Background Methylation of serotonin-related genes has been proposed as a plausible gene-by-environment link
which may mediate environmental stress, depressive and anxiety symptoms. DNA methylation is often measured
in blood cells, but little is known about the association between this peripheral epigenetic modification and brain
serotonergic architecture. Here, we evaluated the association between whole-blood-derived methylation of four CpG
sites in the serotonin transporter (SLC6A4) and six CpG sites of the tryptophan hydroxylase 2 (TPH2) gene and invivo
brain levels of serotonin transporter (5-HTT) and serotonin 4 receptor (5-HT4) in a cohort of healthy individuals
(N = 254) and, for 5-HT4, in a cohort of unmedicated patients with depression (N = 90). To do so, we quantified
SLC6A4/TPH2 methylation using bisulfite pyrosequencing and estimated brain 5-HT4 and 5-HTT levels using positron
emission tomography. In addition, we explored the association between SLC6A4 and TPH2 methylation and measures
of early life and recent stress, depressive and anxiety symptoms on 297 healthy individuals.

Results We found no statistically significant association between peripheral DNA methylation and brain markers
of serotonergic neurotransmission in patients with depression or in healthy individuals. In addition, although SLC6A4
CpG2 (chr17:30,236,083) methylation was marginally associated with the parental bonding inventory overprotection
score in the healthy cohort, statistical significance did not remain after accounting for blood cell heterogeneity.

Conclusions We suggest that findings on peripheral DNA methylation in the context of brain serotonin-related features
should be interpreted with caution. More studies are needed to rule out a role of SLC6A4 and TPH2 methylation
as biomarkers for environmental stress, depressive or anxiety symptoms.

Genomic mechanisms enhancing risk in males may contribute to sex bias in autism. The ubiquitin protein ligase
E3A gene (Ube3a) affects cellular homeostasis via control of protein turnover and by acting as transcriptional coactivator with steroid hormone receptors. Overdosage of Ube3a via duplication or triplication of chromosomal
region 15q11-13 causes 1 to 2% of autistic cases. Here, we test the hypothesis that increased dosage of Ube3a may
influence autism-relevant phenotypes in a sex-biased manner. We show that mice with extra copies of Ube3a exhibit
sex-biasing effects on brain connectomics and autism-relevant behaviors. These effects are associated with
transcriptional dysregulation of autism-associated genes, as well as genes differentially expressed in 15q duplication
and in autistic people. Increased Ube3a dosage also affects expression of genes on the X chromosome, genes
influenced by sex steroid hormone, and genes sex-differentially regulated by transcription factors. These results
suggest that Ube3a overdosage can contribute to sex bias in neurodevelopmental conditions via influence on sex-differential mechanisms.

Journal: Science Advances

Physiology and behavior are structured temporally to anticipate daily cycles of light and dark, ensuring fitness and survival. Neuromodulatory systems in the brain—including those involving serotonin and dopamine—exhibit daily oscillations in neural activity and help shape circadian rhythms. Disrupted neuromodulation can cause circadian abnormalities that are thought to underlie several neuropsychiatric disorders, including bipolar mania and schizophrenia, for which a mechanistic understanding is still lacking. Here, we show that genetically depleting serotonin in
Tph2 knockout mice promotes manic-like behaviors and disrupts daily oscillations of the dopamine biosynthetic enzyme tyrosine hydroxylase (TH) in midbrain dopaminergic nuclei. Specifically, while TH mRNA and protein levels in the Substantia Nigra (SN) and Ventral Tegmental Area (VTA) of wild-type mice doubled between the light and dark phase, TH levels were high throughout the day in Tph2 knockout mice, suggesting a hyperdopaminergic state. Analysis of TH expression in striatal terminal fields also showed blunted rhythms. Additionally, we found low abundance and
blunted rhythmicity of the neuropeptide cholecystokinin (Cck) in the VTA of knockout mice, a neuropeptide whose downregulation has been implicated in manic-like states in both rodents and humans. Altogether, our results point to a previously unappreciated serotonergic control of circadian dopamine signaling and propose serotonergic dysfunction as an upstream mechanism underlying dopaminergic deregulation and ultimately maladaptive behaviors.

