Limits...
The role of dopaminergic and serotonergic systems in neurodevelopmental disorders: a focus on epilepsy and seizure susceptibility.

Tripathi PP, Bozzi Y - Bioimpacts (2015)

Bottom Line: Among these transcription factors, homeobox-containing proteins play a crucial role, and altered expression of these factors can impact the embryonic as well as adult CNS functions.Understanding the embryonic development of these neuronal populations is crucial to elucidate their physiological function including brain excitability in the adult brain.Our results demonstrated that altered development of dopamine (DA) neurons does not interfere with KA seizure susceptibility, while increased serotonin (5-hydroxytryptamine, 5-HT) hyperinnervation leads to resistance to KA-induced seizure.

View Article: PubMed Central - HTML - PubMed

Affiliation: Laboratory of Molecular Neuropathology, Center for Integrative Biology (CIBIO), University of Trento, Trento, Italy.

ABSTRACT

Introduction: The embryonic development of the vertebrate Central Nervous System (CNS) requires the induction of transcription factors regulating the expression of specific subsets of genes in restricted CNS regions. Among these transcription factors, homeobox-containing proteins play a crucial role, and altered expression of these factors can impact the embryonic as well as adult CNS functions. Importantly, the homeobox-containing genes Otx2, Engrailed-1 (En1), and Engrailed-2 (En2) have been described to crucially regulate differentiation of dopaminergic and serotonergic neurons during vertebrate CNS development. Dopaminergic and serotonergic neurons, located in midbrain and hindbrain regions respectively, diffusely innervate several forebrain areas including limbic system, contributing in regulating several physiological functions. Understanding the embryonic development of these neuronal populations is crucial to elucidate their physiological function including brain excitability in the adult brain. New evidence is emerging about the impact of an altered embryonic development of dopamine and serotonin neurons onto seizure susceptibility in the adult life.

Methods: In this mini-review, we summarized our kainic acid (KA) induced seizure susceptibility in adult mutant mouse lines with targeted manipulation of Otx2, En1, and En2 genes.

Results: Our results demonstrated that altered development of dopamine (DA) neurons does not interfere with KA seizure susceptibility, while increased serotonin (5-hydroxytryptamine, 5-HT) hyperinnervation leads to resistance to KA-induced seizure.

Conclusion: We propose that developmental alterations of serotonergic but not dopaminergic circuits play a crucial role in controlling seizure susceptibility in the adult life.

No MeSH data available.


Related in: MedlinePlus

© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4492191&req=5

Mentions: According to this view, it was expected that reduction of DA cells in both En1Cre/+; Otx2flox/flox and EnHT mice would contribute to increase the seizure susceptibility in these animals, while increase in DA cells in En1Cre/+; tOtx2ov/+ mice would contribute to lower seizure susceptibility severity. On the contrary, En1Cre/+; Otx2flox/flox mice were markedly resistant to KA seizures due to 5-HT hyper-innervation, whereas En1Cre/+; tOtx2ov/+ mice and EnHT mice (in which 5-HT levels were unchanged) showed a normal susceptibility to KA induced seizures (Table 1). This is in line with earlier observation that 5-HT levels were inversely proportional to the seizure susceptibility. More importantly, altered level of DA in En1Cre/+; Otx2flox/flox, En1Cre/+; tOtx2ov/+ and EnHT mice had less impact in altering seizure susceptibility. Indeed En1Cre/+; Otx2flox/flox mice (which have reduced level of DA) did not show increased seizure susceptibility, while En1Cre/+; tOtx2ov/+ and EnHT mice (which have higher and lower level of DA, respectively, with no alterations in 5-HT), showed unaltered seizure threshold. Thus, the altered embryonic development of 5-HT neurons seems to have a more prominent effect on the seizure control than the altered development of DA neurons (Fig. 3 and Table 1). Importantly, it is widely known that different genetic background meaning different inbred mouse strains impacts KA-induced seizure susceptibility in the mouse44 but this issue is not discussed here due to space limitations.


