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Reversing learning and memory deficits in a mouse model of Down syndrome
Int. J. Devl Neuroscience 28 (2010) 643–653
Contents lists available at ScienceDirect
International Journal of Developmental Neuroscience journal homepage: www.elsevier.com/locate/ijdevneu
Symposium Abstracts
[S1.1] Reversing neurodevelopmental disorders in adults A.J. Silva University of California, Los Angeles, USA Recent findings in mice suggest that it is possible to reverse certain neurodevelopmental disorders in adults. Changes in development, previously thought to be irreparable in adults, were believed to underlie the neurological and psychiatric phenotypes of a range of common mental health problems with a clear developmental component. As a consequence, most researchers have focused their efforts on understanding the molecular and cellular processes that alter development with the hope that early intervention could present the emergent pathology. Unexpectedly, several different animal model studies published recently suggest that it may be possible to reverse some neurodevelopmental disorders in adults: addressing the underlying molecular and cellular deficits in adults could in several cases dramatically improve the neurocognitive phenotypes in these animal models. For example, mutations in the Neurofibromatosis Type 1 (NF1) gene, encoding Neurofibromin, a p21Ras GTPase Activating Protein (GAP), cause learning disabilities and attention deficits. Our studies have shown that the learning and memory deficits of a mouse model of NF1 (nf1+/− ) are caused by excessive Ras/MAPK signaling leading to hyperphosphorylation of synapsin I, and subsequent enhanced GABA release, which in turn result in impairments in the induction of long-term potentiation (LTP), a cellular mechanism of learning and memory. Consistent with increased GABA-mediated inhibition, we found evidence for hypoactivation of key brain regions in fMRI studies of NF1 patients. Recently, we discovered that statins, at concentrations ineffective in controls, can reverse the enhanced p21Ras activity in the brain of adult nf1+/− mice, rescue their LTP deficits, and reverse their spatial learning and attention impairments. Strikingly, recently completed pilot clinical trials (collaboration with the Elgersma laboratory in Rotterdam) uncovered suggestive evidence that statins may also be able to reverse cognitive deficits in children with NF1. Similarly, our laboratory has also studied the molecular and cellular mechanisms underlying cognitive deficits associated with Tuberous Sclerosis (TSC). We found that hyperactive hippocampal mTOR signaling leads to abnormal hippocampal CA1 LTP and consequently to deficits in hippocampal-dependent learning. Remarkably, our results showed that a brief treatment with the mTOR inhibitor
0736-5748/$36.00
rapamycin in adult mice can rescue not only the synaptic plasticity, but also the behavioral deficits in this animal model of TSC. These and other recent related findings from other laboratories studying Down Syndrome, Rett Syndrome, and Fragile X provide hope to millions of individuals afflicted with a wide range of neurodevelopemntal disorders, since they suggest that it may be possible to treat or even cure them in adults. doi:10.1016/j.ijdevneu.2010.07.010 [S1.3] Reversing learning and memory deficits in a mouse model of Down syndrome A.M. Kleschevnikov ∗ , P.V. Belichenko, W.C. Mobley University of California, San Diego, USA Cognitive impairment in Down syndrome (DS) involves hippocampus. In the dentate gyrus (DG) of the Ts65Dn mouse model of DS, deficient long-term potentiation (LTP) is linked to enhanced inhibition and cognitive deficits. We explored the genetic and synaptic bases of these changes, highlighting signaling through GABAergic receptors. We observed that the efficiency of the GABAergic neurotransmission was enhanced in Ts65Dn DG. Two mechanisms contributed to these changes. First, changes in the size of GABAergic synapses were accompanied by an increased release probability of GABA, resulting in greater GABAA and GABAB receptor-mediated inhibitory postsynaptic potentials (IPSCs) in Ts65Dn DG. Second, an additional increase in postsynaptic GABAB receptor signaling was associated with an increase in Kir3.2 protein, a subunit of inwardly rectifying potassium channels, effectors of postsynaptic GABAB receptors. Selective GABAB receptor antagonists and a Kir3.2-channel blocker restored LTP. Moreover, GABAB antagonists improved hippocampus-dependent memory in Ts65Dn mice without effecting on locomotion or overall activity. The results suggest that, in addition to antagonists of the GABAA receptors, GABAB receptor antagonists and/or Kir3.2channel blockers may improve learning in people with DS. doi:10.1016/j.ijdevneu.2010.07.011
