Systemic Injection of Aged Blood Plasma in Adult C57BL/6 Mice Induces Neurophysiological Impairments in the Hippocampal CA1.

BACKGROUND Aging is characterized by systemic alterations and forms an important risk factor for Alzheimer's disease. Recently, it has been indicated that blood-borne factors present in the systemic milieu contribute to the aging process. Exposing young mice to aged blood plasma results in impaired neurogenesis and synaptic plasticity in the dentate gyrus, as well as impaired cognition. Vice versa, treating aged mice with young blood plasma rescues impairments associated with aging. OBJECTIVE Whether blood-borne factors are sufficient to drive impairments outside the dentate gyrus, how they impact neurophysiology, and how the functional outcome compares to impairments found in mouse models for AD is still unclear. METHODS Here, we treated adult mice with blood plasma from aged mice and assessed neurophysiological parameters in the hippocampal CA1. RESULTS Mice treated with aged blood plasma show significantly impaired levels of long-term potentiation (LTP), similar to those present in APP/PS1 mice. These impaired levels of LTP in plasma-treated mice are associated with alterations in basic properties of glutamatergic transmission and the enhanced activity of voltage-gated Ca2 + channels. CONCLUSION Together, the data presented in this study show that blood-borne factors are sufficient to drive neurophysiological impairments in the hippocampal CA1.

[1]  D. Borchelt,et al.  Reactive astrocytes as treatment targets in Alzheimer's disease—Systematic review of studies using the APPswePS1dE9 mouse model , 2021, Glia.

[2]  J. Kramer,et al.  Blood factors transfer beneficial effects of exercise on neurogenesis and cognition to the aged brain , 2020, Science.

[3]  S. Hasselbalch,et al.  Ageing as a risk factor for neurodegenerative disease , 2019, Nature Reviews Neurology.

[4]  Philip D. Harvey Domains of cognition and their assessment
 , 2019, Dialogues in clinical neuroscience.

[5]  Mariana Temido-Ferreira,et al.  Novel Players in the Aging Synapse: Impact on Cognition , 2019, Journal of caffeine and adenosine research.

[6]  A. Easton,et al.  Changes in presynaptic calcium signalling accompany age‐related deficits in hippocampal LTP and cognitive impairment , 2019, Aging cell.

[7]  T. Südhof,et al.  Specific factors in blood from young but not old mice directly promote synapse formation and NMDA-receptor recruitment , 2019, Proceedings of the National Academy of Sciences.

[8]  C. Hidalgo,et al.  Aging Impairs Hippocampal- Dependent Recognition Memory and LTP and Prevents the Associated RyR Up-regulation , 2017, Front. Aging Neurosci..

[9]  C. Limatola,et al.  Electrophysiological Properties of CA1 Pyramidal Neurons along the Longitudinal Axis of the Mouse Hippocampus , 2016, Scientific Reports.

[10]  E. Masliah,et al.  Preclinical Assessment of Young Blood Plasma for Alzheimer Disease. , 2016, JAMA neurology.

[11]  F. Cayabyab,et al.  Adenosine A1 Receptor-Mediated Endocytosis of AMPA Receptors Contributes to Impairments in Long-Term Potentiation (LTP) in the Middle-Aged Rat Hippocampus , 2016, Neurochemical Research.

[12]  S. Lithfous,et al.  Episodic memory in normal aging and Alzheimer disease: Insights from imaging and behavioral studies , 2015, Ageing Research Reviews.

[13]  T. Gensch,et al.  Direct Interaction of CaVβ with Actin Up-regulates L-type Calcium Currents in HL-1 Cardiomyocytes* , 2014, The Journal of Biological Chemistry.

[14]  Danielle A. Simmons,et al.  Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice , 2014, Nature Medicine.

[15]  M. Mattson,et al.  L-type Ca2+ currents at CA1 synapses, but not CA3 or dentate granule neuron synapses, are increased in 3xTgAD mice in an age-dependent manner , 2014, Neurobiology of Aging.

[16]  D. Murchison,et al.  Characterization of age-related changes in synaptic transmission onto F344 rat basal forebrain cholinergic neurons using a reduced synaptic preparation. , 2014, Journal of neurophysiology.

[17]  Christina M. Weaver,et al.  Dendritic spine changes associated with normal aging , 2013, Neuroscience.

[18]  J. Hell,et al.  Surface L-type Ca2+ channel expression levels are increased in aged hippocampus , 2013, Aging cell.

[19]  H. Eichenbaum,et al.  Interplay of Hippocampus and Prefrontal Cortex in Memory , 2013, Current Biology.

