Three's Company: Neuroimmune activation, sex, and memory at the tripartite synapse

Abstract

The neuroimmune system is required for normal cognitive functions such as learning and memory in addition to its critical role in detecting and responding to invading pathogens and injury. Understanding the functional convergence of neurons, astrocytes, and microglia at the synapse, particularly in the hippocampus, is key to understanding the nuances of such diverse roles. In the healthy brain, communication between all three cells is important for regulating neuronal activation and synaptic plasticity mechanisms, and during neuroinflammation, the activity and functions of all three cells can produce and be modulated by inflammatory cytokines. An important remaining component to this system is the conclusive evidence of sex differences in hippocampal plasticity mechanisms, hormone modulation of synaptic plasticity, functional properties of hippocampal neurons, and in neuroimmune activation. Sex as a biological variable here is necessary to consider given sex differences in the prevalence of memory-related disorders such as Alzheimer's disease and Post-Traumatic Stress disorder, both of which present with neuroimmune dysregulation. To make meaningful progress towards a deeper understanding of sex biases in memory-related disease prevalence, I propose that the next chapter of psychoneuroimmune research must focus on the signal integration and transduction at the synapse between experience-dependent plasticity mechanisms, neuroimmune activation, and the influence of biological sex.

Implication of the PTN/RPTPβ/ζ Signaling Pathway in Acute Ethanol Neuroinflammation in Both Sexes: A Comparative Study with LPS

“…No significant effects of Ptn overexpression or RPTPβ/ζ pharmacological inhibition were detected on gene expression of microglial markers Iba1 and Cd68 (a summary of PTN and MY10 effects on gene expression is presented in Table 3). It is important to note that other authors have reported sex differences in microglial states in healthy brains and in pathological conditions, such as stress or neurodegeneration [52][53][54]. However, in our experimental conditions, ethanol effects on prefrontal Iba1 mRNA levels are independent of sex.…”

Receptor protein tyrosine phosphatase β/ζ regulates loss of neurogenesis in the mouse hippocampus following adolescent acute ethanol exposure

“…In our studies, PFC and hippocampi of female mice showed enhanced morphological parameters of Iba1+ cells, compatible with a more activated state of microglia, independently of the treatment received. Sex differences in microglial state are known in the healthy brain and in conditions such as stress or neurodegeneration (Bilbo et al, 2012;Bollinger, 2021;Posillico, 2021) and are more evident in areas like PFC (Bollinger, 2021), where female rats show microglia with broadened morphology compatible with a surveillant phenotype. In this brain area, we found that these sex differences are more pronounced in animals treated with MY10 and ethanol.…”

Editorial commentary on the special issue emerging psychoneuroimmunology research: Future leaders in focus

“…Sex differences in basic and clinical PNI research are of increasing interest. In this special issue, Posillico (2021) provides a brief overview on synaptic plasticity for learning and memory involving neurons and astrocytes, a process also assisted by microglia. Sex differences in synaptic plasticity range from estrogen receptor distributions, transcription during hippocampal-dependent memory formation, intracellular signaling cascades, hippocampal neurogenesis, to differences in mechanisms and mediators of neuroinflammation.…”