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Insulin-like growth factor-1 rescues synaptic and motor deficits in a mouse model of autism and developmental delay.

Bozdagi O, Tavassoli T, Buxbaum JD - Mol Autism (2013)

Bottom Line: Haploinsufficiency of SHANK3, due to either hemizygous gene deletion (termed 22q13 deletion syndrome or Phelan-McDermid syndrome) or to gene mutation, accounts for about 0.5% of the cases of autism spectrum disorder (ASD) and/or developmental delay, and there is evidence for a wider role for SHANK3 and glutamate signaling abnormalities in ASD and related conditions.Positive effects were observed with an IGF-1 peptide derivative as well.Studies in mouse and human neuronal models of Rett syndrome also show benefits with IGF-1, raising the possibility that this compound may have benefits broadly in ASD and related conditions, even with differing molecular etiology.

View Article: PubMed Central - HTML - PubMed

Affiliation: Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY, USA. joseph.buxbaum@mssm.edu.

ABSTRACT

Background: Haploinsufficiency of SHANK3, due to either hemizygous gene deletion (termed 22q13 deletion syndrome or Phelan-McDermid syndrome) or to gene mutation, accounts for about 0.5% of the cases of autism spectrum disorder (ASD) and/or developmental delay, and there is evidence for a wider role for SHANK3 and glutamate signaling abnormalities in ASD and related conditions. Therapeutic approaches that reverse deficits in SHANK3-haploinsufficiency may therefore be broadly beneficial in ASD and in developmental delay.

Findings: We observed that daily intraperitoneal injections of human insulin-like growth factor 1 (IGF-1) over a 2-week period reversed deficits in hippocampal α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) signaling, long-term potentiation (LTP), and motor performance that we had previously reported in Shank3-deficient mice. Positive effects were observed with an IGF-1 peptide derivative as well.

Conclusions: We observed significant beneficial effects of IGF-1 in a mouse model of ASD and of developmental delay. Studies in mouse and human neuronal models of Rett syndrome also show benefits with IGF-1, raising the possibility that this compound may have benefits broadly in ASD and related conditions, even with differing molecular etiology. Given the extensive safety data for IGF-1 in children with short stature due to primary IGF-1 deficiency, IGF-1 is an attractive candidate for controlled clinical trials in SHANK3-deficiency and in ASD.

No MeSH data available.


Related in: MedlinePlus

(1–3)IGF-1 reverses deficits in LTP and basal synaptic properties in Shank3-deficient mice. Wild-type (WT) and heterozygous (Het) mice were treated with saline or (1–3)IGF-1 for 2 weeks before testing (injections began at postnatal day (PND) 13 to 15 and animals were analyzed immediately after the last injection). Methods for all experiments were as described previously [5], with 3 to 4 mice per group, and 1 to 2 slices per animal. (a) Hippocampal LTP was induced with high-frequency stimulation. Inset: Representative excitatory postsynaptic potential traces at 90 min after LTP induction from saline-injected (1) and (1–3)IGF-1-injected (2) heterozygous mice (scale bar: 0.5 mV, 10 ms). (b) Input–output curves comparing field excitatory postsynaptic potential (EPSP) slopes (mV/ms) as a function of stimulation intensity (mA). EPSP: excitatory postsynaptic potential; Het: heterozygous; LTP: long-term potentiation; PND: postnatal day; WT: wild-type.
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Figure 1: (1–3)IGF-1 reverses deficits in LTP and basal synaptic properties in Shank3-deficient mice. Wild-type (WT) and heterozygous (Het) mice were treated with saline or (1–3)IGF-1 for 2 weeks before testing (injections began at postnatal day (PND) 13 to 15 and animals were analyzed immediately after the last injection). Methods for all experiments were as described previously [5], with 3 to 4 mice per group, and 1 to 2 slices per animal. (a) Hippocampal LTP was induced with high-frequency stimulation. Inset: Representative excitatory postsynaptic potential traces at 90 min after LTP induction from saline-injected (1) and (1–3)IGF-1-injected (2) heterozygous mice (scale bar: 0.5 mV, 10 ms). (b) Input–output curves comparing field excitatory postsynaptic potential (EPSP) slopes (mV/ms) as a function of stimulation intensity (mA). EPSP: excitatory postsynaptic potential; Het: heterozygous; LTP: long-term potentiation; PND: postnatal day; WT: wild-type.

Mentions: To investigate whether IGF-1 could reverse deficits in a preclinical model of SHANK3-haploinsufficiency, we made use of a mouse with hemizygous loss of full-length Shank3 due to targeted disruption of the ankyrin repeat domain (ARD) [5]. This isoform has been directly implicated in ASD, language delay, and intellectual disability (ID), as there exist disruptive de novo point mutations in ARD in patients with ASD and ID [12,13]. In all studies, we compared heterozygous mice with wild-type littermates using heterozygote × heterozygote mating. Consistent with previous results from our group [5], LTP induced by high-frequency stimulation was reduced in the heterozygous mice compared to wild-type littermates in the current experiments (Figures 1a and 2a) (for example, in Figure 2a, repeated measures ANOVA was used for analysis of the last five time points, F(1,6) = 33.71, P = 0.001).


