Perinatal antidepressant exposure alters cortical network function in rodents

Abstract

Serotonin (5-HT) plays a key role in early brain development, and manipulation of 5-HT levels during this period can have lasting neurobiological and behavioral consequences. It is unclear how perinatal exposure to drugs, such as selective serotonin reuptake inhibitors (SSRIs), impacts cortical neural network function and what mechanism(s) may elicit the disruption of normal neuronal connections/interactions. In this article, we report on cortical wiring organization after pre-and postnatal exposure to the SSRI citalopram. We show that manipulation of 5-HT during early development in both in vitro and in vivo models disturbs characteristic chemoarchitectural and electrophysiological brain features, including changes in raphe and callosal connections, sensory processing, and myelin sheath formation. Also, drug-exposed rat pups exhibit neophobia and disrupted juvenile play behavior. These findings indicate that 5-HT homeostasis is required for proper brain maturation and that fetal/infant exposure to SSRIs should be examined in humans, particularly those with developmental dysfunction, such as autism.S erotonin (5-HT) has long been postulated to play a trophic role in brain morphogenesis, including cell proliferation, migration, and differentiation. It is also known to be one of the first neurotransmitters to appear in the central nervous system (1, 2). An obvious question that can be raised relates to whether perinatal exposure to antidepressants, such as selective serotonin reuptake inhibitors (SSRIs), can affect cortical circuit development and function. Perhaps one of the most intriguing previous findings related to 5-HT and early cortical organization was the observation from immunohistochemical and 5-HT transporter (SERT) binding studies that, at postnatal days 2-14 (P2-P14), rodent primary sensory cortex (notably layer IV of visual, auditory, and somatosensory areas) is transiently innervated by aggregates of fine grainlooking 5-HT-containing processes (3)(4)(5). Surprisingly, it became clear that, in early brain development, 5-HT is taken up into glutamatergic thalamocortical terminals (6, 7) and used in combination with the 5-HT 1B receptor on layer IV afferents (8). At present, the functional implication of such transient 5-HT expression and targeting, namely the primary sensory thalamocortical afferents during early development, remains unknown.5-HT and Abnormal Brain Development. Interestingly, manipulations of rodent brain 5-HT levels during early development, either through increases (produced in SERT or monoamine oxidase knockout mice) or decreases (produced by parachlorophenylalanine or other treatments), have been shown to produce the downstream effect of interfering with the formation of the whisker (barrel) representation in the primary somatosensory cortex and promoting aggressive and/or anxiety-related behaviors (9-14). Furthermore, early-life modification of 5-HT levels has been shown to cause overreaction to auditory or tactile sensory stimulation (15) and abnormal response properties of cor...

Behavioral training reverses global cortical network dysfunction induced by perinatal antidepressant exposure

“…Consistent with an earlier study (20), the average frequency bandwidths of tuning curves measured 20 dB above the threshold (BW20s) for male CTM-exposed rats were significantly larger than in controls ( Fig. S1 A and B; P < 0.005-0.00001), indicating decreased spectral response selectivity after perinatal CTM exposure.…”

“…The earlier discovery of selective loss of serotonin transporter (SERT) immunoreactive fiber density in the neocortex and reduced expression of tryptophan hydroxylase (TPH) among the midline subgroups of serotonergic raphe neurons after perinatal exposure to CTM (19,20) led us to examine whether such changes in the serotonergic system were affected by auditory behavioral training (Fig. 3 A-F).…”

“…Recent studies have clearly implicated that early exposure to selective serotonin reuptake inhibitors (SSRIs) could have longterm consequences on neurodevelopment (18). Specifically, rodent studies have shown that perinatal exposure to SSRIs like citalopram (CTM) induce abnormal autistic-like behaviors and cortical network disorganization, including degraded topographic organization and callosal connectivity (19,20). Exposure to SSRIs also alters speech perception in infants (21).…”

Prenatal exposure to serotonin reuptake inhibitor antidepressants and childhood behavior

“…As SRI exposed animals mature they demonstrate decreased serotonergic tone, possibly reflecting prolonged activation of inhibitory receptors (i.e., 5HT 1a ) (9). Together these findings suggest that altered 5HT auto-inhibitory feedback in the presence of high serotonergic tone (i.e., secondary to SRI exposure or genetically absent 5HT transporter (5HTT) protein) results in a constrained maturation and function of the 5HT system in ways that paradoxically link prenatal SRI exposure with an increased risk for affective disorders later in life (10,11). To date, there is a remarkable paucity of human studies of childhood outcomes following fetal modulation of 5HTT functions or exposure to high 5HT levels during fetal brain development.…”

Prenatal Antidepressant Exposure: Clinical and Preclinical Findings

“…A comparison of gestational citalopram exposure and postnatal (PND8-21) exposure showed disruptive behavioral effects of postnatal exposure only. Additionally, abnormal callosal connectivity was observed in postnatally exposed animals (Simpson et al, 2011). This study describes an exquisitely regulated developmental system with serotonin at the center.…”