Sensitive periods: the case of schizophrenia
A significant number of genes that have been reported to be associated with schizophrenia (Butler et al ., 2016) also play a role during sensitive periods of development. For example, genes that mediate the shift of GABAergic neurons from being excitatory to inhibitory as well as a dozen genes that encode for GABAA receptor subunits and other neurotransmitter receptors as well as enzymes that catalyze neurotransmitters. In support of this, benzodiazepines that positively modulate GABAA receptor activity accelerate the onset of plasticity during sensitive phases by speeding up maturation of inhibitory transmission. Patients suffering from schizophrenia show a dysfunction of cortical GABAergic inhibitory circuits reflected by a higher excitatory/inhibitory balance as compared to healthy individuals (O’Donnell et al. , 2017). Furthermore, other genes that show association with schizophrenia concern the plasticity phase of development, especially those involved in synaptic pruning (Li et al ., 2022; Caseras et al ., 2024). In addition, genes that affect the closure phase of the sensitive period have been associated with schizophrenia (Willi & Schwab, 2013). Theses risk genes include genes that represent braking factors that affect the stabilization of synapses ensuring a persistent and balanced ratio of excitatory to inhibitory synapses (e.g., cell adhesion molecules) as well as the formation of perineuronal nets and myelination of axons. Interestingly, when axonal plasticity by myelin-derived restriction is impaired, brain plasticity persists and extends beyond the sensitive periods (McGee et al ., 2005; Yang et al ., 2012).
In neurotypical individuals, there is an increase in inhibitory transmission in the prefrontal cortex up to late adolescence. The decline in the excitation/inhibition ratio is paralleled by active readjustment of GABAergic transmission of interneurons innervating pyramidal neurons of the prefrontal cortex (Caballero et al. , 2021). This process fosters the integration of growing cortico-cortical signals based on complex social and environmental inputs occurring during this period. Being exposed to human-typical cognitive and social niches allows individuals to go through plasticity periods, so that brain areas involved in complex and abstract cognition can develop to acquire high-level thinking and social skills. For example, individuals require reliable social input to master complex skills, including the ability of abstract and symbolic thinking, decision making, and problem solving—all which include the prefrontal cortex. If the available information is heterogeneous or complex, an extended neuroplasticity process may be advantageous to acquire such higher-order cognitive thinking. The human cognitive niche usually enables this through social scaffolding (Caporael et al ., 2014). Due to increasing environmental and social demands that adolescents encounter, this developmental period is highly susceptible to adverse experiences that can alter the trajectory of the inhibitory system and render the prefrontal cortex hypofunctional. If individuals receive contradictory cues or a poverty of external cues, the duration of the sensitive window and thus plasticity may be prolonged as has been shown for the development of brain circuits involved in sensory processing (Fawcett & Frankenhuis, 2015). Similarly, an impaired excitation/inhibition balance can lead to impaired circuit stabilization and perpetually elevated plasticity (Carulli et al ., 2010). A developmental window that remains plastic confers higher vulnerability for individuals exposed to adverse conditions. Therefore, the closing of sensitive windows in a timely manner is crucial and usually regulated by braking factors. In fact, the functional maturation of the GABAergic system confers adult properties to the prefrontal circuit by means of excitatory/inhibitory balance. Interestingly, in patients suffering from schizophrenia, plasticity of the prefrontal cortex seems to extend beyond the sensitive period (McGee et al ., 2005; Yang et al ., 2012). This is supported by the findings of functional impairment of GABAergic parvalbumin interneurons in the prefrontal cortex of schizophrenics (Beasley & Reynolds, 1997).
