Conference Publication Details
Mandatory Fields
MORLEY, S.J., KAAR, A. & RAE, M.G.
Alzheimers Dement
Evoked hippocampal supralinear intracellular calcium responses are absent in 3xTg Alzheimer's mice.
2012
July
Validated
1
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Optional Fields
Recent research suggests that dysregulation of neuronal [Ca2+]i by soluble oligomers of A, rather than amyloid  plaques per se, may in fact precipitate the cognitive deficits associated with AD. Indeed, alterations in neuronal Ca2+-handling have been detected in neurons of transgenic AD mice as young as 4 weeks of age, long before the earliest detectable behavioural and synaptic deficits appear. The current study therefore sought to determine if alterations in the intracellular calcium handling properties of cultured hippocampal neurons from transgenic AD mice (3xTg AD) could be detected at an even earlier age than 4 weeks old. Using a conventional imaging set-up, intracellular calcium levels of cultured hippocampal neurons from 3-6 day old 3xTg AD mice and age-matched controls (incubated for ≥12 days prior to experimentation) were measured in response to various experimental manipulations. In control mice, stimulation of group I metabotropic glutamate receptors (mGluRs), using the specific agonist, DHPG (100 ÁM; 2 min), combined with elevated extracellular K+ (10.8 - 15 mM) - containing HBSS, evoked somatic supralinear [Ca2+]i signals relative to those evoked in the absence of elevated K+ solution (an increase of 223 ▒ 148% determined by area under the curve, n= 25 from 7 separate experiments; P<0.001). In contrast, in the 3xTg AD hippocampal neurones no significant difference in the size of the responses to DHPG either in the absence or presence of elevated extracellular K+ solution were observed (n = 57 from 15 separate experiments). However, control responses to DHPG in 3xTg AD neurons were significantly larger than those observed in neurons from non-transgenic mice (n = 23 vs 56 cells, P<0.01). The present findings suggest that significant alterations in IP3-mediated [Ca2+]i signalling exist in cultured hippocampal neurones of the 3xTg murine model of AD, relative to those observed in neurones from control mice at less than 1 week post-partum. These findings raise the possibility that the cognitive deficits seen in elderly AD patients may in fact be a result of insidious neurotoxic process(es) that are occurring throughout the lifetime of the individual, well before any functional loss becomes apparent.
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