Abstract
Memory dysfunction is a symptomatic feature of many neurologic and neuropsychiatric disorders; however, the basic underlying mechanisms of memory and altered states of circuitry function associated with disorders of memory remain a vast unexplored territory. The initial discovery of endogenous neurosteroids triggered a quest to elucidate their role as neuromodulators in normal and diseased brain function. In this review, based on the perspective of our own research, the advances leading to the discovery of positive and negative neurosteroid allosteric modulators of GABA type-A (GABAA), NMDA, and non-NMDA type glutamate receptors are brought together in a historical and conceptual framework. We extend the analysis toward a state-of-the art view of how neurosteroid modulation of neural circuitry function may affect memory and memory deficits. By aggregating the results from multiple laboratories using both animal models for disease and human clinical research on neuropsychiatric and age-related neurodegenerative disorders, elements of a circuitry level view begins to emerge. Lastly, the effects of both endogenously active and exogenously administered neurosteroids on neural networks across the life span of women and men point to a possible underlying pharmacological connectome by which these neuromodulators might act to modulate memory across diverse altered states of mind.
Highlights
A major question in neuroscience since the initial discovery that somatically released gut peptides could alter central nervous system (CNS) function relates to whether and how the body can influence or modulate brain function
This review summarizes the field from the perspective of our own research, which has spanned the past three decades, and attempts to bring together state-of-the-art findings related to the role of neurosteroids in memory dysfunction, as seen in patients with schizophrenia, depression, and anxiety disorders
Because PREG is a precursor for all steroid hormones, it seems plausible that promotion of cortisol synthesis during stress may attenuate synthesis of other steroid hormones, but this suggestion has not been substantiated. These findings suggest that changes in endogenous brain levels of neurosteroids associated with age, sex, stress, and administration of selective serotonin reuptake inhibitors (SSRIs) may play a key role in the onset and clinical response to pharmacologic interventions in certain anxiety disorders
Summary
A major question in neuroscience since the initial discovery that somatically released gut peptides could alter central nervous system (CNS) function relates to whether and how the body can influence or modulate brain function. As new ideas emerged from clinical studies by Andrew Herzog in the mid 1980s concerning the possible role of estrogen and progesterone in catamenial epilepsy [22], we hypothesized that progesterone might act as a positive allosteric modulator of the GABAAR This led to the early work of Fong-sen Wu and Terrell Gibbs in my lab [23] showing that progesterone did modulate GABAA and glycine receptors. Non-human primate studies suggest that age-dependent changes in the expression of these enzymes could play a role in age-related changes in cognitive function [96, 97]. Neurosteroids and their sulfated conjugates can be characterized based on their core backbone structures as pregnanes, pregnenes, androstanes, progesterones, and deoxycorticosterones. The degree to which neurosteroids produce genomic and non-genomic effects depends on the extent to which they are metabolized (e.g., PREG to progesterone), and the extent to which the parent molecule and its neuroactive metabolites modulate extra- and intracellular receptors [104]
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