ABSTRACT
Autism spectrum disorder (ASD) is thought to result from deviation from normal development of neural circuits and synaptic function. Many genes with mutation in ASD patients have been identified. Here we report that two molecules associated with ASD susceptibility, contactin associated protein-like 2 (CNTNAP2) and Abelson helper integration site-1 (AHI1), are required for synaptic function and ASD-related behavior in mice. Knockdown of CNTNAP2 or AHI1 in layer 2/3 pyramidal neurons of the developing mouse prefrontal cortex (PFC) reduced excitatory synaptic transmission, impaired social interaction and induced mild vocalization abnormality. Although the causes of reduced excitatory transmission were different, pharmacological enhancement of AMPA receptor function effectively restored impaired social behavior in both CNTNAP2- and AHI1-knockdown mice. We conclude that reduced excitatory synaptic transmission in layer 2/3 pyramidal neurons of the PFC leads to impaired social interaction and mild vocalization abnormality in mice.
Subject(s)
Autism Spectrum Disorder/metabolism , Autism Spectrum Disorder/psychology , Prefrontal Cortex/metabolism , Pyramidal Cells/metabolism , Adaptor Proteins, Vesicular Transport/metabolism , Animals , Autism Spectrum Disorder/genetics , Autism Spectrum Disorder/physiopathology , Behavior, Animal , Disease Models, Animal , Humans , Membrane Proteins/genetics , Membrane Proteins/metabolism , Mice , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Synaptic TransmissionABSTRACT
Childhood- or early adulthood-onset type 1 diabetes is associated with modest impairments in cognition, and has an elevated risk of cognitive decline. Although an earlier onset age of diabetes has been identified as one of the strongest risk factors associated with cognitive dysfunction, little is known about the effects of cognitive performance associated with hippocampal function. Our previous study showed impaired working memory and hippocampal long-term depression (LTD) deficits in juvenile-onset diabetes mellitus (JDM) rats. Here, we demonstrated that treatment with the NMDA open-channel blocker, memantine, rescued hippocampal LTD and hippocampal-dependent memory in JDM rats. In addition, the impairment in LTD was attributed to a malfunction in NR2B-containing NMDA receptors. JDM rats exhibited excessive PKA activity, which may play a role in altered NMDA receptor function and impaired LTD. The changes in NR2B-containing NMDA receptors and PKA activity may be involved in learning impairments in JDM rats. Our findings suggest that NMDA open-channel blockers offer a potential strategy to treat cognitive deficits in childhood-onset diabetes.
Subject(s)
CA1 Region, Hippocampal/physiology , Cyclic AMP-Dependent Protein Kinases/metabolism , Diabetes Mellitus, Type 1/metabolism , Long-Term Synaptic Depression , Receptors, N-Methyl-D-Aspartate/metabolism , Spatial Learning/physiology , Animals , CA1 Region, Hippocampal/drug effects , Diabetes Mellitus, Experimental/metabolism , Disease Models, Animal , Excitatory Amino Acid Antagonists/pharmacology , Male , Memantine/pharmacology , Pyramidal Cells/drug effects , Pyramidal Cells/physiology , Rats , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Signal Transduction , Spatial Learning/drug effectsABSTRACT
Childhood-onset type 1 diabetes is associated with modest impairments in cognition and has an elevated risk of cognitive decline. Our previous study showed that working memory and hippocampal long-term depression (LTD) were impaired in juvenile-onset diabetes mellitus (JDM) rats. In this study, we investigated the effect of chotosan (CTS), a traditional herbal formula called a Kampo medicine, which has been clinically demonstrated to be effective for the treatment of vascular dementia, on JDM rats. The repeated treatment with CTS (1 g/kg per day) for 3 - 7 days restored spatial working memory and hippocampal LTD in JDM rats. The expression level of NR2B glutamate receptor subunits, but not other glutamate receptor subunits was enhanced in the hippocampus of JDM rats, and repeated treatment with CTS reversed these changes. These results suggest that CTS improves diabetes-induced cognitive deficits by modulating NMDA-receptor subunit expression.
Subject(s)
Cognition Disorders/etiology , Cognition Disorders/physiopathology , Diabetes Mellitus, Type 1/complications , Drugs, Chinese Herbal/pharmacology , Drugs, Chinese Herbal/therapeutic use , Long-Term Synaptic Depression/drug effects , Medicine, Kampo , Phytotherapy , Animals , Cognition Disorders/drug therapy , Diabetes Mellitus, Experimental , Disease Models, Animal , Male , Memory/drug effects , Rats , Rats, Wistar , Receptors, N-Methyl-D-Aspartate/metabolism , Risk , StreptozocinABSTRACT
We have previously demonstrated that riluzole has anxiolytic-like effects in rats, without affecting spontaneous alternation performance in the Y-maze test. However, the effects of riluzole on hippocampal synaptic plasticity were still unclear. In this study, we showed that bath application of riluzole did not impair long-term potentiation and long-term depression, whereas a benzodiazepine anxiolytic, diazepam, significantly impaired them. Furthermore, the acquisition of spatial memory in the Morris water maze test was impaired in diazepam-treated but not riluzole-treated rats. We thus provide further evidence for the potential usefulness of riluzole as an anxiolytic that does not cause amnesia.
