Investigation of Age-Related Cognitive Decline Using Mice as a Model System: Neurophysiological Correlates

doi:10.1097/01.JGP.0000209404.54310.b3

The American Journal of Geriatric Psychiatry

Volume 14, Issue 12, December 2006, Pages 1012-1021

https://doi.org/10.1097/01.JGP.0000209404.54310.b3 Get rights and content

Objective

Learning and memory impairments without overt pathology often accompany advancing age. To gain a better understanding of the underlying neuronal substrates associated with this age-related cognitive decline, the authors have begun to use mice as an animal model system. As described in the companion paper, mice exhibit age-related impairments in cognition. Here, the authors explore the possibility that age-related changes in neuronal function may be the result of deregulation of cytosolic free calcium homeostasis.

Methods

Calcium homeostasis in young and aged mice was examined by measuring the slow afterhyperpolarization (sAHP) in hippocampal neurons as well as assessing voltage-dependent calcium channel mediated long-term potentiation (vdccLTP). In addition, putative changes in phosphorylation of the L-type channel Ca_V1.2 by cAMP-dependent protein kinase were examined.

Results

Both neurophysiological measures of calcium homeostasis indicated an increase in activity-dependent calcium influx. This increase was not the result of an age-related increase in phosphorylation of the L-type channel Ca_V1.2 by cAMP-dependent protein kinase.

Conclusions

Like in other areas of biomedical research, mice have become an invaluable research tool in the investigation of learning and memory. It is expected that similar benefits can be realized by developing mouse models for age-related cognitive decline.

Section snippets

Mice

All mice used in these experiments were either raised within our own colony or obtained from the National Institutes on Aging colony at Harlan Sprague Dawley (Indianapolis, IN). Mice raised in our own colony were 8–10 generations backcrossed into the C57Bl/6 background and were used to measure the sAHP. C57BL/6Nia mice obtained from NIA were used in all other experiments. Young animals were 4–6 months of age at the start of the experiments and aged animals were 22–24 months of age.

Slice Preparation

Animals were

Measurements of the Slow Afterhyperpolarization and L-Type Voltage-Dependent Calcium Channel-Dependent Long-Term Potentiation

To determine the extent of the age-related increase in activity-dependent calcium influx, we measured the sAHP in neurons in the CA1 region of the hippocampus in slices from young (seven mice/15 neurons) and aged (four mice/11 neurons) C57BL/6 mice. As illustrated in Figure 1, the sAHP recorded from an aged mouse pyramidal neuron (bottom panel A2) is significantly larger in amplitude at its maximum and persists longer than the sAHP recorded from CA1 pyramidal neurons typically found in the

DISCUSSION

Although there are numerous reports regarding age-related increases in the sAHP in rats (for a recent review, see ⁴⁶), much less is known about this phenomenon in mice.³¹ Consistent with the rat literature, we find that there is an age-related increase in the sAHP. These data, together with our observation of an enhanced vdccLTP in aged mice, strongly suggest that there is an increase in activity-dependent cytosolic calcium concentration in neurons within the CA1 region of the hippocampus in

References (51)

S Melov
Modeling mitochondrial function in aging neurons
Trends Neurosci
(2004)
F Serrano et al.
Reactive oxygen species and synaptic plasticity in the aging hippocampus
Ageing Res Rev
(2004)
PK Lund et al.
Transcriptional mechanisms of hippocampal aging
Exp Gerontol
(2004)
G Segovia et al.
Glutamatergic neurotransmission in aging: a critical perspective
Mech Ageing Dev
(2001)
AM Watabe et al.
Age-related changes in theta frequency stimulation-induced long-term potentiation
Neurobiol Aging
(2003)
TC Foster
Regulation of synaptic plasticity in memory and memory decline with aging
Prog Brain Res
(2002)
A Chen et al.
Inducible enhancement of memory storage and synaptic plasticity in transgenic mice expressing an inhibitor of ATF4 (CREB-2) and C/EBP proteins
Neuron
(2003)
LT Thompson et al.
Trace eyeblink conditioning in rabbits demonstrates heterogeneity of learning ability both between and within age groups
Neurobiol Aging
(1996)
DS Woodruff-Pak et al.
Nimodipine ameliorates impaired eyeblink classical conditioning in older rabbits in the long-delay paradigm
Neurobiol Aging
(1997)
K McMonagle-Strucko et al.
Enhanced acquisition of reversal training in a spatial learning task in rats treated with chronic nimodipine
Pharmacol Biochem Behav
(1993)

J Quevedo et al.

