Mitochondria are a cell organelle responsible for the production of energy for cellular activities. This is done mainly by the formation of ATP through oxidative phosphorylation via the mitochondrial respiratory chain. Since neurons are highly active cells, it is not surprising that neurons depends highly on optimal mitochondrial function for their survival and a broad range of physiological activities. Increasingly, neurodegenerative disorders are being identified as having secondary mitochondrial dysfunction. These include Alzheimer’s disease (AD), Parkinson’s disease (PD) and Huntington’s disease (HD). In all of these conditions, cognitive dysfunction is a core symptom with limited effective nootropic therapies currently available. In attempting to understand the role of mitochondrial dysfunction and the implications of this for cognitive processes we have utilized in vitro brain slice preparations. Using this technique, patterns of cortical network activity associated with cognitive processes can be reproduced. In particular, we have examined oscillatory activity in the range of 30-80 Hz, termed the gamma frequency oscillation. This approach also affords sufficient access and manipulation to probe their network, cellular and synaptic underpinnings. Using this approach, data from studies using rodent and human brain slices will be presented which illustrate that the cortical gamma frequency oscillation depends largely on mitochondrial energy formation and highly sensitive to mitochondrial dysfunction, especially complex I inhibition1. We will also provide evidence that within this context, our results suggest that the decline in gamma oscillation power seen with inhibitors of the mitochondrial respiratory chain results primarily from effects on these fast spiking interneurons. These findings may offer insight into pathophysiology of cortical dysfunction in neurodegenerative conditions in which secondary mitochondrial dysfunction is implicated.