Serotonin Depletion and Barrel Cortex Development: Impact of Growth Impairment vs. Serotonin Effects on Thalamocortical Endings

Abstract

Converging evidence supports a role of serotonin (5-hydroxytryptamine; 5-HT) in barrel cortex development. Systemic administration of 5-HT-depleting drugs reduces cross-sectional whisker barrel areas in the somatosensory cortex (SSC) of neonatal rats. Here we assess the relative impact on barrel pattern formation of (i) 5-HT depletion and (ii) decreased brain growth, which is often associated with pharmacological 5-HT depletion, by comparing the effects of 5-HT-depleting drugs with those of reduced protein intake. Left hemisphere 5-HT levels in the SSC and right hemisphere whisker barrel areas were assessed at postnatal day 6 (P6) in the same animal following injection of p-chloroamphetamine (PCA) or p-chlorophenylalanine (PCPA) at P0. Both drugs significantly reduced cortical 5-HT content and mean barrel areas at P6, but also body and brain growth. Differences in brain weight accounted for 84.4% of the variance in barrel size, with negligible contributions by cortical 5-HT content. PCPA-treated animals sacrificed at P14 yielded similar trends, albeit less pronounced. Finally, reduced protein intake resulted in lower body weight and cortical 5-HT levels at P6, but yielded no change in brain weight or mean barrel area. Barrel formation therefore appears markedly less sensitive to 5-HT depletion per se than to drug-induced growth impairment.

Barrel Pattern Formation Requires Serotonin Uptake by Thalamocortical Afferents, and Not Vesicular Monoamine Release

“…Therefore, in conjunction with recent evidence underscoring the role played by body growth impairment and possibly by direct damage of thalamocortical terminals produced by serotonindepleting drugs (Persico et al, 2000), our data suggest that extracellular 5-HT deficiency has a very minor impact, if any, on barrel pattern formation, in contrast with the profound derangements produced by extracellular 5-HT excess.…”

“…Furthermore, when mean barrel area is normalized for brain weight, differences between VMAT2 ko and wt or hz pups disappear (Table 1). This is entirely compatible with an effect of malnutrition, already known to reduce per se cross-sectional barrel areas in neonatal rodents (Vongdokmai, 1980;Persico et al, 2000), that is limited to those VMAT2 ko pups displaying most blunted body growth rates. In this regard, VMAT2 ko mice nicely parallel animals in which 5-HT depletion has been induced by neurotoxins such as parachloroamphetamine and PCPA (Persico et al, 2000).…”

“…The results of our quantitative electron microscopic study provide no evidence of enhanced extracellular 5-HT exerting either a positive or a negative effect on synapse formation. Previous in vivo studies largely focus on the effects of pharmacologically induced 5-HT depletion, the limitations of which have been discussed previously (Persico et al, 2000). We do not exclude the possibility that decreased extracellular 5-HT may affect synapse formation or that enhanced or reduced extracellular 5-HT may yield altered microcircuitry, not necessarily resulting in altered synaptic density.…”

“…C O-stained tangential sections were used to measure single-barrel cross-sectional areas and total posteromedial subfield (PMBSF) surface in V M AT2 animals using the Kontron Imaging System K S100 (Kontron Elektronik, Eching bei, Munchen, Germany), as described (Persico et al, 2000). T issue preparation for electron microscopy: quantitative electron microscopic anal ysis.…”

Postnatal Growth Defects in Mice with Constitutive Depletion of Central Serotonin

“…8 Pharmacological depletion of 5-HT with agents such as the 5-HT synthesis inhibitor para-chlorophenylalanine (pCPA), or the neurotoxin 5,7-dihydroxytryptamine (5,7-DHT), administered during embryonic or postnatal development, were reported to have effects on the maturation of cortical neurons 9,10 and to alter barrel cortex development, 11,12 although this was not confirmed in other reports. 5, 13 However, such pharmacological treatments are difficult to interpret because they are generally not specific in that they affect both central and peripheral sources of 5-HT and can have unwanted side effects on other amines. Moreover, their effects can vary according to the developmental period.…”