[20]  J. Larson,et al.  Evidence for loss of synaptic AMPA receptors in anterior piriform cortex of aged mice , 2013, Front. Aging Neurosci..

[21]  Jack Waters,et al.  Altered Calcium Metabolism in Aging CA1 Hippocampal Pyramidal Neurons , 2013, The Journal of Neuroscience.

[22]  Y. de Koninck,et al.  Differential Balance of Prefrontal Synaptic Activity in Successful versus Unsuccessful Cognitive Aging , 2013, The Journal of Neuroscience.

[23]  K. Magnusson Aging of the NMDA receptor: from a mouse's point of view. , 2012, Future neurology.

[24]  J. Kaye,et al.  The aging systemic milieu negatively regulates neurogenesis and cognitive function , 2011, Nature.

[25]  G. Gerhardt,et al.  Transgenic Expression of Glud1 (Glutamate Dehydrogenase 1) in Neurons: In Vivo Model of Enhanced Glutamate Release, Altered Synaptic Plasticity, and Selective Neuronal Vulnerability , 2009, The Journal of Neuroscience.

[26]  D. Murchison,et al.  Enhanced calcium buffering in F344 rat cholinergic basal forebrain neurons is associated with age-related cognitive impairment. , 2009, Journal of neurophysiology.

[27]  W. Rostène,et al.  Stromal‐cell‐derived factor 1α /CXCL12 modulates high‐threshold calcium currents in rat substantia nigra , 2008, The European journal of neuroscience.

[28]  A. Takashima,et al.  GABAA Receptor-Mediated Acceleration of Aging-Associated Memory Decline in APP/PS1 Mice and Its Pharmacological Treatment by Picrotoxin , 2008, PloS one.

[29]  Bruce L McNaughton,et al.  Synaptic commitment: developmentally regulated reciprocal changes in hippocampal granule cell NMDA and AMPA receptors over the lifespan. , 2008, Journal of neurophysiology.

[30]  F. LaFerla,et al.  Increased intraneuronal resting [Ca2+] in adult Alzheimer’s disease mice , 2008, Journal of neurochemistry.

[31]  Tao Lu,et al.  The aging brain. , 2008, Annual review of pathology.

[32]  D. Holtzman,et al.  Abnormal glutamate homeostasis and impaired synaptic plasticity and learning in a mouse model of tuberous sclerosis complex , 2007, Neurobiology of Disease.

[33]  J. Weiss,et al.  Influence of channel subunit composition on L-type Ca2+ current kinetics and cardiac wave stability. , 2007, American journal of physiology. Heart and circulatory physiology.

[34]  M. Joëls,et al.  Brief RU 38486 Treatment Normalizes the Effects of Chronic Stress on Calcium Currents in Rat Hippocampal CA1 Neurons , 2007, Neuropsychopharmacology.

[35]  F. Schmitt,et al.  Hippocampal synaptic loss in early Alzheimer's disease and mild cognitive impairment , 2006, Neurobiology of Aging.

[36]  P. Landfield,et al.  Early and Simultaneous Emergence of Multiple Hippocampal Biomarkers of Aging Is Mediated by Ca2+-Induced Ca2+ Release , 2006, The Journal of Neuroscience.

[37]  Mark Bowlby,et al.  Early-onset behavioral and synaptic deficits in a mouse model of Alzheimer's disease. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[38]  D. Jaffe,et al.  Caloric restriction prevents aging-associated changes in spike-mediated Ca2+ accumulation and the slow afterhyperpolarization in hippocampal CA1 pyramidal neurons , 2005, Neuroscience.

[39]  Roberto Cabeza,et al.  Effects of healthy aging on hippocampal and rhinal memory functions: an event-related fMRI study. , 2005, Cerebral cortex.

[40]  S. Kanba,et al.  Age-related disturbance of memory and CREB phosphorylation in CA1 area of hippocampus of rats , 2005, Brain Research.

[41]  C. Finch,et al.  Synaptic Targeting by Alzheimer's-Related Amyloid β Oligomers , 2004, The Journal of Neuroscience.

[42]  Ottavio Arancio,et al.  Progressive age‐related development of Alzheimer‐like pathology in APP/PS1 mice , 2004, Annals of neurology.

[43]  M. Gallagher,et al.  Hippocampal CREB1 but not CREB2 is decreased in aged rats with spatial memory impairments , 2004, Neurobiology of Learning and Memory.

[44]  Joanna L. Jankowsky,et al.  Mutant presenilins specifically elevate the levels of the 42 residue β-amyloid peptide in vivo: evidence for augmentation of a 42-specific γ secretase , 2004 .

