Joana Teresa Ferreira Gonçalves - ICNAS, University of Coimbra
Title: Excitation/inhibition balance and glial function in mouse model of neurofibromatosis type 1: distinct susceptibility of hippocampus, prefrontal cortex and striatum
Abstract:
Neurofibromatosis type 1 (NF1) is a monogenic developmental disorder, characterized by altered skin pigmentation, increased tumor predisposition and cognitive deficits. Increasing data have been proposed that alterations in the excitation/inhibition balance are the neural mechanism underlying NF1-mediated cognitive disabilities. Previous studies employing a mouse model of NF1 revealed that γ-aminobutyric acid (GABA) inhibitory neurotransmission were increased in several brain regions, including hippocampus and striatum. Nonetheless, we showed a reduction of GABA concentration in the visual and medial frontal cortex of human patients with NF1. Since the link between animal and human studies remains to be established, it is important to apply to the mice model the same techniques available to investigated the GABA levels in humans. Here, together with molecular and cellular methods, we used magnetic resonance spectroscopy in NF1 mouse model, as this is the only technique accessible to measure GABA in vivo in humans. We found that the excitation vs. inhibition and the pre- vs. post-synapatic phenotype is different in the NF1 mouse hippocampus, when compared to cortical and striatal regions. In fact, both hippocampal GABA and glutamate levels are reduced, without changes in the respective ratio. Moreover, hippocampal GABA(A) α1 subunit receptor levels were increased at the synaptosomal level. On the other hand, striatal and cortical GABA/glutamate ratios are significantly increased, while GABA(A) subunit levels were decreased mainly at synaptosomal level in prefrontal cortex and at the cytosolic level in the striatum. Further, imunolabelling confirmed these results and showed distinct patterns of receptor redistribution in all these structures with patchy zones of dense receptor clusters being more evident in the striatum of the mutant mice. Finally we found evidence that GABA dysfunction is accompanied by changes in astrocytes physiology. Changes in astrocytes physiology are consistent with increased glutamine vs. glutamate levels in the hippocampus and frontal cortex, suggesting abnormalities in the glutamine-glutamate cycle.
Overall, our study reported distinct homeostatic mechanism in the hippocampus, prefrontal cortex and striatum induced by NF1 mutations at both neural and glial levels. These findings are crucial to design novel region specific therapeutics strategies that may need to improve cognitive disabilities in NF1 patients.
Title: Excitation/inhibition balance and glial function in mouse model of neurofibromatosis type 1: distinct susceptibility of hippocampus, prefrontal cortex and striatum
Abstract:
Neurofibromatosis type 1 (NF1) is a monogenic developmental disorder, characterized by altered skin pigmentation, increased tumor predisposition and cognitive deficits. Increasing data have been proposed that alterations in the excitation/inhibition balance are the neural mechanism underlying NF1-mediated cognitive disabilities. Previous studies employing a mouse model of NF1 revealed that γ-aminobutyric acid (GABA) inhibitory neurotransmission were increased in several brain regions, including hippocampus and striatum. Nonetheless, we showed a reduction of GABA concentration in the visual and medial frontal cortex of human patients with NF1. Since the link between animal and human studies remains to be established, it is important to apply to the mice model the same techniques available to investigated the GABA levels in humans. Here, together with molecular and cellular methods, we used magnetic resonance spectroscopy in NF1 mouse model, as this is the only technique accessible to measure GABA in vivo in humans. We found that the excitation vs. inhibition and the pre- vs. post-synapatic phenotype is different in the NF1 mouse hippocampus, when compared to cortical and striatal regions. In fact, both hippocampal GABA and glutamate levels are reduced, without changes in the respective ratio. Moreover, hippocampal GABA(A) α1 subunit receptor levels were increased at the synaptosomal level. On the other hand, striatal and cortical GABA/glutamate ratios are significantly increased, while GABA(A) subunit levels were decreased mainly at synaptosomal level in prefrontal cortex and at the cytosolic level in the striatum. Further, imunolabelling confirmed these results and showed distinct patterns of receptor redistribution in all these structures with patchy zones of dense receptor clusters being more evident in the striatum of the mutant mice. Finally we found evidence that GABA dysfunction is accompanied by changes in astrocytes physiology. Changes in astrocytes physiology are consistent with increased glutamine vs. glutamate levels in the hippocampus and frontal cortex, suggesting abnormalities in the glutamine-glutamate cycle.
Overall, our study reported distinct homeostatic mechanism in the hippocampus, prefrontal cortex and striatum induced by NF1 mutations at both neural and glial levels. These findings are crucial to design novel region specific therapeutics strategies that may need to improve cognitive disabilities in NF1 patients.