Proceedings of The Physiological Society
King's College London (2011) Proc Physiol Soc 22, C06
Aged-related changes to hippocampal intrinsic excitability and Na+ channel gating
J. T. Brown1, A. D. Randall1
1. School of Physiology and Pharmacology, University of Bristol, Bristol, United Kingdom.
Neurological function declines during the normal ageing process resulting in cognitive impairment in the elderly. The cellular mechanisms underlying age-related deficits in cognitive function are not well understood, although changes to hippocampal intrinsic excitability may play a role (Matthews et al. 2009). To explore the effects of ageing on neuronal excitability, we made whole-cell recordings from CA1 hippocampal neurones in slices prepared from 1-2 month (young: Y), 7-9 month (middle aged: M) and 22-24 (aged: A) month old C57/BL6 mice. Current clamp recordings revealed no difference in the resting membrane potential (Y: -77.6 ± 0.5 mV, n=20; M: -76.0 ± 0.4 mV, n=33; A: -76.8 ± 1.0 mV, n=17; P=0.25 1-way ANOVA), input resistance (Y: 131 ± 8 MΩ; M: 123 ± 6 MΩ; A: 123 ± 10 MΩ; n as above, P = 0.74) or sag (Y: 27 ± 1 %; M: 26 ± 2 %; A: 29 ± 1 %; n as above, P = 0.29). In response to a 500 ms, 300 pA current injection all of the recorded neurones fired a series of action potentials (APs). A waveform analysis of the first AP induced by this stimulus revealed that whilst the peak and maximum rate of rise were not affected by age there was a significant difference in AP threshold. Thus, at 7-9 months of age the AP threshold was significantly more hyperpolarised that at the other age points (Table 1). A change in AP threshold is suggestive of a change in the gating properties of the Na+ channels which underlie the AP. To explore this possibility, nucleated macropatches were excised from the soma of CA1 pyramidal neurones and inward, TTX-sensitive Na+ currents (INa) were recorded under voltage clamp, using a Cs-based internal solution. No difference was observed in the absolute conductance or the steady state inactivation properties of INa, however, the V½ of activation was shifted in a hyperpolarised direction at 7-9 months of age, mirroring the shift in AP threshold (Table 1). Thus, CA1 pyramidal neurones exhibit an age-related form of intrinsic plasticity in which hyperpolarising shifts in the activation properties of INa and AP threshold arise during adulthood (from young to middle aged). This may relate to previously reported forms of activity-dependent changes to AP threshold (Xu et al., 2005). The greater excitability observed in mid-life was reversed as ageing continued, such that old animals possess reduced intrinsic excitability, which likely contributes to age-related cognitive impairments.
Where applicable, experiments conform with Society ethical requirements