. 2021 Dec 16;55(1):295–317. doi: 10.1111/ejn.15544

TABLE 3.

Overview table of studies investigating alteration in the PFC and/or the amygdala following early life SSRI exposure

Reference	Type of study	Sex	SSRI (/day)	Time of exposure						Outcome measures	Results
					G0–22	P1–3	P4–7	P8–14	P15–21
Prefrontal cortex
Grimm and Frieder (1987)	Rats	M/F	Zimelidine to dams	G10–G20						5‐HT labelling: measurement of spontaneous release.	No effects.
Grimm and Frieder (1987)			5 mg/kg	P4–P8						5‐HT labelling: measurement of spontaneous release.	No effects.
Cabrera‐Vera et al. (1997)	Rats	M	FLX to dams	G13–G20						HPLC: monoamine and biogenic amines. Radioligand binding assay for 5‐HT uptake sites.	Increased 5‐HT content in the frontal cortex at PD 26 but not PD 70. No effects on SERT binding.
Cabrera‐Vera et al. (1997)			10 mg/kg
Millard et al. (2019)	Rats	M	FLX to dams	G0–P14						Western blot: NR1, NR2a, NR2b, PSD‐95, mGluR1, mGluR5, Homer1b/c and b‐actin.	Decreased cortical level of glutamatergic markers (NR1, NR2a, PSD‐95, GluR1)
Millard et al. (2019)			10 mg/kg
Toffoli et al. (2014)	Rats	M	FLX to dams	G0–P21						DNA samples and global methylation profile.	Increased methylation % in the cortex.
Toffoli et al. (2014)			5 mg/kg							DNA samples and global methylation profile.	Increased methylation % in the cortex.
Zohar et al. (2016)	Rats	M/F	CIT to dams	G7–P21						IHC: serotonin, tryptophan, hydroxylase, 5‐HT1a, and corticotrophin releasing factor 2.	Sex different 5‐HT1a distribution: affected by CIT in males but not females.
Zohar et al. (2016)			10 mg/kg
Gemmel et al. (2018)	Rats	M/F	FLX to dam	G10–P21						HPLC‐Ed measurement of monoamine levels. IHC of synaptophysin, PSD‐95, GR.	Increased 5‐HT in female PFC, decreased turnover. No effect on males.
Gemmel et al. (2018)			5 mg/kg
Ko et al. (2014)	Rats	M	FLX	P0–P4						HPLC analysis of 5‐HIAA and 5‐HT. Western blotting for Tph levels. IHC for Trp. Golgi–Cox staining	No effects on 5‐HT metabolism. Exuberant dendritic branches. Increased dendritic complexity, greater dendritic length. Reduced dendritic densities.
Ko et al. (2014)			20 mg/kg
Bock et al. (2013)	Rat	M	FLX	P1–P15						rtPCR, ICH for S100B positive cells	Long term increased S100B cell density in the PFC and increased mRNA expression following FLX treatment.
Bock et al. (2013)			5 mg/kg							rtPCR, ICH for S100B positive cells
Zhou et al. (2015)	Rat	M/F	CIT	P1–P10						IHC: Tph, SERT.	Reduced SERT, DA, and GABA interneurons cell density in the mPFC following CIT exposure.
Zhou et al. (2015)			10 mg/kg							IHC: Tph, SERT.
Glazova et al. (2014)	Rat	M/F	Fluvoxamine	P1–P14						HPC: DA, NA, DOPAC, 5‐HT and 5‐HIAA.	Increased 5‐HT metabolism at P16. No effect on NA or DA.
Glazova et al. (2014)			10 mg/kg							HPC: DA, NA, DOPAC, 5‐HT and 5‐HIAA.	Increased 5‐HT metabolism at P16. No effect on NA or DA.
Gemmel et al. (2016)	Rat	M/F	FLX to dam	P1–P21						HLPC‐Ed measurement of: DA, DAPAC; HVA, 5‐HT, 5‐HIAA. IHC for double cortin and synaptophysin positive cells.	No effects.
Gemmel et al. (2016)			5 mg/kg								No effects.
Sarkar et al. (2014)	Rat	M	FLX	P2–P21						RT‐qPCR: 5‐HT2a, 2c and 1a receptor	Stimulation of 5‐HT2a by FLX downregulate the receptor, leading to long lasting anxiety and depressive‐like behaviour. Blockade of 5‐HT2a inhibit the decreased mRNA levels.
