GABA, Aging and Exercise: Functional and Intervention Considerations

Abstract

The global growth of an aging population is expected to coincide with an increase in aging-related pathologies, including those related to brain health. Thus, the potential for accelerated cognitive health declines due to adverse aging is expected to have profound social and economic implications. However, the progression to pathological conditions is not an inevitable part of aging. In fact, engaging in activities that improve cardiovascular fitness appears to be a means that offers the benefits of maintaining and/or improving cognitive health in older age. However, to date, the underlying mechanisms responsible for improved central nervous system health and function with exercise are not yet fully elucidated. Consequently, there is considerable interest in studies aimed at understanding the neurophysiological benefits of exercise on aging. One such area of study suggests that the improvements in brain health via exercise are, in part, driven by the recovery of inhibitory processes related to the neurotransmitter gamma-aminobutyric acid (GABA). In the present review, we highlight the opposing effects of aging and exercise on cortical inhibition and the GABAergic system's functional integrity. We highlight these changes in GABA function by reviewing work with in vivo measurements: transcranial magnetic stimulation (TMS) and magnetic resonance spectroscopy (MRS). We also highlight recent and significant technological and methodological advances in assessing the GABAergic system's integrity with TMS and MRS. We then discuss potential future research directions to inform mechanistic GABA study targeted to improve health and function in aging. We conclude by highlighting the significance of understanding the effects of exercise and aging, its influence on GABA levels, and why a better understanding is crucial to allow for more targeted and effective interventions aimed to ultimately improve age-related decline in aging.

Keywords: Gamma-aminobutyric acid (GABA); cortical inhibition; magnetic resonance spectroscopy; transcranial magnetic stimulation.

Figure 1.

GABA metabolism and the GABA Shunt. GABA is created as a metabolite from the breakdown of glutamate via glutamic acid decarboxylase (GAD) in neuronal cells. Two GAD isoforms are present denoted by molecular weight in Daltons (GAD67 and GAD65). GAD67 breaks down glutamate (Glu) into GABA within the cytosol after which GABA diffuses across GABA transporters (GABA-t) into extracellular space. In addition, GAD65 catabolizes glutamate into GABA at the outer mitochondrial membrane in the neuron. It is believed that this GABA is packaged into synaptic vesicles for neurotransmission at the synaptic cleft (not represented). GABA is preserved, particularly, during periods of stress through the GABA shunt. The GABA shunt is afforded by the breakdown of GABA to succinic semialdehyde, which is entrant into the Krebs cycle in the astrocyte mitochondria producing glutamate, which transports to astrocytes for breakdown to glutamate completing the shunt.

Figure 2.

Graphical illustration of the paradigms used to assess GABA receptor-specific cortical inhibition within (SICI, LICI, cSP) and between (SIHI, LIHI, iSP) the primary motor cortices. For Paired-pulse TMS paradigms (SICI/LICI & SIHI/LIHI), single magnetic pulse stimulation (TS) is delivered to the motor cortex to induce a motor evoked potential (MEP). This MEP amplitude (gray EMG signal) is then used as a comparator to MEP amplitudes from the same target muscle (blue EMG signals) under various paired-pulse TMS (ppTMS) conditions. In healthy younger adults (illustrated by SICI/LICI & SIHI/LIHI EMG) MEP amplitudes are reduced during ppTMS due to GABA receptor mediated inhibition. Aging SICI/LICI/SIHI/LIHI plots illustrate an example of an older adult showing disinhibition (increased MEP with ppTMS), which is thought to reflect diminished GABA receptor function. For single-pulse TMS paradigms, a single magnetic pulse is administered to the contralateral (cSP) or ipsilateral (iSP) motor cortex during active contraction of a target hand muscle. This stimulation evokes transient cessation of EMG activity, the duration of which is denoted as the cortical silent period. The aging iSP/cSP plot illustrates aging-related reductions in the duration of this silent period, which is also associated with diminished GABA receptor function.