Early correction of NMDA receptor dysfunction in mouse models of autism

ABSTRACT Reactive oxygen species (ROS) are required in a number of critical cellular signaling events, including those underlying hippocampal synaptic plasticity and hippocampus-dependent memory; however, the source of ROS is unknown. We previously have shown that NADPH oxidase is required for N-methyl-d-aspartate (NMDA) receptor-dependent signal transduction in the hippocampus, suggesting that NADPH oxidase may be required for NMDA receptor-dependent long-term potentiation (LTP) and hippocampus-dependent memory. Herein we present the first evidence that NADPH oxidase is involved in hippocampal synaptic plasticity and memory. We have found that pharmacological inhibitors of NADPH oxidase block LTP. Moreover, mice that lack the NADPH oxidase proteins gp91 phox and p47 phox , both of which are mouse models of human chronic granulomatous disease (CGD), also lack LTP. We also found that the gp91 phox and p47 phox mutant mice have mild impairments in hippocampus-dependent memory. The gp91 phox mutant mice exhibited a spatial memory deficit in the Morris water maze, and the p47 phox mutant mice exhibited impaired context-dependent fear memory. Taken together, our results are consistent with NADPH oxidase being required for hippocampal synaptic plasticity and memory and are consistent with reports of cognitive dysfunction in patients with CGD.

Download Full-text

Glutamate receptor composition of the post-synaptic density is altered in genetic mouse models of NMDA receptor hypo- and hyperfunction

Brain Research ◽

10.1016/j.brainres.2011.03.051 ◽

2011 ◽

Vol 1392 ◽

pp. 1-7 ◽

Cited By ~ 23

Author(s):

Darrick T. Balu ◽

Joseph T. Coyle

Keyword(s):

Nmda Receptor ◽

Mouse Models ◽

Glutamate Receptor ◽

Synaptic Density ◽

Post Synaptic Density ◽

Genetic Mouse Models

Download Full-text

Early dysfunction and progressive degeneration of the subthalamic nucleus in mouse models of Huntington's disease

eLife ◽

10.7554/elife.21616 ◽

2016 ◽

Vol 5 ◽

Cited By ~ 13

Author(s):

Jeremy F Atherton ◽

Eileen L McIver ◽

Matthew RM Mullen ◽

David L Wokosin ◽

D James Surmeier ◽

...

Keyword(s):

Nmda Receptor ◽

Huntington's Disease ◽

Huntington’S Disease ◽

Mouse Models ◽

Subthalamic Nucleus ◽

Glutamate Uptake ◽

Oxidant Stress ◽

Katp Channels ◽

Receptor Antagonism ◽

Progressive Degeneration

The subthalamic nucleus (STN) is an element of cortico-basal ganglia-thalamo-cortical circuitry critical for action suppression. In Huntington's disease (HD) action suppression is impaired, resembling the effects of STN lesioning or inactivation. To explore this potential linkage, the STN was studied in BAC transgenic and Q175 knock-in mouse models of HD. At <2 and 6 months of age autonomous STN activity was impaired due to activation of KATP channels. STN neurons exhibited prolonged NMDA receptor-mediated synaptic currents, caused by a deficit in glutamate uptake, and elevated mitochondrial oxidant stress, which was ameliorated by NMDA receptor antagonism. STN activity was rescued by NMDA receptor antagonism or the break down of hydrogen peroxide. At 12 months of age approximately 30% of STN neurons had been lost, as in HD. Together, these data argue that dysfunction within the STN is an early feature of HD that may contribute to its expression and course.

Download Full-text