Age-related changes in the prefrontal cortex: from single cell properties to neuromodulatory and long-range synaptic connectivity

Abstract

In vitro whole-cell patch clamping experiments were performed in the prefrontal cortex (PFC) of 3-26 months old mice divided into three age cohorts. Many single-cell properties were observed to alter in a U-shaped age-dependent manner. In particular, action potential (AP) width decreased from young (3.05 ± 0.31ms) to mature (1.95 ± 0.10ms), and increased from mature to old (2.64 ± 0.13ms) in putative pyramidal neurons. A similar effect was also observed in putative fast-spiking (FS) interneurons. Moreover, AP properties in pyramidal neurons appeared to be more affected by ageing in male mice than in female ones. To assay strength of functional connectivity between distal brain regions, optogenetics and in vitro electrophysiology techniques were employed to physiologically stimulate afferents in the PFC arriving from the tuberomammillary nucleus (TMN), and to assay ipsilateral-to-contralateral medial PFC (mPFC) strength of connectivity. Overall, histamine and GABA arriving from TMN axons increased the excitability of putative non-accommodating FS interneurons (+96.8% ± 37.4%), dramatically decreased the firing rate of pyramidal neurons (-65.7% ± 8.4%), and left the excitability of accommodating FS interneurons unaffected (-7.3% ± 9.3%). An age-related shift in the PFC towards greater and less specific inhibition from the TMN was also observed, which may adversely impact PFC cognitive abilities. In assessing ipsilateral-to-contralateral mPFC connectivity, preliminary results support the hypothesis of an age-related increase in strength of connectivity (circa 7 times greater) as a compensatory mechanism for dedifferentiation. The validity of this approach was further explored by comparison with a newly-developed anatomical measure of synapse number (mGRASP) in a descending cortico-collicular projection known to exhibit differences in contralateral and ipsilateral projection strength. We postulate that an increasing AP width from mature to old mice represents an adaptive change to counter-act the observed age-related shift towards inhibition in the PFC and the (implied) reduced local functional connectivity.