Insulin-like growth factor-1 rescues synaptic and motor deficits in a mouse model of autism and developmental delay.

Bozdagi O, Tavassoli T, Buxbaum JD - Mol Autism (2013)

(1–3)IGF-1 reverses deficits in LTP and basal synaptic properties in Shank3-deficient mice. Wild-type (WT) and heterozygous (Het) mice were treated with saline or (1–3)IGF-1 for 2 weeks before testing (injections began at postnatal day (PND) 13 to 15 and animals were analyzed immediately after the last injection). Methods for all experiments were as described previously [5], with 3 to 4 mice per group, and 1 to 2 slices per animal. (a) Hippocampal LTP was induced with high-frequency stimulation. Inset: Representative excitatory postsynaptic potential traces at 90 min after LTP induction from saline-injected (1) and (1–3)IGF-1-injected (2) heterozygous mice (scale bar: 0.5 mV, 10 ms). (b) Input–output curves comparing field excitatory postsynaptic potential (EPSP) slopes (mV/ms) as a function of stimulation intensity (mA). EPSP: excitatory postsynaptic potential; Het: heterozygous; LTP: long-term potentiation; PND: postnatal day; WT: wild-type.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC3649942&req=5

Figure 1: (1–3)IGF-1 reverses deficits in LTP and basal synaptic properties in Shank3-deficient mice. Wild-type (WT) and heterozygous (Het) mice were treated with saline or (1–3)IGF-1 for 2 weeks before testing (injections began at postnatal day (PND) 13 to 15 and animals were analyzed immediately after the last injection). Methods for all experiments were as described previously [5], with 3 to 4 mice per group, and 1 to 2 slices per animal. (a) Hippocampal LTP was induced with high-frequency stimulation. Inset: Representative excitatory postsynaptic potential traces at 90 min after LTP induction from saline-injected (1) and (1–3)IGF-1-injected (2) heterozygous mice (scale bar: 0.5 mV, 10 ms). (b) Input–output curves comparing field excitatory postsynaptic potential (EPSP) slopes (mV/ms) as a function of stimulation intensity (mA). EPSP: excitatory postsynaptic potential; Het: heterozygous; LTP: long-term potentiation; PND: postnatal day; WT: wild-type.
Mentions: To investigate whether IGF-1 could reverse deficits in a preclinical model of SHANK3-haploinsufficiency, we made use of a mouse with hemizygous loss of full-length Shank3 due to targeted disruption of the ankyrin repeat domain (ARD) [5]. This isoform has been directly implicated in ASD, language delay, and intellectual disability (ID), as there exist disruptive de novo point mutations in ARD in patients with ASD and ID [12,13]. In all studies, we compared heterozygous mice with wild-type littermates using heterozygote × heterozygote mating. Consistent with previous results from our group [5], LTP induced by high-frequency stimulation was reduced in the heterozygous mice compared to wild-type littermates in the current experiments (Figures 1a and 2a) (for example, in Figure 2a, repeated measures ANOVA was used for analysis of the last five time points, F(1,6) = 33.71, P = 0.001).

Bottom Line: Haploinsufficiency of SHANK3, due to either hemizygous gene deletion (termed 22q13 deletion syndrome or Phelan-McDermid syndrome) or to gene mutation, accounts for about 0.5% of the cases of autism spectrum disorder (ASD) and/or developmental delay, and there is evidence for a wider role for SHANK3 and glutamate signaling abnormalities in ASD and related conditions.Positive effects were observed with an IGF-1 peptide derivative as well.Studies in mouse and human neuronal models of Rett syndrome also show benefits with IGF-1, raising the possibility that this compound may have benefits broadly in ASD and related conditions, even with differing molecular etiology.

View Article: PubMed Central - HTML - PubMed

Affiliation: Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY, USA. joseph.buxbaum@mssm.edu.

ABSTRACT

Background: Haploinsufficiency of SHANK3, due to either hemizygous gene deletion (termed 22q13 deletion syndrome or Phelan-McDermid syndrome) or to gene mutation, accounts for about 0.5% of the cases of autism spectrum disorder (ASD) and/or developmental delay, and there is evidence for a wider role for SHANK3 and glutamate signaling abnormalities in ASD and related conditions. Therapeutic approaches that reverse deficits in SHANK3-haploinsufficiency may therefore be broadly beneficial in ASD and in developmental delay.

Findings: We observed that daily intraperitoneal injections of human insulin-like growth factor 1 (IGF-1) over a 2-week period reversed deficits in hippocampal α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) signaling, long-term potentiation (LTP), and motor performance that we had previously reported in Shank3-deficient mice. Positive effects were observed with an IGF-1 peptide derivative as well.

Conclusions: We observed significant beneficial effects of IGF-1 in a mouse model of ASD and of developmental delay. Studies in mouse and human neuronal models of Rett syndrome also show benefits with IGF-1, raising the possibility that this compound may have benefits broadly in ASD and related conditions, even with differing molecular etiology. Given the extensive safety data for IGF-1 in children with short stature due to primary IGF-1 deficiency, IGF-1 is an attractive candidate for controlled clinical trials in SHANK3-deficiency and in ASD.

No MeSH data available.


Related in: MedlinePlus