INTRODUCTION
The “Brain Development and Disease” class of the Master’s Degree in
Cognitive Science at the University of Trento focuses on brain
development’s molecular and cellular mechanisms. Gene networks
controlling embryonic brain development, neural plasticity during
critical periods, and the pathogenesis of neurodevelopmental disorders
are the key subjects addressed in this class. The class aims to give the
students a comprehensive overview of brain development, addressing the
neurobiological underpinnings of neural development and the possible
pathological consequences of their derangement. For their final exam,
students are asked to write a research article in which they must
describe the expression profile of one gene of their interest, whose
altered expression and function has been related to a brain disorder. We
acknowledge that studying the expression of one gene at a time has its
limitations, since brain disorders are likely of multifactorial origin
and their pathogenic mechanisms involve differential dysregulation of
several genes. However, for didactic reasons, we think that the study of
the expression of one single gene related to a brain disorder is largely
enough for students to generate an adequate amount of data for their
exam. To achieve this goal, students have to collect gene expression
data from the mouse, primate and human Allen Brain Atlases and discuss
the data with respect to the disorder of interest. The teacher first
provides the students with a tutorial helping them to familiarize with
gene expression data collection and analysis. Then, students can
practice data collection during class hours and online, plus one-to-one
sessions with a tutor flanking the teacher. We previously published a
brief report of one of these class activities (Rubino & Bozzi, 2021).
Here we describe, in a more extensive way, a new study resulting from
our students’ work.
Early life stress (ELS) plays a causal role in many psychiatric
disorders, including major depressive disorder (MDD; Cheng et al.,
2022). ELS is relevant to one of the most robust hypotheses of MDD
mechanism: impairment of the hypothalamus-pituitary-adrenal (HPA) axis.
Patients have increased levels of both cortisol and
corticotropin-releasing hormone (CRH) as a result of disruption of the
glucocorticoid receptor (GR) signaling (Ising et al., 2007). GR
signaling disruption then results in impaired feedback inhibition along
the HPA axis (de Kloet et al., 2005). In particular, ELS induces
lifelong disturbances to HPA function, thereby increasing vulnerability
to MDD later in life (Cheng et al., 2022). Importantly, improved HPA
system regulation (as measured by stress hormone response to a
dexamethasone/CRH test) is associated with enhanced response to
treatment (Ising et al., 2007). However, these findings have not yielded
clinically successful medications (Malhi and Mann, 2018).
Neuroinflammation is another critical player in MDD pathogenesis. Not
only does immune system activation induce symptoms that overlap with
those of MDD, but patients with neuroinflammatory diseases also have a
high prevalence of MDD (Setiawan et al., 2015). Elevated proinflammatory
cytokines are reliably found in patients with MDD; and, remarkably,
therapeutically administered cytokines trigger depression approximately
half the time (Raison et al., 2006). Although this systemic immune
activation has been highly studied as a component of MDD, very little is
agreed upon regarding the role or mechanism of action for cytokines in
the brain (Beurel et al., 2020).
Despite monumental research efforts spanning decades, MDD
pathophysiology is not clear (Malhi and Mann, 2018). Consequently,
comprehension of its pharmacological treatment is also insufficient. Low
antidepressant acceptability is mainly due to weeks of delay before the
full effect, and the adverse side effects that can occur during and
after that waiting period (David and Gourion, 2016). Moreover, up to
15% of MDD patients struggle with little to no response to
pharmacological interventions (Berlim and Turecki, 2007), with clinical
guidance limited to trial and error. The scientific community is at a
loss to explain why some patients must suffer through failed treatment
attempts while others do not (Grogans et al., 2022). There are no
clinically relevant methods for predicting which antidepressant may work
best for a given individual (Zeier et al., 2018).
The human FKBP5 gene codes for FK506-binding protein 5, a prolyl
isomerase that binds immunosuppressive drugs such as FK506, rapamycin,
and cyclosporin A. FKBP5 is located on chromosome 6 and its protein
product functions as a cochaperone of heat-shock 90-kD protein-1 (OMIM,
Online Mendelian Inheritance in Man, http://omim.org/, OMIM #602623;
Gene ID 2289, https://www.ncbi.nlm.nih.gov/gene/2289). FKBP5 codes for
an immunophilin, which performs immunoregulation and basic cellular
functions. FKBP5 is also related to glucocorticoid signaling (Vermeer et
al., 2003) and consequently the stress regulation system. Moreover,
FKBP5 alternations in mice have been shown to affect stress responses
through HPA axis activity, inflammation, and depressive- and
anxiety-like behaviors (Häusl et al., 2021; Gan et al., 2022). This gene
may help explain how the HPA axis and immune system mediate
antidepressant efficacy. In the course of a student’s assignment, we
identified the FKBP5 gene as a key player uniting these two major
hypotheses of MDD pathogenesis and treatment response.