Autism spectrum disorder (ASD) is a developmental disability characterized by impairments in social interaction and repetitive behavior, and is also associated with cognitive deficits. There is no current treatment that can ameliorate most of the ASD symptomatology; thus, identifying novel therapies is urgently needed. We used male BTBR /J (BTBR) mice, a model that reproduces most of the core behavioral phenotypes of ASD, to test the effects of systemic administration of insulin-like growth factor II (IGF-II), a polypeptide that crosses the blood-brain barrier and acts as a cognitive enhancer. We show that systemic IGF-II treatments reverse the typical defects in social interaction, cognitive/executive functions, and repetitive behaviors reflective of ASD-like phenotypes. In BTBR mice, IGF-II, via IGF-II receptor, but not via IGF-I receptor, reverses the abnormal levels of the AMPK-mTOR-S6K pathway and of active translation at synapses. Thus, IGF-II may represent a novel potential therapy for ASD. Currently, there is no effective treatment for autism spectrum disorder (ASD), a developmental disability affecting a high number of children. Using a mouse model that expresses most of the key core as well as associated behavioral deficits of ASD, that are, social, cognitive, and repetitive behaviors, we report that a systemic administration of the polypeptide insulin-like growth factor II (IGF-II) reverses all these deficits. The effects of IGF-II occur via IGF-II receptors, and not IGF-I receptors, and target both basal and learning-dependent molecular abnormalities found in several ASD mice models, including those of identified genetic mutations. We suggest that IGF-II represents a potential novel therapeutic target for ASD.

To treat cognitive disorders in humans, new effective therapies that can be easily delivered systemically are needed. Previous studies showed that a bilateral injection of insulin-like growth factor II (IGF-II) into the dorsal hippocampus of rats or mice enhances fear memories and facilitates fear extinction. Here, we report that, in mice, systemic treatments with IGF-II given before training significantly enhance the retention and persistence of several types of working, short-term and long-term memories, including fear conditioning, object recognition, object placement, social recognition, and spatial reference memory. IGF-II-mediated memory enhancement does not alter memory flexibility or the ability for new learning and also occurs when IGF-II treatment is given in concert with memory retrieval. Thus IGF-II may represent a potentially important and effective treatment for enhancing human cognitive and executive functions.

There is evidence for sex differences in cocaine addiction from both clinical and preclinical studies. In particular, preclinical studies indicate that females may be more sensitive than males to stress-induced drug seeking. The dorsal hippocampus (DH) is prominently involved in the stress response, as are the locus coeruleus norepinephrine (LC-NE) and dorsal raphe serotonin (DR 5-HT) systems. Moreover, DH receives strong inputs from LC-NE and DR 5-HT neurons. We hypothesized that the stress associated with non-reinforced drug seeking during early abstinence (on extinction day 1 (ED1)) may contribute to drug seeking via β-adrenergic and 5-HT neurotransmission in DH. We observed decreased drug-seeking behavior on ED1 following 10 mg/kg S-propranolol (β-adrenergic and 5-HT1A/1B receptor antagonist), R-propranolol (5-HT1A/1B receptor antagonist), or racemic propranolol in both male and female rats. ED1 increased Fos expression in DH, LC, and DR, and DH Fos was decreased by systemic S-propranolol. Based on these results, we investigated the effects of blocking 5-HT and β-adrenoceptor transmission in DH on drug seeking during ED1 by infusing a cocktail of WAY100635 plus GR127935 (5-HT1A/1B receptor antagonists), betaxolol plus ICI-118 551 (β1 and β2 antagonists), or S-propranolol alone. In males, WAY100635/ GR127935 was most effective in reducing drug-seeking on ED1, whereas betaxolol/ICI-118 551 was ineffective. In contrast, S-propranolol was most effective in females in reducing drug seeking on ED1, and WAY100635/GR127935 and betaxolol/ICI-118 551 were each partially effective. Our results indicate that drug seeking during initial abstinence involves 5-HT and β-adrenergic signaling in female DH, but only 5-HT signaling in male DH.

Insulin like growth factor 2 (Igf2) is known as a maternally imprinted gene involved in growth and development. Recently, Igf2 was found to also be regulated and required in the adult rat hippocampus for long-term memory formation, raising the question of its allelic regulation in adult brain regions following experience and in cognitive processes. We show that, in adult rats, Igf2 is abundantly expressed in brain regions involved in cognitive functions, like hippocampus and prefrontal cortex, compared to the peripheral tissues. In contrast to its maternal imprinting in peripheral tissues, Igf2 is mainly expressed from the maternal allele in these brain regions. The training-dependent increase in Igf2 expression derives proportionally from both parental alleles, and, hence, is mostly maternal. Thus, Igf2 parental expression in the adult rat brain does not follow the imprinting rules found in peripheral tissues, suggesting differential expression regulation and functions of imprinted genes in the brain.