Sažetak sa skupa
https://doi.org/10.21857/ypn4oc4189
Extended developmental plasticity and vulnerability of human prefrontal microcircuits
Zdravko Petanjek
; University of Zagreb School of Medicine, Department of Anatomy and Clinical Anatomy & Croatian Institute for Brain Research, Zagreb, Croatia
*
Ana Hladnik
; University of Zagreb School of Medicine, Department of Anatomy and Clinical Anatomy & Croatian Institute for Brain Research, Zagreb, Croatia
Marina Čavka
; University of Zagreb School of Medicine, Department of Anatomy and Clinical Anatomy & Croatian Institute for Brain Research, Zagreb, Croatia
Maura Zanze Beader
; University of Zagreb School of Medicine, Department of Anatomy and Clinical Anatomy & Croatian Institute for Brain Research, Zagreb, Croatia
* Dopisni autor.
Sažetak
The transition from childhood to adulthood has become increasingly prolonged, with milestones such as completing education, marriage, and parenthood occurring later than ever before. This shift raises the question of whether adolescence should still be defined as the period between ages 12 and 18 or if its endpoint should be extended. Neurobiological research revealed that synaptic overproduction and developmental remodeling, including substantial elimination of synaptic spines, continue deeply into the third decade of life before stabilizing at adult level (Petanjek et al. 2023). A recent study performing cross-species proteomic mapping of synapse development, tracked changes in over 1,000 postsynaptic density proteins from midgestation to young adulthood comparing human, macaque and mouse neocortex (Wang et al. 2023.). The results showed that human postsynaptic densities develop two to three times more slowly than those of other species, largely due to a higher abundance of RhoGEF proteins in the turquoise module. The turquoise module is linked to synaptic plasticity, human cognitive function and neuropsychiatric disorders. Overexpression of RhoGEFs was found to increase spine density and delay synapse maturation. Several studies have previously demonstrated that gene expression changes during postnatal brain development in the human prefrontal cortex occur significantly later than in chimpanzees and rhesus macaques (Petanjek et al. 2023). The microcircuits responsible for processing the higher cognitive functions have the most extended period of synaptic overproduction, supporting high plasticity, which is crucial for acquiring complex cognitive abilities, including affective modulation of emotional cues, self-conceptualization, mentalization, cognitive flexibility, working memory and social skills. However, this prolonged development also extends the window of vulnerability, potentially increasing susceptibility to factors that may disrupt the formation of neural circuits involved in higher cognitive functions, which are impaired in neuropsychiatric disorders such as autism and schizophrenia (Petanjek et al. 2023). A recent study performing single-nucleus RNA sequencing (Batiuk et al. 2022), found a reduction in GABAergic neurons and a concomitant increase in principal neurons within dorsolateral prefrontal cortex of patients with schizophrenia. The most pronounced changes were observed in the upper cortical layers, suggesting selective vulnerability and general cortico-cortical network impairment as a core substrate associated with schizophrenia symptomatology. The dopamine system, whose disruption is considered to be one of the key features in schizophrenia, undergoes delayed maturation and changes throughout the whole stage of adolescence. Dopamine maturation interacts with changes in endocannabinoid signaling (Peters and Naneix 2022), characterized by transient increases in receptors expression and gradual rise in neurotransmitter levels. These changes enhance the recruitment of GABAergic interneurons and sustain the activity of pyramidal neurons. Prefrontal dopamine signaling refines processing by improving the selection of specific inputs, decreasing the signal-to-noise ratio, most likely through regulation of glutamatergic synaptic spine pruning. Similar adolescent remodeling hasn’t been observed in other neuromodulatory systems. Given their interactions with different neuronal populations and effects at different synaptic sites, dopamine and endocannabinoid signaling play a critical role in the late maturation of prefrontal circuits and their functioning. Extensive reports showed that external factors, including drug use, nutritional habits, and stress, affect the functioning of the prefrontal cortex during adolescence. Research strongly indicates that these factors interfere with the development of dopamine and endocannabinoid pathways, ultimately impacting the reorganization of cortical microcircuits. A recent epidemiological study conducted on a large Danish cohort found an association between cannabis use disorders and the onset of schizophrenia (Hjorthøj et al. 2023). The study indicated that 15-30% of schizophrenia cases in males, and 5-10% in females could potentially be prevented if cannabis use disorders were avoided between ages 15 and 25. This provides a very explicit example of how the adolescent and post-adolescent brain remains extremely plastic and vulnerable to external factors. Recognizing the extended developmental window in humans is crucial, as it entails both increased plasticity and vulnerability of prefrontal microcircuits. The influence of environmental factors on the shaping of these microcircuits is significant and may contribute to the development of late-onset neuropsychiatric disorders. Insights into prolonged neurodevelopment should be carefully considered when designing psychological, social, and educational strategies for adolescents and young adults, with a particular focus on legislation affecting those under 25.
Ključne riječi
prefrontal cortex, dendritic spine, glutamate, dopamine, endocannabinoids
Hrčak ID:
333464
URI
Datum izdavanja:
25.6.2025.
Posjeta: 578 *