In Vivo Sensory Cortex Dysfunction in Pyruvate Dehydrogenase Deficient Mice
Terrill, Tyler A.
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BACKGROUND: Pyruvate Dehydrogenase (PDH) is a critical enzyme in all organisms, providing pyruvate for the Krebs cycle to generate ATP. As a result, PDH-deficient patients develop lactic acidosis and intellectual disability. Processing of sensory information in the cerebral cortex is crucial for intellectual function. We hypothesize that cortical thinning in these patients contributes to aberrant sensory processing and resulting intellectual disability. Specifically, we hypothesize that there exists a deficit in neurotransmission between cortical layers of the primary somatosensory cortex that can be tested in a novel mouse model of PDH deficiency that replicates the cardinal features of the human disorder. METHODS: Wild-type (WT, n=11), GFAP-CrePDHflox/+ heterozygous (GFAPhet, n=7), GFAP-CrePDHflox/flox knockout (GFAPKO, n=10), and Nestin-CrePDHflox/+ heterozygous mice (NChet, n=14) were anesthetized and their cortex exposed. A vertical linear electrode array was modified to stimulate in layer IV and record in layers IV and II. Synaptic activation and neuronal output were reflected on the recorded local field potentials (LFP) and action potentials. In each mouse, we examined spontaneous activity in layer II and IV, evoked response in layer II from stimulation in layer IV, and synchronized spontaneous activity between the two layers. RESULTS: Spontaneous oscillations of synaptic activation in layer II were significantly reduced in amplitude in both the GFAPKO and NChet mice (p=.02, p=.01). Thus, spontaneous synaptic input into a processing unit of the sensory cortex is severely impaired. Evoked LFPs in layer II were decreased in the GFAPhet, GFAPKO, and NChet mice (p<.001, p=.002, p=.02). Hence, neurotransmission from layer IV to layer II is significantly decreased. Synaptic oscillations in layer IV and II were less synchronized in NChet mice (p<.001) indicating a lack of normal cortical network activity. Additionally, there was electrophysiological evidence of paroxysmal, seizure-like activity in layer 2 of the GFAPKO mice (42% of animals, similar to the EEG of human patients. CONCLUSION: We have observed a significant loss of spontaneous electrophysiological activity, evoked response, and synchronization of LFP oscillations in the PDH mutant mice. This implies cortical dysfunction in sensory processing that could contribute to intellectual disability. Treatments targeting this aspect of the phenotype could be beneficial to PDH-deficient patients.