AbstractChromosome 4q21 microdeletion leads to a human syndrome that exhibits restricted growth, facial dysmorphisms, mental retardation, and absent or delayed speech. One of the key genes in the affected region of the chromosome is PRKG2, which encodes cGMP-dependent protein kinase II (cGKII). Mice lacking cGKII exhibit restricted growth and deficits in learning and memory, as seen in the human syndrome. However, speech/vocalization impairments in these mice have not been determined. Moreover, the molecular pathway underlying speech impairment in humans is not fully understood. Here, we employed cGKII knockout (KO) mice as a model for the human microdeletion syndrome to test whether vocalizations are affected by loss of the PRKG2 gene. Mice emit ultrasonic vocalizations (USVs) to communicate in social situations, stress, and isolation. We thus recorded ultrasonic vocalizations as a model for speech in humans. We isolated postnatal day 5-7 pups from the nest to record and analyze USVs and found significant differences in vocalizations of KO mice relative to wild-type and heterozygous mutant mice. KO mice produced fewer calls that were shorter duration, higher frequency, and lower intensity. Because neuronal activity in the hypothalamus is important for the production of animal USVs following isolation from the nest, we assessed hypothalamic activity in KO pups following isolation. Indeed, we found abnormal hyperactivation of hypothalamic neurons in cGKII KO pups after isolation. Taken together, our studies indicate that cGKII is important for neuronal activation in the hypothalamus, which is required for the production of USVs in neonatal mice. We further suggest cGKII KO mice can be a valuable animal model for human microdeletion 4q21 syndrome.HighlightsChromosome 4q21 microdeletion leads to a human syndrome that exhibits restricted growth, mental retardation, and absent or delayed speech.The cGMP-dependent protein kinase II (cGKII) gene is one of the genes located in the affected region of the chromosome.cGKII knockout mice show restricted growth and deficits in learning and memory.Altered ultrasonic vocalizations and abnormal activation in hypothalamic neurons are found when infant cGKII knockout pups are isolated from the nest.cGKII knockout mice can be a valuable animal model for human microdeletion 4q21 syndrome.
Microdeletion at chromosome 4q21 defines a new emerging syndrome with marked growth restriction, mental retardation and absent or severely delayed speech
