elucidating the molecular basis of neuronal transmission, but also for identifying new approaches for correcting or even preventing age-dependent changes in brain function.