When plasticity becomes maladaptive
Recognizing that plastic developmental processes are tightly intertwined
with evolution, despite them operating on very different time scales,
exemplifies the complexity and multidimensionality of evolutionary
processes. One way how plasticity can guide evolution, is through niche
construction (Odling-Smee et al. , 2003). Niche construction
denotes the processes how organisms influence the conditions of their
own evolutionary trajectories by shaping their environment. While
most—if not all—organisms construct their niche to a certain extent,
humans represent the most extreme niche constructors. Due to advanced
cognitive abilities and complex social behaviors, Homo sapiens occupies a unique niche that is referred to as human cognitive niche
(Tooby & DeVore, 1987; Pinker, 2010). This niche is characterized by
features that distinguish it from niches that other species occupy. For
example, humans have evolved sophisticated language capabilities,
allowing for complex communication, collaboration, as well as abstract
and symbolic thinking. These species-typic abilities have prepared the
ground for the development and transmission of cultural practices as
well as scientific and technological advancements.
In order to reliably reproduce the unique skills and cognitive
capabilities required to succeed in this cognitive niche, humans must
undergo an extraordinarily extended period of learning characterized by
heightened neuroplasticity. These periods of plasticity are paralleled
by a formidable increase in grey matter resulting from postnatal
synaptogenesis as well as dendritic and axonal arborization. Prolonged
synaptogenesis allows for a massive increase in possible synaptic
combinations that allows for extensive synaptic pruning to follow.
Unsurprisingly, an exceptionally long maturation process of various
brain areas contributes to the large inter-individual variability
amongst humans. This aligns well with the observation that in mammalian
phylogeny from rodents to primates, there is a continuous increase in
inter-individual differences concerning the densities of synapses, the
amounts of neurotransmitters, and the metabolic activities of cortical
areas (Bourgeois, 1997). Naturally, such differences conferred by
plasticity are the substrate that natural selection can work upon.
A prolonged maturation process that is accompanied by long-lasting
neuroplasticity also increases the vulnerability of the brain if exposed
to adverse environments (Sarto-Jackson, 2022). Since a significant
proportion of brain maturation processes occurs outside of the maternal
womb, “unbuffered” environmental influences can drastically impact the
infant´s developmental trajectories. With the largely unfettered
influence of the environment, synapses and neural circuits are subject
to a rigorous selection process in the course of ontogeny through
idiosyncratic experiences and learning processes. Due to a tremendous
increase in the variability of environmental conditions in the human
niche (e.g., changes in the cultural, technological, and virtual
environment), modern humans may currently experience an excess of
developmental variations of cognitive and social skills. This is in
agreement with the observation from a wide range of species showing that
after the emergence of novelties (such as the expansion of the human
neocortex), there is at first a rapid diversification that gradually
slows down later as the lineages of the species evolve (Uller et
al ., 2018). Importantly, such excessive variation based on plasticity
are not necessarily adaptive, but can include maladaptive responses
(Parsons et al. , 2020). This is an important phenomenon that
might contribute to the emergence of psychopathologies in individuals
living in modern societies.
A psychopathology that may have emerged in the human population fostered
by extensive developmental variabilities within the human socio-cultural
niche is schizophrenia. It is an intriguing evolutionary paradox that a
debilitating psychiatric disease like schizophrenia persist in human
populations despite its negative impact on reproductive fitness (Hunt &
Jaeggi, 2022). Various hypotheses exist that aim at explaining why
negative traits expressed in psychiatric disorders have not been weeded
out by natural selection. Space limitations prevent me from discussing
the different hypotheses. However, most of the theoretical assumptions
why negative traits persist in a population focus on the beneficial
effects of particular traits involved, e.g., advantages of heterozygous
individuals; trade-offs between adverse and fitness-enhancing traits; or
linkage of negative with other, favorable traits. According to these
assumptions, negative traits associated with schizophrenia are an
unfortunate consequence of various mechanisms favoring beneficial
traits, the latter being subject to positive selection. These hypotheses
offer possible explanations why schizophrenia risk genes can still be
found in a population´s gene pool. Importantly, most of these
hypothetical explanations have a conceptual consensus at the core—they
bestow causal primacy upon genes in making distinct traits. Thus,
at the heart of the theoretical underpinning lies a deterministic role
of the individual gene or sets of genes in creating phenotypic
traits. This harks back to textbook examples of well-studied genes
(e.g., those involved in monogenetic diseases) which shall not be the
focus, here. Instead, in this paper, I will draw on insights from
EvoDevo. Here, emphasis is given to developmental processes that are
influenced by genes as “enablers of plasticity,” not on genes as mere
“trait generators.” Rather than trying to elucidate a gene´s role
”for ” a given trait (or roles ”for ” multiple traits in
case of pleiotropy), this alternative approach opts for a closer look at
how genes serve developmental processes. As argued above, the definition
of a gene ”for ” makes only limited sense in the wider context of
developmental processes. Such explanatory shortcomings certainly also
hold true for genes involved in neurodevelopmental diseases. When same
gene product is part of several developmental modules and gets expressed
at different phases during ontogeny, some genetic—or rather
allelic—variants may not be eliminated by natural selection. Due to
their crucial roles in developmental processes at another stage of
development, these genes remain in the gene pool despite contributing to
adverse effects (a type of trade-off). Examples how the same gene
product can exert the same function, but still cause different effects
during ontogeny come from sensitive (or critical11Space
limitation prevents me from discussing the differences between
critical and sensitive periods. For an excellent review see Knudsen
(2004). Importantly, critical and sensitive periods operate by means
of the same set of neural mechanisms (Hensch, 2004; 2005).) periods
(see next section).
