Trends in Molecular Medicine
ReviewMolecular aspects of age-related cognitive decline: the role of GABA signaling
Section snippets
Memory decline in normal aging
Successes in modern medicine have resulted in marked improvements in somatic and peripheral health, and an unprecedented extension of the human lifespan. Such advances, however, are currently outpacing our ability to maintain optimal brain function and cognition later in life. This problem is accentuated by the striking rise in incidence of the age-associated neurological disorder, Alzheimer's disease (AD), characterized by a precipitous decline in cognitive functioning (e.g., loss of memory).
Overview of inhibitory signaling systems
GABA is the primary inhibitory neurotransmitter in the mammalian central nervous system. It is synthesized in presynaptic terminals from L-glutamic acid via a reaction that depends on glutamic acid decarboxylase (GAD; Figure 2). It is loaded into synaptic vesicles by the vesicular GABA transporter (VGAT), and released in an activity-dependent manner when action potentials depolarize the terminal, causing calcium influx and subsequent exocytosis. High concentrations of GABA are transiently
Molecular and cellular alterations in hippocampal GABA signaling
Inhibitory interneurons of the hippocampus undergo marked molecular and phenotypic alterations across the lifespan. In particular, beginning in middle-age, many interneurons cease to express GAD [67]. This reduction would be expected to confer less GABA synthesis and a consequent increase in hippocampal excitability. Consistent with this interpretation, and with data from neuropsychiatric conditions in which aberrant excitation is believed to contribute to memory impairment 68, 69, 70, the
Molecular and cellular alterations in PFC GABA signaling
In agreement with findings from hippocampus, there is a reduction in the number of GAD-expressing cells in aged PFC. Notably, however, such reductions are not unique to interneurons in PFC because a subtle reduction in the number of excitatory pyramidal neurons has also been reported in this brain region 82, 83, 84. Moreover, the density of both symmetric (i.e., inhibitory) and asymmetric (i.e., excitatory) synapses decreases with age in the primate PFC [85]. Consistent with the structural
Targeting inhibitory signaling in humans as a treatment for age-related cognitive decline
Given its history as a treatment for epilepsy, and the preclinical data demonstrating spatial memory improvement in aged rodents, levetiracetam represents a tractable clinical candidate for treating age-related decline of hippocampus-dependent memory. Human neuroimaging studies support a relationship between increased hippocampal excitability and memory dysfunction in aging 93, 94. In particular, patients diagnosed with mild cognitive impairment (MCI), who have clinically detectable memory loss
Concluding remarks and future perspectives
The divergent changes in GABAergic signaling that occur in aged hippocampus and PFC offer unique challenges from the perspective of treating memory decline. Based on the mechanistic data described above, therapeutics that target inhibitory changes in one brain region might be expected to exacerbate age-related dysregulation of GABAergic signaling in another. Indeed, these findings align with other work focused on cAMP/protein kinase A signaling, which suggests the need for unique therapeutic
Acknowledgments
We thank Dr Barry Setlow for critical comments on the manuscript. Supported by AG029421 (J.L.B.), the McKnight Brain Research Foundation (J.L.B., C.J.F.), and a McKnight Brain Institute Fellowship (J.A.M.).
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