Journal: International Journal of Molecular Science

 Depression is one of the most burdensome psychiatric disorders, affecting hundreds of millions of people worldwide. The disease is characterized not only by severe emotional and affective impairments, but also by disturbed vegetative and cognitive functions. Although many candidate mechanisms have been proposed to cause the disease, the pathophysiology of cognitive impairments in depression remains unclear. In this article, we aim to assess the link between cognitive alterations in depression and possible developmental changes in neuronal circuit wiring during critical periods of susceptibility. We review the existing literature and propose a role of serotonin signaling during development in shaping the functional states of prefrontal neuronal circuits and prefronto-thalamic loops. We discuss how early life insults affecting the serotonergic system could be important in the alterations of these local and long-range circuits, thus favoring the emergence of neurodevelopmental disorders, such as depression.

Journal: ACS Chemical Neuroscience

DOI:https://doi.org/10.1021/acschemneuro.3c00837

The recent development of genetically encoded fluorescent neurotransmitter biosensors has opened the door to recording serotonin (5-hydroxytryptamine, 5-HT) signaling dynamics with high temporal and spatial resolution in vivo. While this represents a significant step forward for serotonin research, the utility of available 5-HT biosensors remains to be fully established under diverse in vivo conditions. Here, we used two-photon microscopy in awake mice to examine the effectiveness of specific 5-HT biosensors for monitoring 5-HT dynamics in somatosensory cortex. Initial experiments found that whisker stimulation evoked a striking change in 5-HT biosensor signal. However, similar changes were observed in controls expressing green fluorescent protein, suggesting a potential hemodynamic artifact. Subsequent use of a second control fluorophore with emission peaks separated from the 5-HT biosensor revealed a reproducible, stimulus-locked increase in 5-HT signal. Our data highlight the promise of 5-HT biosensors for in vivo application, provided measurements are carried out with appropriate optical controls.

DOI:https://doi.org/10.1021/acschemneuro.3c00725

BACKGROUND:
During pregnancy, both selective serotonin reuptake inhibitor (SSRI) exposure and maternal depression have been associated with poor offspring neurodevelopmental outcomes. In a population-based cohort, we investigated the association between intrauterine exposure to SSRIs and depressive symptoms and offspring white matter development from childhood to adolescence.
METHODS:
Self-reported SSRI use was verified by pharmacy records. In midpregnancy, women reported on depressive symptoms using the Brief Symptom Inventory. Using diffusion tensor imaging, offspring white matter microstructure, including whole-brain and tract-specific fractional anisotropy (FA) and mean diffusivity, was measured at 3 assessments between ages 7 to 15 years. The participants were divided into 4 groups: prenatal SSRI exposure (n = 37 with 60 scans), prenatal depression exposure (n = 229 with 367 scans), SSRI use before pregnancy (n = 72 with 95 scans), and reference (n = 2640 with 4030 scans).
RESULTS:
Intrauterine exposure to SSRIs and depressive symptoms were associated with lower FA in the whole brain and the forceps minor at 7 years. Exposure to higher prenatal depressive symptom scores was associated with lower FA in the uncinate fasciculus, cingulum bundle, superior and inferior longitudinal fasciculi, and corticospinal tracts. From ages 7 to 15 years, children exposed to prenatal depressive symptoms showed a faster increase in FA in these white matter tracts. Prenatal SSRI exposure was not related to white matter microstructure growth over and above exposure to depressive symptoms.
CONCLUSIONS:
These results suggest that prenatal exposure to maternal depressive symptoms was negatively associated with white matter microstructure in childhood, but these differences attenuated during development, suggesting catch-up growth.

