Age-related changes in synaptic, calcium and cognitive mechanisms in the basal forebrain using an optogenetic mouse model

Abstract

Age-relate cognitive decline is a devastating disorder often associated with serious neurological disease and neurodegeneration. The increased prevalence of neurological diseases, as a result of the aging population, only reinforces the importance of understanding the neurobiological basis of aging and the need for better therapeutics to treat age-related dysfunction. In the current work, studies were designed to utilize our new optogenetic aging mouse model of the basal forebrain (BF) to test the efficacy of a pharmacological treatment across aging and to test the effects of late-onset, short-term intermittent fasting (IF) on well-characterized age-related changes in synaptic and Ca2+ signaling. Finally, we tested whether both synaptic excitation (E) and inhibition (I) changed during aging. Our model utilized a bacterial artificial chromosome (BAC) transgenic mouse line with stable expression of the channelrhodopsin-2 (ChR2) variant H134R [VGAT-ChR2(H134R)-EYFP] in a reduced synaptic preparation that allows for specific optogenetic light stimulation on GABAergic synaptic terminals across aging. Our first study showed that clinically relevant concentrations of amitriptyline (AMI) reduced the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) and reduced quantal content in both young and aged mice. These results suggest a presynaptic mechanism of action of the drug that does not diminish with age. Our second study showed the late-onset, short-term IF reversed age-related changes in Ca2+ buffering and GABAergic synaptic transmission in BF neurons of aged mice. We performed quantal analysis using the method of failures and showed that IF reverses the age-related decrease in quantal content of GABAergic synapses. Our results suggest that late-onset, short-term IF, may show comparable beneficial effects as those of life-long caloric restriction (CR) to improve brain health. Few therapeutics are currently available to treat age-related neurological dysfunction and IF may provide a healthy therapeutic alternative. Finally, we demonstrated that the E/I balance increased with age due to no change in synaptic excitation coupled with decrease in synaptic inhibition in the BF brain slices. E/I imbalance within neural circuits has been implicated in age-related brain dysfunction. Our studies will help advance our knowledge of the neurobiology of the aging and suggest possible new avenues for drug research mechanisms and/or lifestyle changes.