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vascularization focus on in vitro and in vivo strategies. disorganization reflects the neuroanatomical anomalies
In vitro approaches involve co-culturing brain organoids observed in patients and provides a platform for investigating
with vascular cells, embedding them in ECM gels with the underlying mechanisms of the disorder. Research on
endothelial cells, or integrating human umbilical vein Down syndrome has further elucidated the effects of genetic
endothelial cells, fostering spontaneous vascular network mutations on brain development, showing an overproduction
formation. 201,216 Vascularized brain organoids exhibit of OLIG2 progenitors coupled with diminished cortical
+
reduced expression of hypoxia markers, increased size, and neurogenesis (Figure 4). 242-245 These insights offer valuable
enhanced survival, highlighting their potential to model mechanistic explanations for the cognitive deficits commonly
neurodevelopmental processes and disease pathologies. 52,232 associated with Down syndrome.
These advancements pave the way for more physiologically The impact of these genetic alterations extends beyond
relevant brain organoid models suitable for translational individual neuronal populations, influencing broader
applications. neural circuits and structures within the brain. For
7. Integrating molecular mechanisms and instance, alterations in the limbic system are prominent
in schizophrenia,
while disruptions in the cerebellum
246-248
therapeutic strategies in NDDs through are observed in Angelman syndrome (Figure 4). 249-251 The
organoid models ability of organoid models to capture the complexity of
A comprehensive understanding of the molecular and NDDs at both cellular and systems levels underscores their
cellular mechanisms underlying neurodevelopmental significance in advancing mechanistic investigations.
and neuropsychiatric disorders is essential for advancing Moreover, the integration of multi-omics technologies,
targeted therapeutic interventions. Disorders such as autism functional imaging, and gene-editing tools into organoid
spectrum disorder, Timothy syndrome, and schizophrenia research has further enhanced the resolution at which
display distinct yet overlapping neuropathological features, molecular and cellular dysfunctions can be studied. For
including synaptic dysfunction, aberrant neuronal example, modulation of the WNT/β-catenin signaling
migration, and disrupted cortical development. The pathway has shown therapeutic potential in autism
233
application of advanced experimental methodologies – spectrum disorder, 252,253 providing a promising avenue for
such as sc-RNA seq, electrophysiological recordings, and targeted intervention. Similarly, gene therapy approaches
CRISPR gene editing – has significantly expanded our targeting MECP2 offer hope for treating Rett syndrome. 254,255
insights into these complex conditions. Furthermore, Pharmacological strategies, such as mGluR5 inhibitors
the identification of disorder-specific therapeutic targets for Fragile X syndrome and NMDA receptor modulators
highlights the pathophysiological diversity of these for schizophrenia, exemplify the specificity required for
disorders, with strategies ranging from FOXG1 knockdown effective therapeutic development (Figure 4). 256,257
in autism spectrum disorder to the utilization of mTOR Despite these advances, several critical challenges
inhibitors in tuberous sclerosis complex, 234,235 underscoring remain in the development and application of patient-
the translational relevance of these findings.
specific organoid models. One major issue is the variability
Organoid models have emerged as powerful tools for in differentiation potential among iPSC lines derived from
studying NDDs, providing unprecedented opportunities different patients, which can affect the reproducibility and
to investigate the intricate cellular and molecular interpretation of experimental results. Furthermore,
258
abnormalities associated with these conditions (Figure 4). the heterogeneity in genetic background, epigenetic
Derived from patient-specific iPSCs, organoids replicate modifications, and reprogramming artifacts introduces
key aspects of human brain development, enabling additional complexity when comparing phenotypic
researchers to observe disease phenotypes in a 3D context outcomes across samples. 259,260 Standardization of organoid
that closely mimics in vivo conditions. 10,52 In the case of protocols remains limited, with differences in culture media,
autism spectrum disorder, organoid models have revealed growth factors, and timeline of maturation significantly
increased inhibitory synapse formation and aberrant impacting the cellular composition and developmental
progenitor proliferation, particularly within the prefrontal trajectory of the organoids. 261
cortex and hippocampus. 67,236-238 These findings suggest Another significant limitation is the incomplete
that altered synaptic dynamics may contribute to the maturation and lack of vascularization in most brain
characteristic cognitive and behavioral features observed in organoids, which constrains their ability to fully
affected individuals. recapitulate in vivo-like neuronal circuitries and long-range
Similarly, organoid studies in Timothy syndrome connectivity. 201,232 These structural deficits hinder the study
have demonstrated disorganized interneuron migration, of later stages of development and neurodegeneration, as well
a consequence of CaV1.2 dysfunction. 239-241 This cellular as pharmacokinetic modeling of therapeutic compounds.

Volume 1 Issue 3 (2025) 15 doi: 10.36922/OR025100010