Treatment Strategies Targeting Excess Hippocampal Activity Benefit Aged Rats with Cognitive Impairment

Excess neural activity in the CA3 region of the hippocampus has been linked to memory impairment in aged rats. We tested whether interventions aimed at reducing this excess activity would improve memory performance. Aged (24 to 28 months old) male Long–Evans rats were characterized in a spatial memory task known to depend on the functional integrity of the hippocampus, such that aged rats with identified memory impairment were used in a series of experiments. Overexpression of the inhibitory neuropeptide Y 13–36 in the CA3 via adeno-associated viral transduction was found to improve hippocampal-dependent long-term memory in aged rats, which had been characterized with impairment. Subsequent experiments with two commonly used antiepileptic agents, sodium valproate and levetiracetam, similarly produced dose-dependent memory improvement in such aged rats. Improved spatial memory with low doses of these agents was observed in both appetitve and aversive spatial tasks. The benefits of these different modalities of treatment are consistent with the concept that excess activity in the CA3 region of the hippocampus is a dysfunctional condition that may have a key role underlying age-related impairment in hippocampal-dependent memory processes. Because increased hippocampal activation occurs in age-related memory impairment in humans as observed in functional neuroimaging, the current findings also suggest that low doses of certain antiepileptic drugs in cognitively impaired elderly humans may have therapeutic potential and point to novel targets for this indication.

[1]  Mark F. Bear,et al.  Heterosynaptic metaplasticity in the hippocampus in vivo: A BCM-like modifiable threshold for LTP , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[2]  Terence J O'Brien,et al.  Neuropeptide Y suppresses absence seizures in a genetic rat model primarily through effects on Y2 receptors , 2007, The European journal of neuroscience.

[3]  Mark S. Cohen,et al.  Patterns of brain activation in people at risk for Alzheimer's disease. , 2000, The New England journal of medicine.

[4]  R. Sperling,et al.  Hippocampal activation in adults with mild cognitive impairment predicts subsequent cognitive decline , 2007, Journal of Neurology, Neurosurgery, and Psychiatry.

[5]  M. Moser,et al.  Pattern Separation in the Dentate Gyrus and CA3 of the Hippocampus , 2007, Science.

[6]  H Eichenbaum,et al.  Place cell rigidity correlates with impaired spatial learning in aged rats , 2003, Neurobiology of Aging.

[7]  H. Eichenbaum,et al.  Neurocognitive aging: prior memories hinder new hippocampal encoding , 2006, Trends in Neurosciences.

[8]  Edvard I Moser,et al.  Spatial learning with unilateral and bilateral hippocampal networks , 2005, The European journal of neuroscience.

[9]  Howard Eichenbaum,et al.  Cognitive Aging: A Common Decline of Episodic Recollection and Spatial Memory in Rats , 2008, The Journal of Neuroscience.

[10]  M. Gallagher,et al.  Spatial memory is related to hippocampal subcellular concentrations of calcium-dependent protein kinase C isoforms in young and aged rats. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[11]  Carol A Barnes,et al.  Neurobiological changes in the hippocampus during normative aging. , 2009, Archives of neurology.

[12]  E. Rolls,et al.  Computational analysis of the role of the hippocampus in memory , 1994, Hippocampus.

[13]  Vince D. Calhoun,et al.  Alterations in Memory Networks in Mild Cognitive Impairment and Alzheimer's Disease: An Independent Component Analysis , 2006, The Journal of Neuroscience.

[14]  James J. Knierim,et al.  Ensemble Dynamics of Hippocampal Regions CA3 and CA1 , 2004, Neuron.

[15]  G. Sperk,et al.  Neuropeptide Y: emerging evidence for a functional role in seizure modulation , 1999, Trends in Neurosciences.

[16]  W. Colmers,et al.  Neuropeptide Y2 receptors inhibit the frequency of spontaneous but not miniature EPSCs in CA3 pyramidal cells of rat hippocampus. , 1996, Journal of neurophysiology.

[17]  H. Eichenbaum,et al.  Age-Associated Alterations of Hippocampal Place Cells Are Subregion Specific , 2005, The Journal of Neuroscience.

[18]  R. Burwell,et al.  Neuron number in the parahippocampal region is preserved in aged rats with spatial learning deficits. , 2002, Cerebral cortex.

[19]  M. Gallagher,et al.  Preserved neuron number in the hippocampus of aged rats with spatial learning deficits. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[20]  R. Haberman,et al.  Adeno-associated virus-mediated expression and constitutive secretion of NPY or NPY13-36 suppresses seizure activity in vivo , 2007, Gene Therapy.