L-type voltage-dependent calcium channel blocker nifedipine enhances memory retention when infused into the hippocampus

Neurobiol Learn Mem

(1998)

TC Foster

Involvement of hippocampal synaptic plasticity in age-related memory decline

Brain Res Brain Res Rev

(1999)

ES Rosenzweig et al.

Impact of aging on hippocampal function: plasticity, network dynamics, and cognition

Prog Neurobiol

(2003)

GG Murphy et al.

Increased neuronal excitability, synaptic plasticity, and learning in aged Kvβ1.1 knockout mice

Curr Biol

(2004)

MG Blanton et al.

Whole cell recording from neurons in slices of reptilian and mammalian cerebral cortex

J Neurosci Methods

(1989)

MA Davare et al.

The A-kinase anchor protein MAP2B and cAMP-dependent protein kinase are associated with class C L-type calcium channels in neurons

J Biol Chem

(1999)

MA Davare et al.

Protein phosphatase 2A is associated with class C L-type calcium channels (Cav1.2) and antagonizes channel phosphorylation by cAMP-dependent protein kinase

J Biol Chem

(2000)

JW Hell et al.

Differential phosphorylation of two size forms of the neuronal class C L-type calcium channel alpha 1 subunit

J Biol Chem

(1993)

L Yang et al.

Ser1928 is a common site for Cav1.2 phosphorylation by protein kinase C isoforms

J Biol Chem

(2005)

X Wei et al.

Modification of Ca²⁺ channel activity by deletions at the carboxyl terminus of the cardiac alpha 1 subunit

J Biol Chem

(1994)

WW Wu et al.

Age-related biophysical alterations of hippocampal pyramidal neurons: implications for learning and memory

Ageing Res Rev

(2002)

GG Murphy et al.

Investigation of age-related cognitive decline using mice as a model system: behavioral correlates

Am J Geriatr Psychiatry

(2006)

O Thibault et al.

Single-channel and whole-cell studies of calcium currents in young and aged rat hippocampal slice neurons

J Neurosci Methods

(1995)

D Murchison et al.

Reduced mitochondrial buffering of voltage-gated calcium influx in aged rat basal forebrain neurons

Cell Calcium

(2004)

DJ Froc et al.

Reduced synaptic plasticity in the lateral perforant path input to the dentate gyrus of aged C57BL/6 mice

J Neurophysiol

(2003)

Cited by (29)

