In this study, the US research group hypothesized that gender-related differences in glutamatergic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) transmission in the region of medial prefrontal cortex might lead to observed differences in the prevalence of psychiatric disorders. Their results confirmed gender differences in AMPA glutamatergic transmission in the murine medial prefrontal cortex. An increase of synaptosomal expression of the GluA1 and GluA2 AMPA receptor subunits has been found in the medial prefrontal cortex of females compared with males. In addition, ex vivo slice electrophysiology performed on tissues prepared from the medial prefrontal cortex demonstrated a higher amplitude and frequency of spontaneous excitatory postsynaptic currents in female mice than in males.
About gender differences in prefrontal cortex dysfunction
The prefrontal cortex consists predominantly of pyramidal glutamatergic neurons and acts as a driver of goal-directed behavior. The medial prefrontal cortex is crucial to reward processing, attention, and memory. Anxiety, depression, and substance abuse disorders imply a dysregulation in the medial prefrontal cortex. Several gender-specific differences have been reported in the glutamatergic system, including differences in AMPA receptor and N-methyl-d-aspartate (NMDA) receptor signaling.
AMPA receptors mediate fast synaptic transmission in the central nervous system (CNS) and are composed of 4 GluA1-4 subunits, products of separate genes. Recent research has shown that AMPA receptors play a significant role in long-term potentiation and long-term depression. These the most actively investigated forms of long-term synaptic plasticity are thought to represent cellular correlates of particular types of learning and memory. Dysregulation of the AMPA receptor plasticity has been implicated in a number of pathological conditions.
There are significant differences between men and women in the prevalence and presentation of disorders associated with medial prefrontal cortex dysfunction. Rates of depression and anxiety are higher in women than men, and, depressive episodes last longer and occur more frequently in women than men.
It has been suggested that changes in glutamate signalling may contribute to clinically registered differences in the prevalence and presentation of psychiatric disorders among men and women, such as anxiety, substance use disorder, and depression.
About the study
In the present study, the scientists speculated that gender differences in glutamatergic transmission in the region of medial prefrontal cortex might lead to observed differences in the prevalence of psychiatric disorders.
Although gender-specific differences exist in other subtypes of glutamate receptors, such as metabotropic glutamate receptors or NMDA receptors, the researchers focused on the expression and function of the AMPA receptors, the ionotropic glutamate receptors.
The investigation involved 30 adult male and female C57Bl/6J mice. The animals were euthanized, and bilateral tissue samples were taken from the medial prefrontal cortex for western blotting. Both synaptosomal and total AMPA receptor subunits GluA1 and GluA2 levels were measured.
The results showed an increase of synaptosomal expression of the GluA1 and GluA2 AMPA receptor subunits in the medial prefrontal cortex of females compared with males. However, no statistically significant differences were observed in total levels of GluA1 and GluA2.
In the second set of experiments, mice were euthanized, and ex vivo slice electrophysiology was performed on tissues prepared from the medial prefrontal cortex. The researchers examined gender-specific differences in excitatory transmission measured by the frequency and amplitude of spontaneous excitatory postsynaptic currents. The excitatory transmission measurement showed a higher amplitude and frequency of spontaneous excitatory postsynaptic currents in female mice than in males.
The authors concluded that their results confirmed gender differences in AMPA glutamatergic transmission in the murine medial prefrontal cortex and baseline gender differences in excitatory transmission. These findings may explain why certain treatments for psychiatric diseases do not function equally in men and women. Therefore, a development of gender-specific drug therapies could improve the treatment of psychiatric diseases.
The study was published in the scientific journal Biology of Sex Differences. Biol Sex Differ 2022; 13, 66. (Open Access) https://doi.org/10.1186/s13293-022-00468-6