[45]  M. Jensen,et al.  Transient and sustained types of long‐term potentiation in the CA1 area of the rat hippocampus , 2003, The Journal of physiology.

[46]  T. Foster,et al.  Gene Microarrays in Hippocampal Aging: Statistical Profiling Identifies Novel Processes Correlated with Cognitive Impairment , 2003, The Journal of Neuroscience.

[47]  Wendy W. Wu,et al.  Age-Related Enhancement of the Slow Outward Calcium-Activated Potassium Current in Hippocampal CA1 Pyramidal Neurons In Vitro , 2002, The Journal of Neuroscience.

[48]  J. Logan,et al.  Under-Recruitment and Nonselective Recruitment Dissociable Neural Mechanisms Associated with Aging , 2002, Neuron.

[49]  Philip W. Landfield,et al.  Elevated Postsynaptic [Ca2+]iand L-Type Calcium Channel Activity in Aged Hippocampal Neurons: Relationship to Impaired Synaptic Plasticity , 2001, The Journal of Neuroscience.

[50]  F. Mora,et al.  Glutamatergic neurotransmission in aging: a critical perspective , 2001, Mechanisms of Ageing and Development.

[51]  N Spruston,et al.  Resting and active properties of pyramidal neurons in subiculum and CA1 of rat hippocampus. , 2000, Journal of neurophysiology.

[52]  Shuxian Hu,et al.  β-Chemokines and human immunodeficiency virus type-1 proteins evoke intracellular calcium increases in human microglia , 2000, Neuroscience.

[53]  Jialin Zheng,et al.  Intracellular CXCR4 signaling, neuronal apoptosis and neuropathogenic mechanisms of HIV-1-associated dementia , 1999, Journal of Neuroimmunology.

[54]  E. Kandel,et al.  Age-related defects in spatial memory are correlated with defects in the late phase of hippocampal long-term potentiation in vitro and are attenuated by drugs that enhance the cAMP signaling pathway. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[55]  L. Zhang,et al.  Differential Modulation of Synaptic Transmission by Calcium Chelators in Young and Aged Hippocampal CA1 Neurons: Evidence for Altered Calcium Homeostasis in Aging , 1999, The Journal of Neuroscience.

[56]  Y. Izumi,et al.  LTP in CA1 of the adult rat hippocampus and voltage‐activated calcium channels , 1998, Neuroreport.

[57]  D. Murchison,et al.  Increased calcium buffering in basal forebrain neurons during aging. , 1998, Journal of neurophysiology.

[58]  T. Foster,et al.  Reversal of Age-Related Alterations in Synaptic Plasticity by Blockade of L-Type Ca2+ Channels , 1998, The Journal of Neuroscience.

[59]  C. Barnes,et al.  Age-Related Decrease in the N-Methyl-d-AspartateR-Mediated Excitatory Postsynaptic Potential in Hippocampal Region CA1 , 1997, Neurobiology of Aging.

[60]  C. Elger,et al.  Properties of voltage-activated Ca2+ currents in acutely isolated human hippocampal granule cells. , 1997, Journal of neurophysiology.

[61]  K. Kawasaki,et al.  Amyloid β Protein Potentiates Ca2+ Influx Through L‐Type Voltage‐Sensitive Ca2+ Channels: A Possible Involvement of Free Radicals , 1997, Journal of neurochemistry.

[62]  Lee W. Campbell,et al.  Aging Changes in Voltage-Gated Calcium Currents in Hippocampal CA1 Neurons , 1996, The Journal of Neuroscience.

[63]  M. Charlton,et al.  Accumulation and extrusion of permeant Ca2+ chelators in attenuation of synaptic transmission at hippocampal CA1 neurons , 1996, Neuroscience.

[64]  B. McNaughton,et al.  Functional integrity of NMDA-dependent LTP induction mechanisms across the lifespan of F-344 rats. , 1996, Learning & memory.

[65]  T. Foster,et al.  Increased Susceptibility to Induction of Long-Term Depression and Long-Term Potentiation Reversal during Aging , 1996, The Journal of Neuroscience.

[66]  M. Gallagher,et al.  In vitro autoradiography of ionotropic glutamate receptors in hippocampus and striatum of aged Long–Evans rats: relationship to spatial learning , 1996, Neuroscience.

[67]  Philip W. Landfield,et al.  Increase in Single L-Type Calcium Channels in Hippocampal Neurons During Aging , 1996, Science.

[68]  D. Murchison,et al.  Low-voltage activated calcium currents increase in basal forebrain neurons from aged rats. , 1995, Journal of neurophysiology.

