The synapse, as the site of functional neural interaction, has been suggested as a possible substrate for age-related impairment of cognitive ability. Using the physical disector probe with tissue prepared for ultrastructural analysis, we find an age-related decline in the numerical density of presumptive inhibitory synapses in layer 2 of the sensorimotor cortex of the Brown Norway x Fisher 344 rat. This age-related decline in presumptive inhibitory synapses is maintained when the density of synapses is combined with the numerical density of neurons quantified from the same anatomical space to arrive at a ratio of synapses per neuron. The numerical density of these synapses declines between middle-aged (18 months) and old (29 months) animals by 36% whereas numerical density of neurons does not change between these ages, resulting in a decline in the ratio of presumptive inhibitory synapses per neuron in this cortical area. This study demonstrates a deficit in the intrinsic inhibitory circuitry of the aging neocortex, which suggests an anatomical substrate for age-related cognitive impairment.

Alterations in the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA-R) receptor and N-methyl-D-aspartate receptor (NMDA-R) have been documented in aged animals and may contribute to changes in hippocampal-dependent memory. Growth Hormone (GH) regulates AMPA-R and NMDA-R-dependent excitatory transmission and decreases with age. Chronic GH treatment mitigates age-related cognitive decline. An in vitro CA1 hippocampal slice preparation was used to compare hippocampal excitatory transmission and plasticity in old animals treated for 6–8 months with either saline or GH. Our findings indicate that GH treatment restores NMDA-R dependent basal synaptic transmission in old rats to young adult levels and enhances both AMPA-R-dependent basal synaptic transmission and long-term potentiation. These alterations in synaptic function occurred in the absence of changes in presynaptic function, as measured by paired-pulse ratios, the total protein levels of AMPA-R and NMDA-R subunits or in plasma or hippocampal levels of insulin-like growth factor-I. These data suggest a direct role for GH in altering age-related changes in excitatory transmission and provide a possible cellular mechanism through which GH changes the course of cognitive decline.

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Fractionated partial or whole-brain irradiation (fWBI) is a widely used, effective treatment for primary and metastatic brain tumors, but it also produces radiation-induced brain injury, including cognitive impairment. Radiation-induced neural changes are particularly problematic for elderly brain tumor survivors who also experience age-dependent cognitive impairment. Accordingly, we investigated, i] radiation-induced cognitive impairment, and ii] potential biomarkers of radiationinduced brain injury in a rat model of aging. Fischer 344 × Brown Norway rats received fractionated whole-brain irradiation (fWBI rats, 40 Gy, 8 fractions over 4 wk) or sham-irradiation (Sham-IR rats) at 12 months of age; all analyses were performed at 26-30 months of age. Spatial learning and memory were measured using the Morris water maze (MWM), hippocampal metabolites were measured using proton magnetic resonance spectroscopy ( 1 H MRS), and hippocampal glutamate receptor subunits were evaluated using Western blots. Young rats (7-10 month-old) were included to control for age effects. The results revealed that both Sham-IR and fWBI rats exhibited age-dependent impairments in MWM performance; fWBI induced additional impairments in the reversal MWM. 1 H MRS revealed age-dependent decreases in neuronal markers, increases in glial markers, but no detectable fWBI-dependent changes. Western blot analysis revealed age-dependent, but not fWBI-dependent, glutamate subunit declines. Although Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. previous studies demonstrated fWBI-induced changes in cognition, glutamate subunits, and brain metabolites in younger rats, age-dependent changes in these parameters appear to mask their detection in old rats, a phenomenon also likely to occur in elderly fWBI patients >70 years of age. NIH Public Access

When ferrets are born, four weeks before the onset of hearing, few synapses are evident in the medial superior olive (MSO). The synapses present are immature and almost exclusively found in the neuropil. The MSO somata are virtually devoid of synaptic contacts but are contacted by fine glial processes that increasingly ensheathe the somata during the first postnatal week. By P12, somatic synaptogenesis in the MSO is evident. Initially the terminals contain vesicles of irregular shape, size, and distribution. The glial lamellae appear to withdraw as the synaptic contacts form but continue to cover the asynaptic portions of the cell surface. The lamellae frequently extend from ensheathing the soma to encapsulate the immature terminals. During the next two weeks, synaptic density and terminal encapsulation proceed until the somata is surrounded by encapsulated synaptic terminals as in the adult ferret MSO. While most immature terminals contain round vesicles, during the first postnatal week some terminals with nonround vesicles can be distinguished. The first distinction between types of nonround vesicle-containing terminals, i.e., pleiomorphic and ovoid, is in the second postnatal week. This distinction becomes increasingly clear and by the end of the first postnatal month, terminal types can be reliably categorized. These observations indicate that: (1) synapses are present in the MSO neuropil one month prior to the onset of hearing, (2) the major period of synaptogenesis begins approximately two weeks prior to the onset of hearing, and (3) glial lamellae ensheathe MSO somata prior to the onset of somatic synaptogenesis, withdraw as synapses form, and subsequently re-extend to encapsulate newly formed synapses.