Blunted Neuronal Calcium Response to Hypoxia in Naked Mole-Rat Hippocampus

Abstract

Naked mole-rats are highly social and strictly subterranean rodents that live in large communal colonies in sealed and chronically oxygen-depleted burrows. Brain slices from naked mole-rats show extreme tolerance to hypoxia compared to slices from other mammals, as indicated by maintenance of synaptic transmission under more hypoxic conditions and three fold longer latency to anoxic depolarization. A key factor in determining whether or not the cellular response to hypoxia is reversible or leads to cell death may be the elevation of intracellular calcium concentration. In the present study, we used fluorescent imaging techniques to measure relative intracellular calcium changes in CA1 pyramidal cells of hippocampal slices during hypoxia. We found that calcium accumulation during hypoxia was significantly and substantially attenuated in slices from naked mole-rats compared to slices from laboratory mice. This was the case for both neonatal (postnatal day 6) and older (postnatal day 20) age groups. Furthermore, while both species demonstrated more calcium accumulation at older ages, the older naked mole-rats showed a smaller calcium accumulation response than even the younger mice. A blunted intracellular calcium response to hypoxia may contribute to the extreme hypoxia tolerance of naked mole-rat neurons. The results are discussed in terms of a general hypothesis that a very prolonged or arrested developmental process may allow adult naked mole-rat brain to retain the hypoxia tolerance normally only seen in neonatal mammals.

No oxygen? No problem! Intrinsic brain tolerance to hypoxia in vertebrates

“…The results from the calcium imaging experiments are consistent with this and, incidentally, the ability to load slice neurons from naked mole-rats with fura-2 far beyond weaning age is also highly suggestive (Peterson et al, 2012a). The 'neoteny hypothesis' for naked molerat brain also explains two other observations that we made in our initial studies of neuronal electrophysiology in hippocampal slices: a lack of synaptic (paired-pulse) facilitation and an insensitivity to exogenous adenosine -two features only observed in hippocampus of typical lab rodents very early in postnatal development (Larson and Park, 2009).…”

“…6) . Evidence of blunted excitotoxicity and blunted calcium responses to glutamate is consistent with similar phenomena in the naked mole-rat (Peterson et al, 2012a;Peterson et al, 2012b). …”

“…A key element of the hypoxia cascade that determines whether the cellular response is reversible or leads to cell death is the accumulation of free intracellular calcium ions, which trigger cytotoxic mechanisms (Deshpande et al, 1987;Lee et al, 1991). In a study using the calcium indicator, fura-2, we found that calcium accumulation during hypoxia is very much lower in brain slices from naked molerats compared with age-matched mice (Peterson et al, 2012a). Fig.…”

Cellular Basis for Learning Impairment in Fragile X Syndrome

“…The results from the calcium imaging experiments are consistent with this and, incidentally, the ability to load slice neurons from naked mole-rats with fura-2 far beyond weaning age is also highly suggestive (Peterson et al, 2012a). The 'neoteny hypothesis' for naked molerat brain also explains two other observations that we made in our initial studies of neuronal electrophysiology in hippocampal slices: a lack of synaptic (paired-pulse) facilitation and an insensitivity to exogenous adenosine -two features only observed in hippocampus of typical lab rodents very early in postnatal development (Larson and Park, 2009).…”

“…A key element of the hypoxia cascade that determines whether the cellular response is reversible or leads to cell death is the accumulation of free intracellular calcium ions, which trigger cytotoxic mechanisms (Deshpande et al, 1987; Lee et al, 1991). In a study using the calcium indicator, fura-2, we found that calcium accumulation during hypoxia is very much lower in brain slices from naked molerats compared with age-matched mice (Peterson et al, 2012a). Fig.…”