Journal: Biological Psychiatry CNNI

DOI:https://doi.org/10.1021/acschemneuro.3c00648

IMPORTANCE
Clinical decision-making on antidepressant treatment during pregnancy, particularly selective serotonin reuptake inhibitors (SSRIs), is challenging, as both prenatal SSRI exposure and maternal depressive symptoms may be associated with negative outcomes in offspring.
OBJECTIVE
To investigate the association between intrauterine SSRI exposure and maternal depressive symptoms and structural brain development in offspring from mid-childhood to early puberty.
DESIGN, SETTING, AND PARTICIPANTS
This prospective, population-based cohort study was embedded in the Generation R Study in Rotterdam, the Netherlands. All pregnant individuals
with an expected delivery date between April 1, 2002, and January 31, 2006, were invited to participate. Data were analyzed from February 1 to September 30, 2022.
EXPOSURE
Maternal-reported SSRI use verified by pharmacy records. In mid-pregnancy and 2 and 6 months after delivery, participants reported depressive symptoms using the Brief Symptom Inventory and were divided into 5 groups: SSRI use during pregnancy (n = 41; 80 scans), SSRI use only before pregnancy (n = 77; 126 scans), prenatal depressive symptoms without prenatal SSRI use (n = 257; 477 scans), postnatal depressive symptoms only (n = 74; 128 scans), and nonexposed control individuals (n = 2749; 4813 scans).
MAIN OUTCOMES AND MEASURES
The main outcomewas brain morphometry in offspring, including global and cortical brain volumes, measured at 3 magnetic resonance imaging assessments from 7 to 15 years of age.
RESULTS
The study included 3198 mother-child dyads. A total of 3198 mothers (100%) identified as women; mean (SD) age at intake was 31.1 (4.7) years. Children (1670 [52.2%] female) underwent brain imaging assessment from 7 to 15 years of age with 5624 total scans. Most brain gray matter volumes showed an inverted U–shaped trajectory. Compared with nonexposed controls, children prenatally exposed to SSRIs had less cerebral gray matter (β [SE], −20 212.2 [7285.6]mm3; P = .006), particularly within the corticolimbic circuit, which persisted up to 15 years of age. Children exposed to SSRIs prenatally showed a steeper increase in volumes of the amygdala (age interaction: β [SE], 43.3 [13.4]mm3; P = .006) and fusiform gyrus (age interaction: β [SE], 168.3 [51.4]mm3; P = .003) from 7 to 15 years of age. These volumetric differences in the amygdala and fusiform observed in childhood did not persist until early adolescence. Prenatal depression was associated with a smaller volume in the rostral anterior cingulate gyrus (β [SE], −166.3 [65.1]mm3; P = .006), and postnatal depression was associated with a reduced fusiform gyrus (β [SE], −480.5 [189.2]mm3; P = .002). No association of SSRI use before pregnancy with brain outcomes was observed.
CONCLUSIONS AND RELEVANCE
The results of this cohort study suggest that prenatal SSRI exposure may be associated with altered developmental trajectories of brain regions involved
in emotional regulation in offspring. Further research on the functional implications of these findings is needed.

DOI:https://doi.org/10.1001/jamapsychiatry.2023.3161

Journal: JAMA Psychiatry.
This article had an editorial which can be found here:https://doi.org/10.1001/jamapsychiatry.2023.2664

PCDH19 epilepsy (DEE9) is an X-linked syndrome associated with cognitive and behavioral
disturbances. Since heterozygous females are affected, while mutant males are spared, it is likely
that DEE9 pathogenesis is related to disturbed cell-to-cell communication associated with mosaicism.
However, the effects of mosaic PCDH19 expression on cortical networks are unknown. We mimicked
the pathology of DEE9 by introducing a patch of mosaic protein expression in one hemisphere of the
cortex of conditional PCDH19 knockout mice one day after birth. In the contralateral area, PCDH19
expression was unaffected, thus providing an internal control. In this model, we characterized the
physiology of the disrupted network using local field recordings and two photon Ca2+ imaging in
urethane anesthetized mice. We found transient episodes of hyperexcitability in the form of brief
hypersynchronous spikes or bursts of field potential oscillations in the 9–25 Hz range. Furthermore,
we observed a strong disruption of slow wave activity, a crucial component of NREM sleep. This
phenotype was present also when PCDH19 loss occurred in adult mice, demonstrating that PCDH19
exerts a function on cortical circuitry outside of early development. Our results indicate that a focal
mosaic mutation of PCDH19 disrupts cortical networks and broaden our understanding of DEE9

DOI:https://doi.org/10.3390/cells11121939