Contents lists available at ScienceDirect
International Journal of Developmental Neuroscience journal homepage: www.elsevier.com/locate/ijdevneu
Symposium Abstracts
[S1.1] Reversing neurodevelopmental disorders in adults A.J. Silva University of California, Los Angeles, USA Recent findings in mice suggest that it is possible to reverse certain neurodevelopmental disorders in adults. Changes in development, previously thought to be irreparable in adults, were believed to underlie the neurological and psychiatric phenotypes of a range of common mental health problems with a clear developmental component. As a consequence, most researchers have focused their efforts on understanding the molecular and cellular processes that alter development with the hope that early intervention could present the emergent pathology. Unexpectedly, several different animal model studies published recently suggest that it may be possible to reverse some neurodevelopmental disorders in adults: addressing the underlying molecular and cellular deficits in adults could in several cases dramatically improve the neurocognitive phenotypes in these animal models. For example, mutations in the Neurofibromatosis Type 1 (NF1) gene, encoding Neurofibromin, a p21Ras GTPase Activating Protein (GAP), cause learning disabilities and attention deficits. Our studies have shown that the learning and memory deficits of a mouse model of NF1 (nf1+/− ) are caused by excessive Ras/MAPK signaling leading to hyperphosphorylation of synapsin I, and subsequent enhanced GABA release, which in turn result in impairments in the induction of long-term potentiation (LTP), a cellular mechanism of learning and memory. Consistent with increased GABA-mediated inhibition, we found evidence for hypoactivation of key brain regions in fMRI studies of NF1 patients. Recently, we discovered that statins, at concentrations ineffective in controls, can reverse the enhanced p21Ras activity in the brain of adult nf1+/− mice, rescue their LTP deficits, and reverse their spatial learning and attention impairments. Strikingly, recently completed pilot clinical trials (collaboration with the Elgersma laboratory in Rotterdam) uncovered suggestive evidence that statins may also be able to reverse cognitive deficits in children with NF1. Similarly, our laboratory has also studied the molecular and cellular mechanisms underlying cognitive deficits associated with Tuberous Sclerosis (TSC). We found that hyperactive hippocampal mTOR signaling leads to abnormal hippocampal CA1 LTP and consequently to deficits in hippocampal-dependent learning. Remarkably, our results showed that a brief treatment with the mTOR inhibitor
0736-5748/$36.00
rapamycin in adult mice can rescue not only the synaptic plasticity, but also the behavioral deficits in this animal model of TSC. These and other recent related findings from other laboratories studying Down Syndrome, Rett Syndrome, and Fragile X provide hope to millions of individuals afflicted with a wide range of neurodevelopemntal disorders, since they suggest that it may be possible to treat or even cure them in adults. doi:10.1016/j.ijdevneu.2010.07.010 [S1.3] Reversing learning and memory deficits in a mouse model of Down syndrome A.M. Kleschevnikov ∗ , P.V. Belichenko, W.C. Mobley University of California, San Diego, USA Cognitive impairment in Down syndrome (DS) involves hippocampus. In the dentate gyrus (DG) of the Ts65Dn mouse model of DS, deficient long-term potentiation (LTP) is linked to enhanced inhibition and cognitive deficits. We explored the genetic and synaptic bases of these changes, highlighting signaling through GABAergic receptors. We observed that the efficiency of the GABAergic neurotransmission was enhanced in Ts65Dn DG. Two mechanisms contributed to these changes. First, changes in the size of GABAergic synapses were accompanied by an increased release probability of GABA, resulting in greater GABAA and GABAB receptor-mediated inhibitory postsynaptic potentials (IPSCs) in Ts65Dn DG. Second, an additional increase in postsynaptic GABAB receptor signaling was associated with an increase in Kir3.2 protein, a subunit of inwardly rectifying potassium channels, effectors of postsynaptic GABAB receptors. Selective GABAB receptor antagonists and a Kir3.2-channel blocker restored LTP. Moreover, GABAB antagonists improved hippocampus-dependent memory in Ts65Dn mice without effecting on locomotion or overall activity. The results suggest that, in addition to antagonists of the GABAA receptors, GABAB receptor antagonists and/or Kir3.2channel blockers may improve learning in people with DS. doi:10.1016/j.ijdevneu.2010.07.011