SummaryAs it was established that aging is not associated with massive neuronal loss, as was believed in the mid‐20th Century, scientific interest has addressed the influence of aging on particular neuronal subpopulations and their synaptic contacts, which constitute the substrate for neural plasticity. Inhibitory neurons represent the most complex and diverse group of neurons, showing distinct molecular and physiological characteristics and possessing a compelling ability to control the physiology of neural circuits. This review focuses on the aging of GABAergic neurons and synapses. Understanding how aging affects synapses of particular neuronal subpopulations may help explain the heterogeneity of aging‐related effects. We reviewed the literature concerning the effects of aging on the numbers of GABAergic neurons and synapses as well as aging‐related alterations in their presynaptic and postsynaptic components. Finally, we discussed the influence of those changes on the plasticity of the GABAergic system, highlighting our results concerning aging in mouse somatosensory cortex and linking them to plasticity impairments and brain disorders. We posit that aging‐induced impairments of the GABAergic system lead to an inhibitory/excitatory imbalance, thereby decreasing neuron's ability to respond with plastic changes to environmental and cellular challenges, leaving the brain more vulnerable to cognitive decline and damage by synaptopathic diseases.

Molecular synaptic aging perturbs neurotransmission and decreases the potential for neuroplasticity. The direction and degree of changes observed in aging are often region or cell specific, hampering the generalization of age-related effects. Using real-time PCR and Western blot analyses, we investigated age-related changes in several presynaptic markers (Vglut1, Vglut2, Gad65, Gad67, Vgat, synaptophysin) involved in the initial steps of glutamatergic and GABAergic neurotransmission, in several cortical regions, in young (3–4 months old), middle-aged (1 year old), and old (2 years old) mice. We found age-related changes mainly in protein levels while, apart from the occipital cortex, virtually no significant changes in mRNA levels were detected, which suggests that aging acts on the investigated markers mainly through post-transcriptional mechanisms depending on the brain region. Principal component analysis (PCA) of protein data revealed that each brain region possessed a type of “biochemical distinctiveness” (each analyzed brain region was best characterized by higher variability level of a particular synaptic marker) that was lost with age. Analysis of glutamate and γ-aminobutyric acid (GABA) levels in aging suggested that mechanisms keeping an overall balance between the two amino acids in the brain are weakened in the hippocampus. Our results unravel the differences in mRNA/protein interactions in the aging brain.

Behavioral flexibility is subserved by the prefrontal cortex and the basal ganglia. Orbitofrontal cortex (OFC) and dorsomedial striatum (DMS) form a functional frontocorticostriatal circuit crucial for the mediation of flexibility during reversal learning via dopamine (DA) neurotransmission. The regulatory control in maintaining DA homeostasis and function is provided by the dopamine transporter (DAT), which therefore likely plays a significant role in controlling the influence of DA on cognitive processes. Here we used a gene knockout mouse model to investigate the role of DAT in the performance on the Attentional Set-Shifting Task (ASST) stages dependent upon the OFC and the DMS. Additionally, behavior of mice after repeated administration of selective DAT inhibitor, GBR 12909, was examined.The animals were treated with the inhibitor to elicit a compensatory DAT up-regulation following withdrawal. Learning was slower and the number of errors during reversal learning and intra-dimensional shift stages was higher in DAT+/− mutant mice than in WT mice. GBR 12909-treated mice had deficits in reversal stages of the ASST. Neuronal activation in the OFC and DMS during the ASST was examined with early growth response proteins 1 and 2 (egr-1, egr-2) immunohistochemistry. Density of egr-2 labeled cells in the OFC was lower in mutant mice than in wild-types during reversal learning and the expression of the egr-1 was lower in mutant mice in the OFC and DMS during reversal and intra-dimensional shift stages. Mice with decreased DAT levels displayed behavioral difficulties that were accompanied by a lower task-induced activation of neurons in brain regions involved in the reversal learning. Altogether, these data indicate the role of the DAT in the behavioral flexibility.