Sarkar et al. (2014)			10 mg/kg							RT‐qPCR: 5‐HT2a, 2c and 1a receptor
Kozisek et al. (2008)	Rat	M/F	ESCI; desipramine	P9–P12						ELISA: BDNF. rtPCR: BDNF and TrkB.	Increased in extracellular 5‐HT. Increased BDNF levels in the PFC at P13.
Kozisek et al. (2008)			1–15 mg/kg	P17–P20						ELISA: BDNF. rtPCR: BDNF and TrkB.
Simpson et al. (2011)	Rat	M/F	CIT	P8–P21						IHC and quantification: SERT and TPH. Colossal connectivity and ultrastructural analysis.	Decreased SERT density in mPFC (male)
Simpson et al. (2011)			5‐15 mg/kg								Decreased SERT density in mPFC (male)
Maciag et al. (2006)	Rat	M	CIT (5 mg/kg)	P8–P21						IHC: Tph, SERT and neuron specific nuclear protein.	Decreased SERT immunoreactivity in the mPFC.
Maciag et al. (2006)			Clomipramine (15 mg/kg)							IHC: Tph, SERT and neuron specific nuclear protein.	Decreased SERT immunoreactivity in the mPFC.
Witteveen et al. (2013)	Rat	M/F	SERT‐KO	SERT‐KO						3D collagen co‐cultures of embryonic raphe nuclei to mPFC projections. IHC anti‐Satb2 and anti‐5‐HT and anti‐Tuji.	Maturation of the dorsal raphe to mPFC projection is SERT dependent.
Brivio et al. (2019)	Rat	M	SERT‐KO	SERT‐KO						RT‐qPCR and Western blot: GluNI, PSD95, CDC42 and SEPT7.	Decreased NMDA level in the PFC and decrease synaptic density. Altered spine formation throughout life.
Calabrese et al. (2013)	Rat	M	SERT‐KO	SERT‐KO						RT‐qPCR: BDNF (exon I, IV and VI), Npas4, Creb, Craf, Dnmt1, GABAay2, Gad67, Vgat. Western blot: BDNF. Methylated DNA Immunoprecipitation: BDNF exon IV.	Decreased of BDNF level (gene expression and mBDNF) in the PFC. Epigenetic modulation involved.
Velasquez et al. (2019)	Mouse	M/F	CIT to dams	G8–G17						HPLC: fetal brain CIT, 5‐HT and 5‐HIAA. IHC: serotonin, netrinG1, TBR1.	Decreased serotonergic tissue levels.
Velasquez et al. (2019)			260 mg/L								Decreased serotonergic tissue levels.
Meyer et al. (2018)	Mouse	M/F	G0–P1: SET to dams	G0–P14						RT‐qPCR for serotonin transporter and serotonin receptor expression.	Increased cortical levels of 5‐HT1a, 2a, 2c, 5‐HTT and Tph2.
Meyer et al. (2018)			P1–P14: 1.5 mg/kg
Soiza‐Reilly et al. (2019)	Mouse	M/F	FLX	P2–P14						IHC: 5‐HT, GFP, DsRed; Cux1; Foxp2; cfos. In situ hybridization: SERT. Array tomography: VGLUT1,2 or GAD. Western blot: VGLUT1 and GAD. Patch clamp electrophysiology. Cell sorting and RNA‐sequencing.	SERT expressed in glutamatergic pyramidal neurons, and FLX down or up regulate synaptic and circuit modelling. PFC‐SERT+ neurons involved in the top‐down modulation of emotional circuits
Soiza‐Reilly et al. (2019)	SERT‐KO		10 mg/kg
Rebello et al. (2014)	Mouse	M/F	FLX	P2–P21; P2–P11; P12–P21						Golgi stain. Electrophysiology: whole cell and patch clamp.	Morphological changes in pyramidal neurons. Altered mPFC output. No change in Glutamatergic inputs.
Rebello et al. (2014)			10 mg/kg	P2–P21; P2–P11; P12–P21						Golgi stain. Electrophysiology: whole cell and patch clamp.
Molteni et al. (2009)	Mouse	F	SERT‐KO	SERT‐KO						Plasma corticosterone levels. In situ hybridization: Arc, Zif.268 and B‐actin.	Lower arc in the PFC, and hyper responsiveness of arc following stress. Structural remodelling.
Altamura et al. (2007)	Mouse	M/F	SERT‐KO	SERT‐KO						Nissls, Giesma staining.	Increase cellular density. Decrease cortical thickness.