[69]  S. Oja,et al.  Age-related changes in the uptake and release of glutamate and aspartate in the mouse brain , 1995, Mechanisms of Ageing and Development.

[70]  M. Greenberg,et al.  L-type Voltage-sensitive Ca2+ Channel Activation Regulates c-fos Transcription at Multiple Levels (*) , 1995, The Journal of Biological Chemistry.

[71]  J. C. Chisholm,et al.  The Ca2+ influx induced by beta-amyloid peptide 25-35 in cultured hippocampal neurons results from network excitation. , 1995, Journal of neurobiology.

[72]  J. Meldolesi,et al.  Cytosolic Ca2+ Binding Proteins during Rat Brain Ageing: Loss of Calbindin and Calretinin in the Hippocampus, with no Change in the Cerebellum , 1994, The European journal of neuroscience.

[73]  M Moscovitch,et al.  Contributions of surface and conceptual information to performance on implicit and explicit memory tasks. , 1994, Journal of experimental psychology. Learning, memory, and cognition.

[74]  J. Disterhoft,et al.  Nimodipine decreases calcium action potentials in rabbit hippocampal CA1 neurons in an age‐dependent and concentration‐dependent manner , 1994, Hippocampus.

[75]  D. Turner,et al.  Age-related alterations in potentiation in the CA1 region in F344 rats , 1993, Neurobiology of Aging.

[76]  T. Bliss,et al.  A synaptic model of memory: long-term potentiation in the hippocampus , 1993, Nature.

[77]  G. Rose,et al.  Hippocampal plasticity induced by primed burst, but not long‐term potentiation, stimulation is impaired in area CA1 of aged fischer 344 rats , 1993, Hippocampus.

[78]  J F Disterhoft,et al.  Nimodipine increases excitability of rabbit CA1 pyramidal neurons in an age- and concentration-dependent manner. , 1992, Journal of neurophysiology.

[79]  B. McNaughton,et al.  Region‐specific age effects on AMPA sensitivity: Electrophysiological evidence for loss of synaptic contacts in hippocampal field CA1 , 1992, Hippocampus.

[80]  F. Morrell,et al.  Age‐related loss of axospinous synapses formed by two afferent systems in the rat dentate gyrus as revealed by the unbiased stereological dissector technique , 1992, Hippocampus.

[81]  P. Dutar,et al.  Alterations in the properties of hippocampal pyramidal neurons in the aged rat , 1992, Neuroscience.

[82]  A. Martínez-Serrano,et al.  Calcium binding to the cytosol and calcium extrusion mechanisms in intact synaptosomes and their alterations with aging. , 1992, The Journal of biological chemistry.

[83]  D. Salmon,et al.  Physical basis of cognitive alterations in alzheimer's disease: Synapse loss is the major correlate of cognitive impairment , 1991, Annals of neurology.

[84]  M. Charlton,et al.  Postsynaptic and presynaptic effects of the calcium chelator BAPTA on synaptic transmission in rat hippocampal dentate granule neurons , 1991, Brain Research.

[85]  D. Flood,et al.  Region-specific stability of dendritic extent in normal human aging and regression in Alzheimer's disease. I. CA1 of hippocampus , 1991, Brain Research.

[86]  G. Gibson,et al.  Selective alteration of mouse brain neurotransmitter release with age , 1987, Neurobiology of Aging.

[87]  F. Morrell,et al.  Loss of perforated synapses in the dentate gyrus: morphological substrate of memory deficit in aged rats. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[88]  T. A. Pitler,et al.  Prolonged Ca2+-dependent afterhyperpolarizations in hippocampal neurons of aged rats. , 1984, Science.

[89]  M. Segal Changes in neurotransmitter actions in the aged rat hippocampus , 1982, Neurobiology of Aging.

[90]  J. D. McGaugh,et al.  Impaired synaptic potentiation processes in the hippocampus of aged, memory-deficient rats , 1978, Brain Research.

[91]  A. Bacci,et al.  Caspase-3 triggers early synaptic dysfunction in a mouse model of Alzheimer's disease , 2011, Nature Neuroscience.

[92]  C. Barnes,et al.  Neural plasticity in the ageing brain , 2006, Nature Reviews Neuroscience.

[93]  Julie A. Markham,et al.  Sexually dimorphic aging of dendritic morphology in CA1 of hippocampus , 2005, Hippocampus.

[94]  J. Meldolesi,et al.  [3H]-CGP 39653 mapping of glutamatergic N-methyl-D-aspartate receptors in the brain of aged rats , 1993 .

[95]  Lucien T. Thompson,et al.  Functional Aspects of Calcium‐Channel Modulation , 1993, Clinical neuropharmacology.