A prolonged plasticity is particularly hazardous when at the same time synaptic pruning is still ongoing or even accelerated. Because both, accelerated and decelerated timelines result in diminished cortical organization (Szakács et al ., 2024) which ultimately can contribute to psychopathologies. In neurotypically developing individuals, the elimination of synapses occurs during the plastic phase of the sensitive period until braking factors set physical barriers by myelination and the formation of perineuronal nets that prevent further neuroplastic changes to the established networks. Normally, the process of synaptic trimming is crucial for the maturation of the prefrontal cortex thereby enabling many species-typical, high-level skills in humans due to reducing signal-to-noise ratio of synaptic inputs and increasing reliability and specificity of circuits. In people suffering from schizophrenia, however, adolescence coincides with an excess of pruning of synaptic connections in the prefrontal cortex which is probably causally related to a reduced frontotemporal and frontoparietal connectivity, a decreased dendritic branching, and an overall diminished number of synaptic connections (Keshavan et al ., 2020). In other words, schizophrenia may be the result of extreme “overpruning” at the prefrontal cortex. This phenomenon is either attributable to an acceleration of pruning processes during this late ontogenetic stage or to pruning processes that continue much longer due a disruption of braking factors at the late stage of sensitive periods. In support of the latter, a reduced perineuronal net formation was found in patients with schizophrenia (Berretta et al. , 2015; Enwright et al ., 2016; Mauney et al. , 2013). Thus, the pathological mechanisms of schizophrenia seem to involve an excess of synaptic pruning as well as an overall delay in closing of the sensitive period of development that causes a prolonged plasticity. These processes can be understood as trade-off effects of heterochrony. Under positive conditions, extended sensitive periods of heightened neuroplasticity of the neocortex allows the development of sophisticated, species-typical skills in humans adapted to their cognitive niche. In contrast, the heterochronic effects that have proven beneficial for the evolution of the species may induce detrimental neurodevelopment in individuals with schizophrenia-risk genes when they encounter adverse conditions in their sociocultural niche.
Being adapted to a niche ensures a temporal alignment between intrinsic maturational processes and environmental input guiding brain development (Reh et al ., 2020). Sensitive periods in neurodevelopment are usually characterized by a changeover from intrinsic, experience-independent, and gene-governed mechanisms to experience-dependent mechanisms that are triggered and/or modulated by extrinsic inputs (Bourgeois, 1997). Complex behaviors depend on multiple sensitive periods. In fact, sensitive periods for low-level, more fundamental perceptual circuits end earlier than those for higher order aspects of perceptual circuits (Daw, 1997; Jones, 2000; Knudsen, 2004). This sequencing of sensitive periods is a fundamental neurodevelopmental principle as higher levels in brain hierarchy depend on precise and reliable information from lower levels in order to accomplish their functions. Subsequent sensitive periods require the timely progression of previous cascades of sensitive periods as well as non-random, circuit-specific experience. When individuals are deprived of adequate experience the opening of certain sensitive periods are delayed (Mower & Christen, 1985; Daw, 1997). The developmentally tightly regulated and stimulus-dependent progression of sensitive periods ensure high adaptability to a given environment by fostering adaptive wiring of the brain in response to highly specific environmental influences. This adaptability enabled by plastic responses allows the organism to integrate past information with ad-hoc sensory experiences and new, species-specific skills learned during ontogeny. The late sensitive periods in human development enable advanced cognitive abilities and further complex social behaviors. Some extraordinary human skills, including sophisticated language capabilities11Language development in humans is a complex, multi-stage process that typically spans from early infancy through late adolescence and early adulthood. The most sophisticated and refined aspects of language skills that develop in adolescence and beyond include abstract language use (e.g., metaphors, sarcasm, idioms) and specialized vocabulary related to specific interest and one´s social group., the ability of abstract and symbolic thinking, as well as the propensity for social collaboration and collective problem-solving are those that develop last during adolescence. And these skills are amongst the ones that are most strongly afflicted in schizophrenia. However, cascades of sensitive periods may cause cumulative effects of environmental insults. The impaired development of the prefrontal cortex may, therefore, also be the result of insults during earlier stages of ontogeny (e.g., pre- and perinatal stages) (Selemon & Zecevic, 2015). Or it may be the result of insults occurring at more than a single stage of development, as hypothesized in the “2-hit” model (Keshavan & Hogarty, 1999; Gildawieet al ., 2021).