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.