Rotem‐Kohavi et al. (2019)	Clinical	M/F	FLX, PAR,SET, CIT	Prenatal						Structural, microstructural and resting state functional and metabolic imaging (T1 MRI) at 40.9 weeks (postmenstrual age)	Higher connectivity in the frontal superior orbital left lobe.
Amygdala
Ehrlich et al. (2015)	Rat	F	ESCI to dams	G0–P1						RT‐PCR: Nkcc1, Kcc2, 5‐HT1a.	ESCI upregulate 5‐HT1a.
Ehrlich et al. (2015)			12.2 mg/kg							RT‐PCR: Nkcc1, Kcc2, 5‐HT1a.	ESCI upregulate 5‐HT1a.
Francis‐Oliveira et al. (2013)	Rat	M/F	FLX to dams	G0–P21						IHC (anti‐Fos) after stressor.	Affect amygdala circuits (down regulate activity following stressor in male, upregulate in female)
Francis‐Oliveira et al. (2013)			5 mg/kg							IHC (anti‐Fos) after stressor.
Glover et al. (2015)	Rat	M	PAR to dams	G0–P21						Assessment of PARA levels in the brain and serum. RNA labelling and array hybridization, micro array analysis.	3 genes are upregulated at P7 (bLR strain), and a greater number are downregulated from P14 through adulthood.
Glover et al. (2015)			10 mg/kg
Ko et al. (2014)	Rat	M	FLX	P0–P4						HPLC: 5‐HIAA and 5‐HT. Western blotting and IHC: Tph. Golgi–Cox staining.	No change in dendritic complexity, length, diameter and number. Decreased spine density in FLX treated animals.
Ko et al. (2014)			20 mg/kg
Bijlsma et al. (2015)	Rat	M	SERT‐KO	SERT‐KO						In situ hybridization: CRF 1 receptor mRNA.	No effects.
Narboux‐Nême et al. (2008)	Mouse	M/F	SERT‐KO	SERT‐KO						Histology: with Xgal.	No SERT expression.
Nietzer et al. (2011)	Mouse	M	SERT‐KO	SERT‐KO						Golgi–Cox. Morphometry.	SERT KO show an increase spine and dendritic branching.
Wellman et al. (2007)	Mouse	M	SERT‐KO	SERT‐KO						Histology and morphological analysis.	Hyperconnectivity in the amygdala.
Lugo‐Candelas et al. (2018)	Clinical	M/F		Prenatal						5‐HTT polymorphism. Maternal depression. T2 MRI scanner for structural and diffusion MRI	Increased: right amygdala grey matter volume, and connectivity to the right insula.

Note: Most preclinical studies were performed on rats or mice. Two clinical studies were encounter. Studies are display according to the following criteria: (1) animal model used (rats, mouse, other); (2) Time of SSRI exposure (prenatal administration, perinatal administration, P1 to P3, P4 to P7, P8 to P14 and P15 to P21, SERT‐KO). Arc: activity‐regulated cytoskeleton‐associated protein; b‐actin: beta‐actin; BDNF: brain‐derived neurotrophic factor; BNZ: benzodiazepine; 5‐HIAA: 5‐hydroxyindoleacetic acid; 5‐HT1a: serotonin 1A receptor; CDC42: cell division control protein 42 homolog; CIT: citalopram; Cux1: cut like homeobox 1; DA: dopamine; DEX: dexamethasone; ELISA: enzyme‐linked immunosorbent assay; ESCI: escitalopram; F: female; FLX: fluoxetine; Foxp2: forkhead box protein P2; G: gestational day; GFP: green fluorescent protein; GR: glucocorticoids receptor; HLPC: high‐performance liquid chromatography; HLPC‐Ed: high‐performance liquid chromatography with electrochemical detection; ICH: immunohistochemistry; Kcc2: Ke‐Cl cotransporter 2; M: Male; mGluR1: glutamate receptor, metabotropic 1; mGluR5: glutamate receptor, metabotropic 5; Nkcc1: Na‐K‐Cl cotransporter; NR1: glutamate receptor 1; NR2a: glutamate receptor 2a; NR2b: glutamate receptor 2b; P: postnatal day; PCR: polymerase chain reaction; PSD‐95: postsynaptic density protein 95; rtPCR: real‐time polymerase chain reaction; rtqPCR: real‐time quantitative polymerase chain reaction; S100B: S100 calcium‐binding protein B; SEPT7: Septin‐7; SERT‐KO: serotonin transporter‐knock out; SET: sertraline; Tph: tryptophan hydroxylase; Trp: tryptophan synthase; Zif‐268: zinc finger binding protein clone 268.