Neuroscience Letters 397 (2006) 64–68 Imbalance towards inhibition as a substrate of aging-associated cognitive impairment Tak Pan Wong a,1 , Giorgio Marchese a,2 , Maria Antonietta Casu a,2 , Alfredo Ribeiro-da-Silva a,b , A. Claudio Cuello a,b,c , Yves De Koninck a,d,∗ a Department of Pharmacology and Therapeutics, McGill University, Montr´ eal, Que., Canada H3G 1Y6 b Department of Anatomy and Cell Biology, McGill University, Montr´ eal, Que., Canada H3G 1Y6 c Department of Neurology and Neurosurgery, McGill University, Montr´ eal, Que., Canada H3G 1Y6 d Division de neurobiologie cellulaire, Centre de recherche Universit´ e Laval-Robert Giffard, 2601 Chemin de la Canardi` ere, Beauport, Que. Canada G1J 2G3 Received 12 September 2005; received in revised form 29 November 2005; accepted 30 November 2005 Abstract The number of synapses in the cerebral cortex decreases with aging. However, how this structural change translates into the cognitive impairment observed in aged animals remains unknown. Aged animals are not a homogenous group with respect to their cognitive performances; but instead, they can be separated into aged cognitively unimpaired (“normal”) and aged cognitively impaired groups using a spatial memory task such as the Morris water maze. These two aged groups provide an unprecedented opportunity to isolate synaptic properties that relate to cognitive impairment from unrelated factors associated with normal aging. Using such classification, we conducted whole-cell patch-clamp recordings to measure basal spontaneous miniature excitatory (mEPSCs) and inhibitory synaptic currents (mIPSCs) bombarding layer V pyramidal neurons in the parietal cortex. We found that the frequencies of both mEPSC and mIPSC were lower in aged normal rats when compared with young rats. In contrast, aged cognitively impaired rats displayed a reduction in mEPSC frequency only. This results in an imbalance towards inhibition that may be an important substrate of the cognitive impairment in aged animals. We also found that pyramidal neurons in both aged normal and aged cognitively impaired rats exhibit similar structural attritions. Thus, cognitive impairment may be more related to an altered balance between different neurotransmitter systems than a mere reduction in synaptic structures. © 2005 Elsevier Ireland Ltd. All rights reserved. Keywords: Whole-cell patch-clamp recording; Morris water maze; Morphological analysis; Cerebral cortex; Aging; Cognitive impairment Synaptic reduction is commonly reported as one of the salient structural modifications in the aging cerebral cortex [1,14,31]. Yet, it still remains controversial whether there is a causal rela- tionship between these structural modifications and cognitive impairments that occur in aged individuals. First, as we now know that some synapses can be functionally ‘silent’ in the absence of corresponding receptors on the postsynaptic mem- ∗ Corresponding author at: Division de neurobiologie cellulaire, Centre de recherche Universit´ e Laval-Robert Giffard, 2601 Chemin de la Canardi` ere, Beauport, Que. Canada G1J 2G3. Tel.: +1 418 663 5747; fax: + 1 418 663 5873. E-mail address: Yves.DeKoninck@crulrg.ulaval.ca (Y. De Koninck). 1 Present address: 2211 Wesbrook Mall, Brain Research Centre, University of British Columbia, Vancouver, BC, Canada V6T 2B5. 2 Present address: Neuroscienze S.c.ar.l., Via Palabanda 9, 09123 Cagliari, Italy. brane [15,19], one cannot necessarily equate synapse numbers with synaptic function. Second, since most studies of aging com- pare aged animals with young cognitively unimpaired animals, it has not been possible to dissociate the process of aging from cognitive impairment. Thus, for example, while the reported changes in synaptic structure and/or function may be associated with normal aging, they may not be the direct substrate of the cognitive impairments. Therefore, to assess functional input and to isolate the cogni- tive impairment from the aging process, in the present study we decided to compare the synaptic activity that bombards layer V neocortical pyramidal neurons in the parietal cortex from two groups of aged animals: one with a normal pattern of cognitive performance (“aged normal”) and the other with distinctively marked cognitive impairment (“aged cognitively impaired”) [9,29,38]. We chose the parietal cortex because this cortical area is known to be involved in spatial perception [12] and memory 0304-3940/$ – see front matter © 2005 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.neulet.2005.11.055