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

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.

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.

Figure 2

IGF-1 reverses deficits in LTP, AMPA signaling, and motor function in Shank3-deficient mice. Wild-type (WT) and heterozygous (Het) mice were treated with saline or recombinant human IGF-1 (rhIGF-1) for 2 weeks (beginning at PND 13 to 15) before testing and analyzed immediately after the last injection. Methods for all experiments were as described previously [5,7], with 4 to 9 mice per group. (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 rhIGF-1-injected (2) heterozygous mice (scale bar: 0.5 mV, 10 ms). (b) Slices were incubated in the presence of the N-Methyl-D-aspartate (NMDA) antagonist R-2-amino-5-phosphonopentanoate (APV) to expose AMPA receptor signaling. (c) Mice were tested for motor performance and motor learning by measuring latencies to fall off a rotating rod over three trials. Het: heterozygous; LTP: long-term potentiation; NMDA: N-Methyl-D-aspartate; rhIGF-1: recombinant human IGF-1; WT: wild-type.