ABSTRACT
ATP-sensitive potassium (KATP) gain-of-function (GOF) mutations cause neonatal diabetes, with some individuals exhibiting developmental delay, epilepsy, and neonatal diabetes (DEND) syndrome. Mice expressing KATP-GOF mutations pan-neuronally (nKATP-GOF) demonstrated sensorimotor and cognitive deficits, whereas hippocampus-specific hKATP-GOF mice exhibited mostly learning and memory deficiencies. Both nKATP-GOF and hKATP-GOF mice showed altered neuronal excitability and reduced hippocampal long-term potentiation (LTP). Sulfonylurea therapy, which inhibits KATP, mildly improved sensorimotor but not cognitive deficits in KATP-GOF mice. Mice expressing KATP-GOF mutations in pancreatic ß-cells developed severe diabetes but did not show learning and memory deficits, suggesting neuronal KATP-GOF as promoting these features. These findings suggest a possible origin of cognitive dysfunction in DEND and the need for novel drugs to treat neurological features induced by neuronal KATP-GOF.
Subject(s)
Cognition Disorders/etiology , Diabetes Mellitus/psychology , Epilepsy/psychology , Hippocampus/metabolism , Infant, Newborn, Diseases/psychology , KATP Channels/genetics , Motor Disorders/etiology , Psychomotor Disorders/psychology , Animals , Diabetes Mellitus/etiology , Diabetes Mellitus/metabolism , Disease Models, Animal , Epilepsy/etiology , Epilepsy/metabolism , Female , Gain of Function Mutation , Infant, Newborn, Diseases/etiology , Infant, Newborn, Diseases/metabolism , Learning Disabilities/drug therapy , Learning Disabilities/etiology , Long-Term Potentiation , Male , Memory Disorders/drug therapy , Memory Disorders/etiology , Mice, Transgenic , Psychomotor Disorders/etiology , Psychomotor Disorders/metabolism , Sulfonylurea Compounds/therapeutic useABSTRACT
The interpretation of social cues is a fundamental function of human social behavior, and resolution of inconsistencies between spoken and gestural cues plays an important role in successful interactions. To gain insight into these underlying neural processes, we compared neural responses in a traditional color/word conflict task and to a gesture/word conflict task to test hypotheses of domain-general and domain-specific conflict resolution. In the gesture task, recorded spoken words ("yes" and "no") were presented simultaneously with video recordings of actors performing one of the following affirmative or negative gestures: thumbs up, thumbs down, head nodding (up and down), or head shaking (side-to-side), thereby generating congruent and incongruent communication stimuli between gesture and words. Participants identified the communicative intent of the gestures as either positive or negative. In the color task, participants were presented the words "red" and "green" in either red or green font and were asked to identify the color of the letters. We observed a classic "Stroop" behavioral interference effect, with participants showing increased response time for incongruent trials relative to congruent ones for both the gesture and color tasks. Hemodynamic signals acquired using functional near-infrared spectroscopy (fNIRS) were increased in the right dorsolateral prefrontal cortex (DLPFC) for incongruent trials relative to congruent trials for both tasks consistent with a common, domain-general mechanism for detecting conflict. However, activity in the left DLPFC and frontal eye fields and the right temporal-parietal junction (TPJ), superior temporal gyrus (STG), supramarginal gyrus (SMG), and primary and auditory association cortices was greater for the gesture task than the color task. Thus, in addition to domain-general conflict processing mechanisms, as suggested by common engagement of right DLPFC, socially specialized neural modules localized to the left DLPFC and right TPJ including adjacent homologous receptive language areas were engaged when processing conflicting communications. These findings contribute to an emerging view of specialization within the TPJ and adjacent areas for interpretation of social cues and indicate a role for the region in processing social conflict.
