Hilar interneuron vulnerability distinguishes aged rats with memory impairment

Abstract

Hippocampal interneuron populations are reportedly vulnerable to normal aging. The relationship between interneuron network integrity and age-related memory impairment, however, has not been tested directly. That question was addressed in the present study using a well-characterized model in which outbred, aged, male Long-Evans rats exhibit a spectrum of individual differences in hippocampal-dependent memory. Selected interneuron populations in the hippocampus were visualized for stereological quantification with a panel of immunocytochemical markers, including glutamic acid decarboxylase-67 (GAD67), somatostatin, and neuropeptide Y. The overall pattern of results was that, although the numbers of GAD67- and somatostatin-positive interneurons declined with age across multiple fields of the hippocampus, alterations specifically related to the cognitive outcome of aging were observed exclusively in the hilus of the dentate gyrus. Because the total number of NeuN-immunoreactive hilar neurons was unaffected, the decline observed with other markers likely reflects a loss of target protein rather than neuron death. In support of that interpretation, treatment with the atypical antiepileptic levetiracetam at a low dose shown previously to improve behavioral performance fully restored hilar SOM expression in aged, memory-impaired rats. Age-related decreases in GAD67- and somatostatin-immunoreactive neuron number beyond the hilus were regionally selective and spared the CA1 field of the hippocampus entirely. Together these findings confirm the vulnerability of hippocampal interneurons to normal aging and highlight that the integrity of a specific subpopulation in the hilus is coupled with age-related memory impairment.

Old-onset caloric restriction effects on neuropeptide Y- and somatostatin-containing neurons and on cholinergic varicosities in the rat hippocampal formation

“…Supporting this hypothesis is also the present data showing that old-onset caloric-restriction treatment recovers the total number of NPY-IR and SS-IR neurons to levels similar to the younger adult control values. Furthermore, given that NPY-and SS-IR neurons are part of the hippocampal interneuronal population, the present results also corroborate previous studies where it was showed that agerelated decrease of the number of glutamate decarboxylase-67 immunopositive hippocampal interneurons reflects a reduction of the protein expression rather than cell death (Stanley and Shetty 2004;Spiegel et al 2013).…”

“…Furthermore, we have also found, in the same hippocampal regions, that aging induced significant reduction of the total number of SS-IR neurons. This finding was as well described by others that found reduction not only in the hippocampal SS-IR neuronal number (Spiegel et al 2013) and density (Potier et al 2006;Gavilán et al 2007;Stanley et al 2012) but also in its mRNA levels (Vela et al 2003;Gavilán et al 2007). The reduction of NPY-IR and SS-IR neurons during aging could be due to several reasons including cell death, decrease of activity, or even alteration of the protein conformation (Cadacio et al 2003;Vela et al 2003;Gavilán et al 2007).…”

“…The reduction of NPY-IR and SS-IR neurons during aging could be due to several reasons including cell death, decrease of activity, or even alteration of the protein conformation (Cadacio et al 2003;Vela et al 2003;Gavilán et al 2007). However, several factors, such as treatment with drugs and neurotrophins, are capable to induce partial or total recover of those neuropeptide levels to adult control values in aged rats (Cardoso et al 2006;Spiegel et al 2013). Therefore, it is likely that this reduction does not reflect irreversible loss of neurons.…”

“…Indeed, it has been shown that aging is associated with a reduction of the GABAergic subpopulations that express neuropeptide Y (NPY) and somatostatin (SS) in several brain areas such as the hypothalamus, striatum, and cortical regions (Kowalski et al 1992;Cha et al 1996;Zhang et al 1998;Cadacio et al 2003;Cardoso et al 2006;Stanley et al 2012;Spiegel et al 2013). One of those cortical regions is the hippocampal formation (HF), a limbic area involved in several cognitive functions, including spatial learning and memory (Morris 1984;Eichenbaum 1999;Aggleton and Brown 2006;Cardoso et al 2011).…”

Potential of GABA-ergic cell therapy for schizophrenia, neuropathic pain, and Alzheimer׳s and Parkinson׳s diseases

“…Hence, loss or impaired function of GABA-ergic interneurons can lead to learning and memory dysfunction. In rodent models, significant decreases in numbers of GABA-ergic interneurons are one of the conspicuous alterations seen in the aged hippocampus (Shetty and Turner, 1998;Stanley and Shetty, 2004;Shetty et al, 2009;Koh et al, 2010;Kuruba et al, 2011;Spiegel et al, 2013). Alterations in the function of GABA-ergic interneurons leads to increased neural activity in the CA3 region of the aged hippocampus, which contributes to memory dysfunction as the hyperactive CA3 pyramidal neurons are unable to encode new information in a pattern that is typically done in the young hippocampus (Wilson et al, 2003;Koh et al, 2010).…”