Loss of mnemonic function is among the earliest and most disconcerting consequences of the aging process. This study was designed to provide a comprehensive profile of spatial mnemonic abilities in male Fischer 344 (F344) rats across the lifespan. Young, middle-aged, and aged F344 rats were trained in spatial reference and working memory versions of the water maze task. There was a progressive age-related decline in spatial reference memory across the lifespan. Reliable individual differences were observed among aged rats, with some aged rats performing as well as young cohorts and other performing outside this range. An age-related delay-dependent decline was observed on a working memory version of the water maze task although no relationship between performance on reference and working memory tasks was present. Notably, middle-aged rats were impaired relative to young on both tasks. Together these data demonstrate that individual differences in spatial reference memory exist among aged F344 rats and provide novel data demonstrating an unrelated decline in working memory across the lifespan, suggesting that age-related mnemonic dysfunction may occur across multiple brain systems.

Murchison D, McDermott AN, LaSarge CL, Peebles KA, Bizon JL, Griffith WH. Enhanced calcium buffering in F344 rat cholinergic basal forebrain neurons is associated with age-related cognitive impairment. J Neurophysiol 102: 2194 -2207, 2009. First published August 12, 2009 doi:10.1152/jn.00301.2009. Alterations in neuronal Ca 2ϩ homeostasis are important determinants of age-related cognitive impairment. We examined the Ca 2ϩ influx, buffering, and electrophysiology of basal forebrain neurons in adult, middle-aged, and aged male F344 behaviorally assessed rats. Middle-aged and aged rats were characterized as cognitively impaired or unimpaired by water maze performance relative to young cohorts. Patch-clamp experiments were conducted on neurons acutely dissociated from medial septum/nucleus of the diagonal band with post hoc identification of phenotypic marker mRNA using single-cell RT-PCR. We measured whole cell calcium and barium currents and dissected these currents using pharmacological agents. We combined Ca 2ϩ current recording with Ca 2ϩ -sensitive ratiometric microfluorimetry to measure Ca 2ϩ buffering. Additionally, we sought changes in neuronal firing properties using current-clamp recording. There were no age-or cognitionrelated changes in the amplitudes or fractional compositions of the whole cell Ca 2ϩ channel currents. However, Ca 2ϩ buffering was significantly enhanced in cholinergic neurons from aged cognitively impaired rats. Moreover, increased Ca 2ϩ buffering was present in middle-aged rats that were not cognitively impaired. Firing properties were largely unchanged with age or cognitive status, except for an increase in the slow afterhyperpolarization in aged cholinergic neurons, independent of cognitive status. Furthermore, acutely dissociated basal forebrain neurons in which choline acetyltransferase mRNA was detected had the electrophysiological profiles of identified cholinergic neurons. We conclude that enhanced Ca 2ϩ buffering by cholinergic basal forebrain neurons may be important during aging.

Medial Septum/Diagonal Band (MS/DB) neurons display age‐dependent acceleration of GABA miniature postsynaptic current (mPSC) frequency, amplitude and decay rate in brain slices over postnatal day (PD) 4–16 (DuBois and Frye SfN Abst, 34: 913.11, 2004). ‘Binge‐like’ alcohol exposure on PD 4–9 equivalent to 3rd trimester of human pregnancy blunted this maturation, possibly by disrupting clustering of α1 containing GABAARs at synapses (Wang and Frye SfN Abst, 34: 570, 2006). In the present study, potentiation by zopidem (0.3–100 μM), a positive allosteric modulator with preferred selectivity for α1 subunit containing GABAARs, was examined in MS/DB neurons in brain slices from PD 4–9 Naïve pup and older rats of 3–4, 17 or 24 months. Zolpidem potentiation after binge‐like ethanol on PD 4–9 (5.25g/kg/day) was investigated during PD 11–16 and PD 80–85. GABAAR–mediated mPSCs were recorded in presence of zolpidem and amplitude, frequency and decay kinetics were analyzed. Zolpidem (0.3–100 μM) showed an age‐dependent potentiation of mPSC decay during PD 4–16 and plateaued in adulthood. The fast decay potentiation by zolpidem in adult and old rats resembled that of PD 4–9 naïve pups; Potentiation of the slow decay resembled that of PD 11–16 control rats. Binge ethanol exposure on PD 4–9 blunted zolpidem potentiation on PD 11–16, which persists through PD 80–85. No gender differences in baseline or zolpidem sensitivity on PD 11–16 were observed after binge ethanol treatment on PD 4–9. These results suggest binge ethanol exposure in developing MS/DB neurons appears to cause long‐term distortion of pharmacological sensitivity of postsynaptic GABAARs, which could contribute to cognitive deficits identified in fetal alcohol spectrum disorders. Supported in part by NIH R56AA12386 (GDF), RO1 AG007805(WHG), T32 MH65728 (ANM)