The aging mouse brain: cognition, connectivity and calcium
2021, Cell Calcium
Aging is a complex process that differentially impacts multiple cognitive, sensory, neuronal and molecular processes. Technological innovations now allow for parallel investigation of neuronal circuit function, structure and molecular composition in the brain of awake behaving adult mice. Thus, mice have become a critical tool to better understand how aging impacts the brain. However, a more granular systems-based approach, which considers the impact of age on key features relating to neural processing, is required. Here, we review evidence probing the impact of age on the mouse brain. We focus on a range of processes relating to neuronal function, including cognitive abilities, sensory systems, synaptic plasticity and calcium regulation. Across many systems, we find evidence for prominent age-related dysregulation even before 12 months of age, suggesting that emerging age-related alterations can manifest by late adulthood. However, we also find reports suggesting that some processes are remarkably resilient to aging. The evidence suggests that aging does not drive a parallel, linear dysregulation of all systems, but instead impacts some processes earlier, and more severely, than others. We propose that capturing the more fine-scale emerging features of age-related vulnerability and resilience may provide better opportunities for the rejuvenation of the aged brain.
Interleukin 6 reduces allopregnanolone synthesis in the brain and contributes to age-related cognitive decline in mice
2020, Journal of Lipid Research
Cognitive decline with age is a harmful process that can reduce quality of life. Multiple factors have been established to contribute to cognitive decline, but the overall etiology remains unknown. Here, we hypothesized that cognitive dysfunction is mediated, in part, by increased levels of inflammatory cytokines that alter allopregnanolone (AlloP) levels, an important neurosteroid in the brain. We assessed the levels and regulation of AlloP and the effects of AlloP supplementation on cognitive function in 4-month-old and 24-month-old male C57BL/6 mice. With age, the expression of enzymes involved in the AlloP synthetic pathway was decreased and corticosterone (CORT) synthesis increased. Supplementation of AlloP improved cognitive function. Interestingly, interleukin 6 (IL-6) infusion in young animals significantly reduced the production of AlloP compared with controls. It is notable that inhibition of IL-6 with its natural inhibitor, soluble membrane glycoprotein 130, significantly improved spatial memory in aged mice. These findings were supported by in vitro experiments in primary murine astrocyte cultures, indicating that IL-6 decreases production of AlloP and increases CORT levels. Our results indicate that age-related increases in IL-6 levels reduce progesterone substrate availability, resulting in a decline in AlloP levels and an increase in CORT. Furthermore, our results indicate that AlloP is a critical link between inflammatory cytokines and the age-related decline in cognitive function.
Senescent neurophysiology: Ca<sup>2+</sup> signaling from the membrane to the nucleus
2019, Neurobiology of Learning and Memory
Citation Excerpt :
These recordings revealed an age-related increase in the Ca2+ activated, and K+-mediated, AHP that follows a burst of action potentials (Fig. 1A). An increase in the amplitude of the AHP is now a well-established marker of aging in CA1 pyramidal neurons and has been observed in rabbits, mice, and rats, both male and female (Disterhoft et al., 1996; Kaczorowski & Disterhoft, 2009; Kumar and Foster, 2002, 2004; Landfield & Pitler, 1984; Murphy, Shah, Hell, & Silva, 2006; Power, Wu, Sametsky, Oh, & Disterhoft, 2002; Tombaugh, Rowe, & Rose, 2005). The larger hyperpolarization influences the relative refractory period of the action potential, reducing the number of action potentials evoked during depolarization (spike frequency accommodation) and shifts the discharge activity evoked by distinct patterns of afferent stimulation (Gant & Thibault, 2009).
The current review provides a historical perspective on the evolution of hypothesized mechanisms for senescent neurophysiology, focused on the CA1 region of the hippocampus, and the relationship of senescent neurophysiology to impaired hippocampal-dependent memory. Senescent neurophysiology involves processes linked to calcium (Ca²⁺) signaling including an increase in the Ca²⁺-dependent afterhyperpolarization (AHP), decreasing pyramidal cell excitability, hyporesponsiveness of N-methyl-D-aspartate (NMDA) receptor function, and a shift in Ca²⁺-dependent synaptic plasticity. Dysregulation of intracellular Ca²⁺ and downstream signaling of kinase and phosphatase activity lies at the core of senescent neurophysiology. Ca²⁺-dysregulation involves a decrease in Ca²⁺ influx through NMDA receptors and an increase release of Ca²⁺ from internal Ca²⁺ stores. Recent work has identified changes in redox signaling, arising in middle-age, as an initiating factor for senescent neurophysiology. The shift in redox state links processes of aging, oxidative stress and inflammation, with functional changes in mechanisms required for episodic memory. The link between age-related changes in Ca²⁺ signaling, epigenetics and gene expression is an exciting area of research. Pharmacological and behavioral intervention, initiated in middle-age, can promote memory function by initiating transcription of neuroprotective genes and rejuvenating neurophysiology. However, with more advanced age, or under conditions of neurodegenerative disease, epigenetic changes may weaken the link between environmental influences and transcription, decreasing resilience of memory function.
A novel mouse model of the aged brain: Over-expression of the L-type voltage-gated calcium channel Ca<inf>V</inf>1.3
2017, Behavioural Brain Research
The aged population is growing rapidly, which has sparked tremendous interest in elucidating mechanisms of aging in both the body and the brain. Animal models have become an indispensable tool in biomedical science, but because of the cost and extended timeframe associated with aging animals to appropriate time points, studies that rely on using aged animals are often not feasible. Somewhat surprisingly, there are relatively few animal models that have been specifically engineered to mimic physiological changes known to occur during “normal” aging. Developing transgenic animal models that faithfully mimic key aspects of aging would likely be of great utility in studying both age-related deficits in the absence of overt pathology as well as an adjunct for transgenic models of diseases where aging is a primary risk factor.
In particular, there are several alterations in the aged brain that are amenable to being modeled genetically. We have focused on one key aspect that has been repeatedly demonstrated in aged animals – an increase in the L-type voltage-gated calcium channel Ca_V1.3. Here we present a novel transgenic mouse line in which expression of Ca_V1.3 is increased by approximately 50% in the forebrain of young mice. These mice do not display any overt physical or non-cognitive deficits, exhibiting normal exploratory behavior, motor function, and affective-like responses, suggesting that these mice can be successfully deployed to assess the impact of an “aged brain” in a variety of conditions.
Age-Related Alterations in Neural Plasticity
2016, Handbook of the Biology of Aging: Eighth Edition
A decline in cognitive function often accompanies aging even in the absence of disorders like Alzheimer’s disease. Unlike cases of clinical dementia, age-related cognitive decline does not typically involve significant brain atrophy but instead is thought to be mediated by alterations in neuronal function. One prominent feature that is significantly affected by aging is neural plasticity (a change in neuronal responsiveness due to a change in intrinsic or synaptic properties), which is thought to represent the cellular analog of learning and memory. Distinct forms of neural plasticity occur in different time domains (ranging from milliseconds to days), but have a common dependence on calcium signaling. Thus, age-related dysregulation of calcium signaling may underlie deficits in neural plasticity, and may ultimately be responsible for cognitive decline that occurs in the healthy, non-demented aging population.
NMDA receptors interact with the retrieval memory enhancing effect of pioglitazone in mice
2014, Pharmacology Biochemistry and Behavior
Citation Excerpt :
Considerable evidence suggests the re-establishment of calcium homeostasis as one of the important mechanisms by which pioglitazone improves cognition and memory. Calcium dysregulation, an important hallmark of cognition decline (Murphy et al., 2006), is present in AD models (Cheung et al., 2008) and in cells of AD patients (Etcheberrigaray et al., 1998). Calcium ions are second messengers of NMDARs, and have a key role in the function of these receptors in the brain (Rogawski, 2013).
The present study has been undertaken to investigate the possible involvement of the glutamatergic pathway in the beneficial effects of pioglitazone on consolidation and retrieval phases of memory.
The Y-maze task was used to assess short-term spatial recognition memory in animals. Scopolamine (1 mg/kg, i.p.) or MK-801 (dizocilpine) (0.03, 0.1 and 0.3 mg/kg, i.p.) were administered immediately after the training session to impair memory consolidation or 30 min before the retention trial to impair memory retrieval. Pioglitazone (10, 20, 40 and 80 mg/kg, p.o.) was administered 2 h before the retention session in memory retrieval experiments or immediately after the training session in consolidation experiments. And finally NMDA (N-methyl-d-aspartate) (75 mg/kg, i.p) was administered 15 min before the administration of pioglitazone.
1) MK-801 (0.3 mg/kg) impaired the retrieval of spatial recognition memory. 2) Pioglitazone failed to improve MK-801 induced impairment of retrieval of spatial recognition memory. 3) The 20 mg/kg dose of pioglitazone significantly improved memory in mice with scopolamine induced impairment of memory retrieval. 4) Sub-effective dose of MK-801 (0.1 mg/kg) was capable of reversing the beneficial effect of pioglitazone on retrieval of memory in scopolamine-treated mice, 5) Administration of NMDA (75 mg/kg) and a sub-effective dose of pioglitazone (10 mg/kg) reversed the effect of scopolamine and promoted memory retrieval. 6) MK-801 did not affect the consolidation phase of spatial recognition memory. 7) Pioglitazone did not affect scopolamine-induced impairment of memory consolidation.
Sub-effective dose of MK-801 is capable of reversing the protective action of pioglitazone on scopolamine-induced impairment of memory retrieval. Additionally, co-administration of 75 mg/kg NMDA and a sub-effective dose of pioglitazone potentiated the effect of pioglitazone on memory retrieval impaired by scopolamine. These results support the idea that pioglitazone plays its memory retrieval enhancement role through the glutamatergic pathway.