[21]  G. Sperk,et al.  The anti‐epileptic actions of neuropeptide Y in the hippocampus are mediated by Y2 and not Y5 receptors , 2005, The European journal of neuroscience.

[22]  R. Haberman,et al.  Attenuation of seizures and neuronal death by adeno-associated virus vector galanin expression and secretion , 2003, Nature Medicine.

[23]  R. Morris,et al.  Delay‐dependent impairment of a matching‐to‐place task with chronic and intrahippocampal infusion of the NMDA‐antagonist D‐AP5 , 1999, Hippocampus.

[24]  T. Südhof,et al.  SV2 Renders Primed Synaptic Vesicles Competent for Ca2+-Induced Exocytosis , 2009, The Journal of Neuroscience.

[25]  W. Abraham.  Metaplasticity: tuning synapses and networks for plasticity , 2008, Nature Reviews Neuroscience.

[26]  C. Nemeroff,et al.  Effects of Sodium Valproate on Corticotropin-Releasing Factor Systems in Rat Brain , 2001, Neuropsychopharmacology.

[27]  M. De Vivo,et al.  Phosphodiesterase inhibitors for cognitive enhancement. , 2005, Current pharmaceutical design.

[28]  I. Tulloch,et al.  The relationship between plasma concentration of valproic acid and its anticonvulsant and behavioural effects in the rat , 1982, Neuropharmacology.

[29]  L. Gjerstad,et al.  Up‐regulation of hippocampal glutamate transport during chronic treatment with sodium valproate , 2001, Journal of neurochemistry.

[30]  M. Albert,et al.  Increased hippocampal activation in mild cognitive impairment compared to normal aging and AD , 2005, Neurology.

[31]  A. Chiba,et al.  A re-examination of the role of basal forebrain cholinergic neurons in spatial working memory , 1998, Neuropharmacology.

[32]  B. Caffo,et al.  Familial risk for Alzheimer's disease alters fMRI activation patterns. , 2006, Brain : a journal of neurology.

[33]  Maija Pihlajamäki,et al.  Increased fMRI responses during encoding in mild cognitive impairment , 2007, Neurobiology of Aging.

[34]  B. Cubelos,et al.  The glutamate transporter GLT1b interacts with the scaffold protein PSD‐95 , 2008, Journal of neurochemistry.

[35]  R. Sperling,et al.  Age-related memory impairment associated with loss of parietal deactivation but preserved hippocampal activation , 2008, Proceedings of the National Academy of Sciences.

[36]  J. Morrison,et al.  Circuit-Specific Alterations in Hippocampal Synaptophysin Immunoreactivity Predict Spatial Learning Impairment in Aged Rats , 2000, The Journal of Neuroscience.

[37]  E. Perucca,et al.  Pharmacological and Therapeutic Properties of Valproate , 2002, CNS drugs.

[38]  D. Margineanu,et al.  Electrophysiological, neurochemical and regional effects of levetiracetam in the rat pilocarpine model of temporal lobe epilepsy , 2003, Seizure.

[39]  S. Josselyn,et al.  CREB, synapses and memory disorders: past progress and future challenges. , 2005, Current drug targets. CNS and neurological disorders.

[40]  A. Treves,et al.  Distinct Ensemble Codes in Hippocampal Areas CA3 and CA1 , 2004, Science.

[41]  C. Large,et al.  Effects of lamotrigine and levetiracetam on seizure development in a rat amygdala kindling model , 2003, Epilepsy Research.

[42]  M. Gallagher,et al.  Aging, spatial learning, and total synapse number in the rat CA1 stratum radiatum , 2004, Neurobiology of Aging.

[43]  P. Patsalos,et al.  Benefit of combination therapy in epilepsy: A review of the preclinical evidence with levetiracetam , 2009, Epilepsia.

[44]  M. Albert,et al.  Medial temporal lobe function and structure in mild cognitive impairment , 2004, Annals of neurology.

[45]  P. Pinheiro,et al.  Up‐regulation of neuropeptide Y levels and modulation of glutamate release through neuropeptide Y receptors in the hippocampus of kainate‐induced epileptic rats , 2005, Journal of neurochemistry.

[46]  Tadao Serikawa,et al.  Long‐lasting Antiepileptic Effects of Levetiracetam against Epileptic Seizures in the Spontaneously Epileptic Rat (SER): Differentiation of Levetiracetam from Conventional Antiepileptic Drugs , 2005, Epilepsia.