Selective Serotonin Reuptake Inhibitor (SSRI) treatment of early postnatal mice reverses their prenatal stress-induced brain dysfunction

In paper citation: (Ishiwata, Shiga & Okado, 2005).

The last review that I read about SSRIs in development talked about their paradoxical effects, and the long-term damage that they can cause. This paper comes in from a completely different angle and looks at the benefits of SSRIs immediately after birth. I have to say that I am simply fascinated at the extent to which SSRIs seem to affect development.

Important background:

• Serotonin concentration and synaptic density in the hippocampus, as well as spatial learning ability are reduced after prenatal stress (Hayashi, et al., 1998)
• 5HT and noradrenaline (NA) are involved in the regulation of mineralocorticoid (MR) and glucocorticoid (GR) mRNA expression (Seckl & Fink, 1992)
• SSRIs suppress HPA axis activity, decrease CRF mRNA expression and increase neurogenesis in the hippocampus of adult rodents.
• There were five groups in this study:
• Mice from non-stressed mothers, no SSRI treatment (C)
• Mice from non-stressed mothers with SSRI treatment from 1-3 weeks (CS)
• Mice from stressed mothers with no SSRI treatment (S)
• Mice from stressed mothers with SSRI treatment from 1-3 weeks (SS)
• Mice from stressed mothers who received SSRIs at 6-8 weeks of age (L-SS)

The new findings from this paper:

• Corticosterone levels:
• Mice from group S had 21% higher circulating corticosterone after restraint stress at week 3.
• Mice from group SS had corticosterone concentrations similar to controls.
• Monoamine concentrations:
• Mice from group SS and CS had significantly higher levels of serotonin (5-HT) than controls at postnatal week 3 and 6 by about 30% in the control treated mice and 60% in the stressed treated mice. 
• The 5-HT metabolite, 5HIAA was elevated in S mice compared to C mice. 
• Thus the 5-HT turnover rate was markedly elevated (77% greater) compared to controls. 
• Dendritic spine and synapse density:
• At week 3, spine density at the stratum radiatum in the S mice was 21% less than the control mice.
• At week 3, the SS mice had significantly more spines than S mice and resembled the control mice.
• At week 9, the S mice had 19% less spine and synapse density than controls.
• At week 9, the SS mice looked like normal mice.
• The mice with later SSRI treatment increased their spine density by 10%, but this was not significant.
• Spatial learning:
• C, CS, and SS mice all performed equally well at the Morris Water maze, but the S and LSS mice had learning impairments at the second and third exposure to the maze. These two groups also showed impairments at the reversal. 

Further information:

• Neonatal handling also reverses prenatal stress-induced behavioral deficits (Wakshlak & Weinstock, 1990).
• Chronic tianeptine treatment also reverses immobility time in the forced swim task (Morley-Fletcher, et al., 2003) *I'm surprised that this wasn't mentioned in the animal model overview.
• Hippocampal glucocorticoids are reduced in prenatally stressed animals, which is not what you would expect at first for cell death (Szuran, et al., 2000).
• The age of the rat may account for its stress response differences between prenatally stressed rats and controls (McCormick et al., 1995). 
• The first 3 postnatal weeks are very important for the development of the HPA axis. The concentration of GR in the rat hippocampus is low during week 1, then increases to adult values (Olpe & McEwen, 1976; Clayton, et al., 1977). The HPA axis reached adult levels of functionality by postnatal week 3. 

Remaining questions:

What happens to mice from stressed mothers who are raised by surrogates? Is it the mother's glucocorticoid levels that programs these mice or is it the mother's caregiving behaviors?

What happens to female rats who are in the same paradigm?

How did they get monoamine concentrations from both week 3 and week 6? Did they just plow through mice?

If mice postnatal week 0- postnatal week 2 correlate to the third trimester of primate births, could SSRI therapy actually help reverse learning impairments if administered acutely and early?