The role of dopaminergic and serotonergic systems in neurodevelopmental disorders: a focus on epilepsy and seizure susceptibility.

Tripathi PP, Bozzi Y - Bioimpacts (2015)

© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4492191&req=5

Mentions: According to this view, it was expected that reduction of DA cells in both En1Cre/+; Otx2flox/flox and EnHT mice would contribute to increase the seizure susceptibility in these animals, while increase in DA cells in En1Cre/+; tOtx2ov/+ mice would contribute to lower seizure susceptibility severity. On the contrary, En1Cre/+; Otx2flox/flox mice were markedly resistant to KA seizures due to 5-HT hyper-innervation, whereas En1Cre/+; tOtx2ov/+ mice and EnHT mice (in which 5-HT levels were unchanged) showed a normal susceptibility to KA induced seizures (Table 1). This is in line with earlier observation that 5-HT levels were inversely proportional to the seizure susceptibility. More importantly, altered level of DA in En1Cre/+; Otx2flox/flox, En1Cre/+; tOtx2ov/+ and EnHT mice had less impact in altering seizure susceptibility. Indeed En1Cre/+; Otx2flox/flox mice (which have reduced level of DA) did not show increased seizure susceptibility, while En1Cre/+; tOtx2ov/+ and EnHT mice (which have higher and lower level of DA, respectively, with no alterations in 5-HT), showed unaltered seizure threshold. Thus, the altered embryonic development of 5-HT neurons seems to have a more prominent effect on the seizure control than the altered development of DA neurons (Fig. 3 and Table 1). Importantly, it is widely known that different genetic background meaning different inbred mouse strains impacts KA-induced seizure susceptibility in the mouse44 but this issue is not discussed here due to space limitations.

Bottom Line: Among these transcription factors, homeobox-containing proteins play a crucial role, and altered expression of these factors can impact the embryonic as well as adult CNS functions.Understanding the embryonic development of these neuronal populations is crucial to elucidate their physiological function including brain excitability in the adult brain.Our results demonstrated that altered development of dopamine (DA) neurons does not interfere with KA seizure susceptibility, while increased serotonin (5-hydroxytryptamine, 5-HT) hyperinnervation leads to resistance to KA-induced seizure.

View Article: PubMed Central - HTML - PubMed

Affiliation: Laboratory of Molecular Neuropathology, Center for Integrative Biology (CIBIO), University of Trento, Trento, Italy.

ABSTRACT

Introduction: The embryonic development of the vertebrate Central Nervous System (CNS) requires the induction of transcription factors regulating the expression of specific subsets of genes in restricted CNS regions. Among these transcription factors, homeobox-containing proteins play a crucial role, and altered expression of these factors can impact the embryonic as well as adult CNS functions. Importantly, the homeobox-containing genes Otx2, Engrailed-1 (En1), and Engrailed-2 (En2) have been described to crucially regulate differentiation of dopaminergic and serotonergic neurons during vertebrate CNS development. Dopaminergic and serotonergic neurons, located in midbrain and hindbrain regions respectively, diffusely innervate several forebrain areas including limbic system, contributing in regulating several physiological functions. Understanding the embryonic development of these neuronal populations is crucial to elucidate their physiological function including brain excitability in the adult brain. New evidence is emerging about the impact of an altered embryonic development of dopamine and serotonin neurons onto seizure susceptibility in the adult life.

Methods: In this mini-review, we summarized our kainic acid (KA) induced seizure susceptibility in adult mutant mouse lines with targeted manipulation of Otx2, En1, and En2 genes.

Results: Our results demonstrated that altered development of dopamine (DA) neurons does not interfere with KA seizure susceptibility, while increased serotonin (5-hydroxytryptamine, 5-HT) hyperinnervation leads to resistance to KA-induced seizure.

Conclusion: We propose that developmental alterations of serotonergic but not dopaminergic circuits play a crucial role in controlling seizure susceptibility in the adult life.

No MeSH data available.


Related in: MedlinePlus