Ablation of the distal end of the short arm of chromosome 1 (1p36 deletion syndrome) is one of the most commonly occurring terminal deletion syndrome in humans, occurring in about 1 in 5000 newborns. Subjects with 1p36 deletion syndrome (1p36DS) exhibit a wide range of clinical features including growth delay, congenital heart defects and craniofacial dysmorphism. In addition, individuals with 1p36DS have rather profound neurological disorders: moderate to severe mental retardation and seizure activity are common clinical features. Although there is significant variability with regard to the extent of the deletion, several genes have been mapped to region 1p36 as candidate genes that may underlie the neurological phenotype in 1p36DS. One such gene-KCNAB2-which encodes the potassium channel auxiliary subunit Kv?2, has recently been linked to epilepsy in patients with 1p36DS. To determine to what extent loss of Kv?2 contributes to the neurological phenotype of 1p36DS we have begun to examine mice in which the mouse homologue of KCNAB2 has been deleted by homologous recombination (Kv?2 KO mice). Our preliminary experiments reveal that the Kv?2 KO mice exhibit hippocampal-dependent learning/memory impairments and spontaneous seizures. These neurological abnormalities occur in the absence of alterations in basal synaptic transmission within the hippocampus. In this Exploratory/Developmental application we seek to build upon these studies to further develop this mouse model. The experiments outlined in Specific Aim I will further explore the learning/memory impairments in the Kv?2 KO mice in two additional hippocampal-dependent learning/memory tasks: the Morris water maze and the Olton 8-arm radial maze.
In Specific Aim II standard video/EEG methodology will be utilized to define the frequency, severity and prevalence of the spontaneous seizures in the Kv?2 KO mice.
In Specific Aim III we will determine to what extent long-term potentiation and intrinsic neuronal excitability are altered by deletion of Kv?2. We anticipate that the results obtained from this Exploratory/Developmental will not only provide important insights into the relative contribution of KCNAB2 deletion to the neurological phenotype observed in 1p36 DS but will also help to elucidate the neuronal function of Kv?2. ject Narrative 1p36 deletion syndrome is a chromosome disorder in which the end of the short arm of either copy of chromosome 1 is deleted. Patients with 1p36 exhibit a wide variety of symptoms including several neurological abnormalities. This application proposes to use genetically engineered mice to examine the neurological impact of deleting a specific gene (KCNA2B) known to be lost in 1p36 deletion syndrome. ? ? ?
| Perkowski, John J; Murphy, Geoffrey G (2011) Deletion of the mouse homolog of KCNAB2, a gene linked to monosomy 1p36, results in associative memory impairments and amygdala hyperexcitability. J Neurosci 31:46-54 |
