Brain region-specific effects of cGMP-dependent kinase II knockout on AMPA receptor trafficking and animal behavior

Kim, Seonil; Pick, Joseph; Abera, Sinedu; Khatri, Latika; Ferreira, Danielle Dias Pinto; Sathler, Matheus F.; Morison, Sage L.; Hofmann, Franz; Ziff, Edward B.

doi:10.1101/lm.042960.116

Cited by 12 publications

(12 citation statements)

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“…Discussion 4q21 microdeletion syndrome is a human genomic disorder, which is characterized by neonatal hypotonia, intellectual disability, absent or delayed speech, growth retardation, and brain malformation and facial dysmorphism [1,2]. Given that mice carrying a null mutation of the cGKII gene exhibit postnatal dwarfism and learning disability similar to that observed in the reported patients [6,20,21], it has been proposed that the PRKG2 gene is one of the key genes for the 4q21 microdeletion syndrome [1,2]. Additionally, cGKII is abundantly expressed in the brain and regulates neuronal activity and cognitive function [12,13,20,21].…”

supporting

confidence: 59%

“…cGKII KO animals were maintained in the C57Bl6 background as previously described [20]. Pups, a mixture of males and females, were produced from breeding heterozygous cGKII KO mice.…”

Section: Animalsmentioning

confidence: 99%

“…Membranes were blotted with anti-cGKII [12,20] (Covance, 1:1000) and anti-actin (Abcam, 1:2000) antibodies and developed with chemiluminescence.…”

Section: Tissue Sample Preparation and Immunoblotsmentioning

confidence: 99%

“…The copyright holder for this preprint this version posted January 7, 2021. ; https://doi.org/10.1101/2021.01.06.425531 doi: bioRxiv preprint 6 which is important for learning and memory [12,13,19]. In fact, cGKII knockout (KO) mice exhibit severe impairment in hippocampus-dependent learning and memory [20,21], which is relevant to mental retardation found in human microdeletion 4q21 syndrome [1,2]. Taken together, loss of the cGKII gene may underlie neurological symptoms in microdeletion 4q21 syndrome, which includes intellectual disability and speech defects.…”

Section: Introductionmentioning

confidence: 99%

“…Given that mice carrying a null mutation of the cGKII gene exhibit postnatal dwarfism and learning disability similar to that observed in the reported patients [6,20,21], it has been proposed that the PRKG2 gene is one of the key genes for the 4q21 microdeletion syndrome [1,2]. Additionally, cGKII is abundantly expressed in the brain and regulates neuronal activity and cognitive function [12,13,20,21]. However, a role of cGKII in speech has not been investigated.…”

mentioning

confidence: 99%

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Loss of cGMP-dependent protein kinase II alters ultrasonic vocalizations in mice, a model for speech impairment in human microdeletion 4q21 syndrome

Tran¹,

Sherwood²,

Sathler³

et al. 2021

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Chromosome 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.

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supporting

confidence: 59%

“…cGKII KO animals were maintained in the C57Bl6 background as previously described [20]. Pups, a mixture of males and females, were produced from breeding heterozygous cGKII KO mice.…”

Section: Animalsmentioning

confidence: 99%

“…Membranes were blotted with anti-cGKII [12,20] (Covance, 1:1000) and anti-actin (Abcam, 1:2000) antibodies and developed with chemiluminescence.…”

Section: Tissue Sample Preparation and Immunoblotsmentioning

confidence: 99%