Synapsin-GFP AAV (Serotype 9)

Reduced insulin-like growth factor 1 (IGF-1) is associated with cognitive impairment and increased risk of neurodegenerative diseases in advanced age. The researchers hypothesized that IGF-1 continues to promote the structure and function of hippocampal neurons after development and therefore, loss of IGF-1 signaling in adult neurons would result in impaired spatial learning and memory. To test this, the IGF-1 receptor (IGF-1R) was genetically targeted in hippocampal neurons of adult male and female mice. Male mice deficient in neuronal IGF-1R exhibited spatial learning impairments as evidenced by increased path length and errors in the radial arm water maze. There were no differences in learning and memory in female mice. Golgi-Cox staining revealed a reduction in the number of dendrites in neurons in the CA1 region of the hippocampus of male mice. Decreased MAPK and increased ROCK activity were also observed in these tissues. In vitro studies showed that the impaired neurite outgrowth due to inhibition of IGF-1R signaling could be rescued by pharmacological inhibitors of ROCK. However, ROCK inhibition did not fully rescue learning impairments or synaptic nuclei number in mice deficient in neuronal IGF-1R. Altogether, these findings highlight that IGF-1 continues to support spatial learning and memory as well as neuronal architecture in adulthood.

Hippocampal neuron-specific IGF-1R deletion (*IGFR-KO) was induced in male and female igfrf/f mice at 3-4 months of age by stereotaxic injection of Cre recombinase encoding a viral vector (AAV9-Syn-Cre or control AAV9-Syn-GFP) (Figure 1A). The mRNA expression of IGFR, IGF-1, and other growth-promoting signals was quantified in the dorsal hippocampus to verify the specific reduction of the floxed region of IGF-1R exon 3. These neuron-specific *IGFR-KO male and female mice had a 39.6% reduction in IGF-1R compared with GFP-transduced controls (*IGFR-WT) (Figure 1B). No significant differences in growth hormone receptor (GHR), insulin receptor (InsR), or IGF-1 expression were observed in the hippocampi of *IGFR-KO mice (Figure 1B). Both *IGFR-WT and *IGFR-KO mice learned how to find the escape platform during the three-day training phase, as evidenced by a reduction in the total path length to the escape platform (Figure 1C) and a reduction in the total number of errors in finding the platform (Figure 1E). However, *IGFR-KOs traveled significantly more and made more errors than controls throughout the learning phase (Figure 1C and E). When memory extinction and relearning were assessed during the reversal phase of the maze, male *IGFR-KO mice again traveled significantly more and made more errors than controls (Figure 1D and F).

Figure 1. Adult IGF-1R Signaling in Neurons Regulates Spatial Learning and Memory in Male Mice. (Hayes C A, et al., 2021)