Let´s suppose that schizophrenia risk genes play crucial roles in
neuroplasticity and in the regulation of sensitive periods of brain
development. If this is the case, schizophrenia risk genes will be
functionally active during various plasticity periods of development.
The recurring activity might make these genes unassailable for negative
selection if they have adverse effects only at one particular life stage
but not at others. Similarly, these genes may escape negative selection
when they contribute to pernicious trait development in periods of high
plasticity only when the organism is exposed to a certain environment
but not when exposed to a variety of other environments. In other words,
schizophrenia-susceptibility genes may confer plasticity and thereby
variability to traits rather than being genes ”for ” positive or
negative traits. In support of this view, it is now generally
acknowledged that schizophrenia is a neurodevelopmental disorder of
multifactorial causation. If risk genes for schizophrenia are the same
ones that contribute to the regulation of plasticity involved in complex
neuronal connectivity and brain maturation, this may account for the
persistence of schizophrenia in the human population. Schizophrenia
would then represent a costly trade-off in the evolution of temporal
modules that comprise the same components (gene products, regulatory
elements, etc.) which are recruited during development at different life
stages22This is most likely not the only cause of the disease,
but it may be an important one that has not yet received enough
attention, in my opinion..
Let us return to the previously discussed SRGAP2 gene.
Intriguingly, genome-wide association studies and genetic linkage
analyses have identified associations between variations in theSRGAP2 gene (within the regulatory elements) and susceptibility
to schizophrenia. It may, therefore, be tempting to say that theSRGAP2 gene is a gene ”for ” schizophrenia. But in light of
the discussion above, this seems as vague as saying that theSRGAP2 gene is a gene ”for ” the expansion of the
neocortex, or a gene ”for ” dendritic spine maturation, and so on.
So, how can we better capture SRGAP2 gene´s function and maybe
also the function of other schizophrenia-susceptibility genes? As
already mentioned, the SRGAP2 gene is a multifunctional gene that
contributes to cell proliferation, neuronal migration, axonal targeting,
and spine maturation. The SRGAP2 genes, specifically theSRGAP2A gene and its SRGAP2C paralog, are expressed during
specific periods of brain development when the brain undergoes
significant growth and reorganization. During these neuroplastic phases,
the developing brain is also highly receptive to environmental inputs.
Such phases of heightened plasticity are considered sensitive periods.
Most noteworthy, it has been shown previously that activity of a newly
discovered SRGAP2 effector protein coincides with the opening of
a critical period of plasticity in cortical pyramidal neurons (Assendorpet al ., 2024).
To sum up, I argue that researchers may have to rethink their
understanding of the role of genes in the expression and development of
diseases. Studying the genetic factors that contribute to psychiatric
disorders, does not only require the formulation of a mechanistic
explanation of specific gene functions, an elucidation of their
spatiotemporal expression dimensions, and the identification how they
contribute to gene regulatory networks or protein-protein interaction
networks. It also necessitates a reappraisal of the very data under a
philosophical and conceptual lens. This is where philosophy of biology
might be helpful. Neuroscientists can take advantage of already
established theoretical concepts that were honed through
interdisciplinary discourse between EvoDevo scientists and philosophers.