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).