Perhaps the most fearsome aspect of aging is that it degrades and ultimately destroys the function of the mind. With the exception of those who suffer neurodegenerative conditions - such as Alzheimer's disease - that in their late stages cause widespread cell death in the brain, most of the infrastructure of the mind remains largely intact even in very late life, however. This is despite the widespread small-scale damage due to broken blood vessels. The operation of that infrastructure is disrupted, however, and that disruption manifests as a progression of the various forms of cognitive decline. Analogously to the situation observed in aging stem cell populations, in which the cells are still present but not functioning as they did in youth, this suggests that some degree of restoration of lost cognitive function could be achieved rapidly if the right underlying damage could be repaired, the right signaling changed.
Cognitive aging is a consequence of molecular and biochemical aging. Alterations in gene expression, influencing the levels of proteins in many biological pathways, can be regarded as a hallmark of molecular aging. Changes in the biochemical composition of neural cells, which affect the efficiency of their synapses and whole circuits, impair the plasticity of the brain, that is the ability to reorganize, learn and remember. In this way, the disturbances of synaptic machinery profoundly contribute to the cognitive impairments as well as to the age-related brain disorders.
The majority of studies concerning the plasticity of neural circuits have focused on excitatory synapses. However, the role of inhibitory interactions in neuroplastic changes has recently been widely recognized. The most basic role of inhibitory neurons is to control the excitability of the principal cells, ensuring a proper homeostatic balance and preventing runaway excitation. Strong network inhibition suppresses the excitatory population response, providing the circuit with an intrinsic mechanism enabling precise contrast-gain control. Therefore, even though excitatory neurons are a large majority of cortical neurons, local inhibitory interneurons shape their firing and timing. There is increasing support for the hypothesis that disruption of inhibitory circuits is responsible for some of the clinical features of many neurodegenerative disorders. Many of them have been proposed to be synaptopathies - diseases related to the dysfunction of synapses. Brain aging is, in this context, considered a phenomenon promoting biological alterations associated with the above-mentioned disorders, resulting in so-called late-onset diseases.
The difficulty in understanding the mechanisms of interneurons aging, along with its relationship to plasticity impairments, cognitive decline and brain disorders, lies in the tremendous diversity of inhibitory neurons. Inhibition can be performed by perisomatically, dendritically or axonally targeting interneurons, which can be devoted to different inhibitory tasks. Furthermore, over 20 subtypes of potentially inhibitory neurons using GABA as a neurotransmitter have been recognized. Nevertheless, this diversity makes interneurons a potent and complex regulatory machinery controlling the physiology of neural circuits, and their molecular and biochemical aging can significantly contribute to the cognitive deficits observed in the aged brain. The role of neuroplasticity is to compensate for those age-related changes and to maintain the proper function of inhibitory circuits, supporting the balance between excitation and inhibition and the correct cognitive performance.
Age-related loss of synaptic contacts, decreased neurotransmitter release and reduced postsynaptic responsiveness to neurotransmitters result in a decline in synaptic strength, contributing to age-related cognitive decline. Molecular aging, defined as age-related transcriptome changes, and biochemical protein-related alterations within synapses weaken the plastic potential of neurons. Inhibitory neurons, despite being in the minority, are powerful regulators of neuronal excitability and, being particularly susceptible to aging-related alterations, are involved in many aging-induced cognitive impairments and brain disorders.
In the aged mouse somatosensory cortex, we have shown that although potential for learning-related plasticity is preserved there, the corresponding mechanisms are weakened and need longer stimulation to trigger plastic changes. We have postulated that the decreased effectiveness of the GABAergic system in the aged mouse somatosensory cortex contributes to the deficits in learning-induced plasticity. 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. This is an intermediate stage of the transition from healthy aging to age-related cognitive decline and then to disease. Pharmacological and/or environmental reinforcement of the GABAergic system thus seems to be a promising therapeutic target for aging-related brain disorders.
Link: https://dx.doi.org/10.1111/acel.12605
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