Energy deficit in parvalbumin neurons leads to circuit dysfunction, impaired sensory gating and social disability.
Parvalbumin-expressing, fast spiking interneurons have high-energy demands, which make them particularly susceptible to energy impairment. Recent evidence suggests a link between mitochondrial dysfunction in fast spiking cortical interneurons and neuropsychiatric disorders. However, the effect of mitochondrial dysfunction restricted to parvalbumin interneurons has not been directly addressed in vivo. To investigate the consequences of mitochondrial dysfunction in parvalbumin interneurons in vivo, we generated conditional knockout mice with a progressive decline in oxidative phosphorylation by deleting cox10 gene selectively in parvalbumin neurons (PV-Cox10 CKO). Cox10 ablation results in defective assembly of cytochrome oxidase, the terminal enzyme of the electron transfer chain, and leads to mitochondrial bioenergetic dysfunction. PV-Cox10 CKO mice showed a progressive loss of cytochrome oxidase in cortical parvalbumin interneurons. Cytochrome oxidase protein levels were significantly reduced starting at postnatal day 60, and this was not associated with a change in parvalbumin interneuron density. Analyses of intrinsic electrophysiological properties in layer 5 primary somatosensory cortex revealed that parvalbumin interneurons could not sustain their typical high frequency firing, and their overall excitability was enhanced. An increase in both excitatory and inhibitory input onto parvalbumin interneurons was observed in PV-Cox10 CKO mice, resulting in a disinhibited network with an imbalance of excitation/inhibition. Investigation of network oscillations in PV-Cox10 CKO mice, using local field potential recordings in anesthetized mice, revealed significantly increased gamma and theta frequency oscillation power in both medial prefrontal cortex and hippocampus. PV-Cox10 CKO mice did not exhibit muscle strength or gross motor activity deficits in the time frame of the experiments, but displayed impaired sensory gating and sociability. Taken together, these data reveal that mitochondrial dysfunction in parvalbumin interneurons can alter their intrinsic physiology and network connectivity, resulting in behavioral alterations similar to those observed in neuropsychiatric disorders, such as schizophrenia and autism.
Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY, United States.
Melis
M
Inan
Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY, United States; Department of Neurological Surgery, Weill Cornell Medical College, New York, NY, United States.
Mingrui
M
Zhao
Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY, United States.
Monica
M
Manuszak
Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY, United States.
Cansu
C
Karakaya
Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY, United States; Department of Pediatric Neurology, Weill Cornell Medical College, New York, NY, United States; Department of Anesthesiology, Weill Cornell Medical College, New York, NY, United States.
Anjali M
AM
Rajadhyaksha
Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY, United States.
Virginia M
VM
Pickel
Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY, United States; Department of Neurological Surgery, Weill Cornell Medical College, New York, NY, United States.
Theodore H
TH
Schwartz
Department of Anesthesiology, Weill Cornell Medical College, New York, NY, United States; Department of Medicine, Weill Cornell Medical College, New York, NY, United States. Electronic address: pag2014@med.cornell.edu.
Peter A
PA
Goldstein
Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY, United States. Electronic address: gim2004@med.cornell.edu.
Giovanni
G
Manfredi
D000818:Animals; D006624:Hippocampus / Q000378:metabolism; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism*; D010320:Parvalbumins / Q000378:metabolism*; D017397:Prefrontal Cortex / Q000378:metabolism*; D055139:Sensory Gating / Q000502:physiology*; D066107:Social Skills; D013003:Somatosensory Cortex / Q000378:metabolism
D010320:Parvalbumins
COX; Interneurons; Mitochondria; Oscillations; Parvalbumin