View all citing articles on Scopus

This work was supported by NIH grants to AJS (R01 AG17499), JWH (R01 AG17502), and GGM (F32 AG5858). Additional support was provided by the Bank of America Giannini Foundation (GGM) and a faculty scholar award (94-033) from the Alzheimer's Association (JWH).

Dr. Murphy is currently affiliated with the Molecular and Behavioral Neuroscience Institute & Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan.

View full text

Regular Research ArticlesInvestigation of Age-Related Cognitive Decline Using Mice as a Model System: Neurophysiological Correlates

Objective

Methods

Results

Conclusions

Section snippets

Mice

Slice Preparation

Measurements of the Slow Afterhyperpolarization and L-Type Voltage-Dependent Calcium Channel-Dependent Long-Term Potentiation

DISCUSSION

Trends Neurosci

Ageing Res Rev

Exp Gerontol

Mech Ageing Dev

Neurobiol Aging

Prog Brain Res

Neuron

Neurobiol Aging

Neurobiol Aging

Pharmacol Biochem Behav

Neurobiol Learn Mem

Brain Res Brain Res Rev

Prog Neurobiol

Curr Biol

J Neurosci Methods

J Biol Chem

J Biol Chem

J Biol Chem

J Biol Chem

J Biol Chem

Ageing Res Rev

Am J Geriatr Psychiatry

J Neurosci Methods

Cell Calcium

Reduced synaptic plasticity in the lateral perforant path input to the dentate gyrus of aged C57BL/6 mice

J Neurophysiol

Regular Research Articles
Investigation of Age-Related Cognitive Decline Using Mice as a Model System: Neurophysiological Correlates