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High serotonin levels during brain development alter the structural input-output connectivity of neural networks in the rat somatosensory layer IV.

Miceli S, Negwer M, van Eijs F, Kalkhoven C, van Lierop I, Homberg J, Schubert D - Front Cell Neurosci (2013)

Bottom Line: Despite the presence of multiple genetic models, the effect of high extracellular 5-HT levels on the structure and function of developing intracortical neural networks is far from being understood.Our results confirmed previous findings that high levels of 5-HT during development lead to a reduction of the topographical precision of TCA projections toward the barrel cortex.In layer IV, both excitatory SpSt and pyramidal cells showed a significantly reduced intracolumnar organization of their axonal projections.

View Article: PubMed Central - PubMed

Affiliation: Department of Cognitive Neuroscience, Centre for Neuroscience, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Nijmegen Medical Centre Nijmegen, Netherlands.

ABSTRACT
Homeostatic regulation of serotonin (5-HT) concentration is critical for "normal" topographical organization and development of thalamocortical (TC) afferent circuits. Down-regulation of the serotonin transporter (SERT) and the consequent impaired reuptake of 5-HT at the synapse, results in a reduced terminal branching of developing TC afferents within the primary somatosensory cortex (S1). Despite the presence of multiple genetic models, the effect of high extracellular 5-HT levels on the structure and function of developing intracortical neural networks is far from being understood. Here, using juvenile SERT knockout (SERT(-/-)) rats we investigated, in vitro, the effect of increased 5-HT levels on the structural organization of (i) the TC projections of the ventroposteromedial thalamic nucleus toward S1, (ii) the general barrel-field pattern, and (iii) the electrophysiological and morphological properties of the excitatory cell population in layer IV of S1 [spiny stellate (SpSt) and pyramidal cells]. Our results confirmed previous findings that high levels of 5-HT during development lead to a reduction of the topographical precision of TCA projections toward the barrel cortex. Also, the barrel pattern was altered but not abolished in SERT(-/-) rats. In layer IV, both excitatory SpSt and pyramidal cells showed a significantly reduced intracolumnar organization of their axonal projections. In addition, the layer IV SpSt cells gave rise to a prominent projection toward the infragranular layer Vb. Our findings point to a structural and functional reorganization of TCAs, as well as early stage intracortical microcircuitry, following the disruption of 5-HT reuptake during critical developmental periods. The increased projection pattern of the layer IV neurons suggests that the intracortical network changes are not limited to the main entry layer IV but may also affect the subsequent stages of the canonical circuits of the barrel cortex.

No MeSH data available.


Related in: MedlinePlus

Representative cytochrome oxidase stained tangential sections of layer IV SERT+/+ (A1) and SERT−/− (A2) P21 rats (SERT+/+n = 6; SERT−/−n = 6). The sections were photographed and barrel areas (C and E) and septal distances (D and E) were quantitatively analyzed (B). Barrel areas of SERT−/− rats were determined corresponding to rows A-B: 1–4; C-D-E: 1–5, septa were divided into rows A–E and Arcs 1–5. The edges of the barrel borders were evaluated in the gray level pixel values (Δ GL) over distance from the barrel to the septa (D) and showed a reduced steepness in SERT−/− compared to SERT+/+(F). Scale bars = 1 mm. *P < 0.05; **P < 0.01; ***P < 0.001.
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Figure 2: Representative cytochrome oxidase stained tangential sections of layer IV SERT+/+ (A1) and SERT−/− (A2) P21 rats (SERT+/+n = 6; SERT−/−n = 6). The sections were photographed and barrel areas (C and E) and septal distances (D and E) were quantitatively analyzed (B). Barrel areas of SERT−/− rats were determined corresponding to rows A-B: 1–4; C-D-E: 1–5, septa were divided into rows A–E and Arcs 1–5. The edges of the barrel borders were evaluated in the gray level pixel values (Δ GL) over distance from the barrel to the septa (D) and showed a reduced steepness in SERT−/− compared to SERT+/+(F). Scale bars = 1 mm. *P < 0.05; **P < 0.01; ***P < 0.001.

Mentions: Synaptic transmission of peripheral input from the thalamus to the cortex is crucial for the development and refinement of layer IV topographic maps. Previous studies have shown a reduced definition of the barrel borders or in some cases, a complete abolishment of barrel field formation in rodents having been exposed to high 5-HT levels during early developmental periods (for review see van Kleef et al., 2012). In order to evaluate the general barrel field morphology, cytochrome oxidase staining was used to visualize the neuronal densities of the PMBSF centers in tangential slices of SERT+/+ (n = 6) and SERT−/− (n = 6) rats. In contrast to previous reports where high levels of 5-HT during development have completely impaired barrel field formation, we could identify a complete barrel field containing distinct barrels in our SERT−/− rats (Figure 2A). However, compared to the barrel field of SERT+/+ rats, the barrel borders in SERT−/− rats appeared less sharp and the septal areas more extensive. We quantified the area allocated to both, barrels and septa, respectively (Figure 2B). On average, SERT−/− rats had a more than 25% reduced barrel size (25.3 ± 1.4%, p = 0.0075; Figure 2C). These differences in size were most prominent in the large barrels of the D and E rows. In contrast, in SERT−/− rats, the width of the septa between the barrels was robustly increased almost 2-fold along the rows (190.3 ± 1.4%; p = 0.01; Figure 2D) and more than 2.5-fold along the arcs (261.9 ± 15%; p = 0.0075). The combination of decreased barrel size and increased septa width (see Figure 2E) resulted in a barrel field that, as a whole, remained similar in size for both genotypes.


High serotonin levels during brain development alter the structural input-output connectivity of neural networks in the rat somatosensory layer IV.

Miceli S, Negwer M, van Eijs F, Kalkhoven C, van Lierop I, Homberg J, Schubert D - Front Cell Neurosci (2013)

Representative cytochrome oxidase stained tangential sections of layer IV SERT+/+ (A1) and SERT−/− (A2) P21 rats (SERT+/+n = 6; SERT−/−n = 6). The sections were photographed and barrel areas (C and E) and septal distances (D and E) were quantitatively analyzed (B). Barrel areas of SERT−/− rats were determined corresponding to rows A-B: 1–4; C-D-E: 1–5, septa were divided into rows A–E and Arcs 1–5. The edges of the barrel borders were evaluated in the gray level pixel values (Δ GL) over distance from the barrel to the septa (D) and showed a reduced steepness in SERT−/− compared to SERT+/+(F). Scale bars = 1 mm. *P < 0.05; **P < 0.01; ***P < 0.001.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Figure 2: Representative cytochrome oxidase stained tangential sections of layer IV SERT+/+ (A1) and SERT−/− (A2) P21 rats (SERT+/+n = 6; SERT−/−n = 6). The sections were photographed and barrel areas (C and E) and septal distances (D and E) were quantitatively analyzed (B). Barrel areas of SERT−/− rats were determined corresponding to rows A-B: 1–4; C-D-E: 1–5, septa were divided into rows A–E and Arcs 1–5. The edges of the barrel borders were evaluated in the gray level pixel values (Δ GL) over distance from the barrel to the septa (D) and showed a reduced steepness in SERT−/− compared to SERT+/+(F). Scale bars = 1 mm. *P < 0.05; **P < 0.01; ***P < 0.001.
Mentions: Synaptic transmission of peripheral input from the thalamus to the cortex is crucial for the development and refinement of layer IV topographic maps. Previous studies have shown a reduced definition of the barrel borders or in some cases, a complete abolishment of barrel field formation in rodents having been exposed to high 5-HT levels during early developmental periods (for review see van Kleef et al., 2012). In order to evaluate the general barrel field morphology, cytochrome oxidase staining was used to visualize the neuronal densities of the PMBSF centers in tangential slices of SERT+/+ (n = 6) and SERT−/− (n = 6) rats. In contrast to previous reports where high levels of 5-HT during development have completely impaired barrel field formation, we could identify a complete barrel field containing distinct barrels in our SERT−/− rats (Figure 2A). However, compared to the barrel field of SERT+/+ rats, the barrel borders in SERT−/− rats appeared less sharp and the septal areas more extensive. We quantified the area allocated to both, barrels and septa, respectively (Figure 2B). On average, SERT−/− rats had a more than 25% reduced barrel size (25.3 ± 1.4%, p = 0.0075; Figure 2C). These differences in size were most prominent in the large barrels of the D and E rows. In contrast, in SERT−/− rats, the width of the septa between the barrels was robustly increased almost 2-fold along the rows (190.3 ± 1.4%; p = 0.01; Figure 2D) and more than 2.5-fold along the arcs (261.9 ± 15%; p = 0.0075). The combination of decreased barrel size and increased septa width (see Figure 2E) resulted in a barrel field that, as a whole, remained similar in size for both genotypes.

Bottom Line: Despite the presence of multiple genetic models, the effect of high extracellular 5-HT levels on the structure and function of developing intracortical neural networks is far from being understood.Our results confirmed previous findings that high levels of 5-HT during development lead to a reduction of the topographical precision of TCA projections toward the barrel cortex.In layer IV, both excitatory SpSt and pyramidal cells showed a significantly reduced intracolumnar organization of their axonal projections.

View Article: PubMed Central - PubMed

Affiliation: Department of Cognitive Neuroscience, Centre for Neuroscience, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Nijmegen Medical Centre Nijmegen, Netherlands.

ABSTRACT
Homeostatic regulation of serotonin (5-HT) concentration is critical for "normal" topographical organization and development of thalamocortical (TC) afferent circuits. Down-regulation of the serotonin transporter (SERT) and the consequent impaired reuptake of 5-HT at the synapse, results in a reduced terminal branching of developing TC afferents within the primary somatosensory cortex (S1). Despite the presence of multiple genetic models, the effect of high extracellular 5-HT levels on the structure and function of developing intracortical neural networks is far from being understood. Here, using juvenile SERT knockout (SERT(-/-)) rats we investigated, in vitro, the effect of increased 5-HT levels on the structural organization of (i) the TC projections of the ventroposteromedial thalamic nucleus toward S1, (ii) the general barrel-field pattern, and (iii) the electrophysiological and morphological properties of the excitatory cell population in layer IV of S1 [spiny stellate (SpSt) and pyramidal cells]. Our results confirmed previous findings that high levels of 5-HT during development lead to a reduction of the topographical precision of TCA projections toward the barrel cortex. Also, the barrel pattern was altered but not abolished in SERT(-/-) rats. In layer IV, both excitatory SpSt and pyramidal cells showed a significantly reduced intracolumnar organization of their axonal projections. In addition, the layer IV SpSt cells gave rise to a prominent projection toward the infragranular layer Vb. Our findings point to a structural and functional reorganization of TCAs, as well as early stage intracortical microcircuitry, following the disruption of 5-HT reuptake during critical developmental periods. The increased projection pattern of the layer IV neurons suggests that the intracortical network changes are not limited to the main entry layer IV but may also affect the subsequent stages of the canonical circuits of the barrel cortex.

No MeSH data available.


Related in: MedlinePlus