Requirement for enhanced metabolic efficiency in hippocampal LTP

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Abstract Hippocampal long term potentiation (LTP) is the enhancement of synaptic transmission that may underlie long term memory storage. This form of synaptic plasticity has been highly studied in the hippocampal CA3 to CA1 synapse. Hebb predicted in the 1940s before any molecular understanding of LTP was known, that LTP must be dependent upon “some growth process or METABOLIC change” taking place in one or both cells so that “A's EFFICIENCY as one of the cells firing B is increased.” After high frequency stimulation in the hippocampus, acute and persisting growth processes do occur including regulation of Ca2+ flux through NMDA receptors into the CA1 neuron, and enhanced insertion of AMPA receptors into the postsynaptic membrane but a METABOLIC change required to alter the EFFICIENCY of synaptic transmission to induce and/or sustain LTP has never been found. In this application we will test if a long term change in mitochondrial efficiency dependent upon Bcl-xL is required for the onset of LTP. We have found previously that mitochondria manifest improved metabolic efficiency upon expression of the Bcl- 2 family protein Bcl-xL. Bcl-xL is highly expressed in cancer cells resistant to cell death, but also contributes to changes in synaptic strength. Bcl-xL targets to mitochondria, localizes these organelles to synapses and increases the number and size of synapses and the rate of spontaneous neurotransmitter release events. Most importantly for this study, we have found that Bcl-xL increases the production of ATP by mitochondria through its ability to decrease the probability of opening of a leak channel found within the ATP synthase c-subunit. Upon high frequency synaptic stimulation, Bcl-xL moves to mitochondria and a halo of ATP forms around the mitochondria, and this persistently enhanced mitochondrial ATP level appears to be dependent on Bcl-xL and required for LTP. In this proposed study, we will determine if LTP requires a true change in efficiency of mitochondrial function. We will consider that there is an increase in efficiency if we find a relative decrease or no change in oxygen consumption by mitochondria during enhanced ATP production. We will confirm if targeting of Bcl-xL to the ATP synthase is required for the change in efficiency of ATP production. We will determine if the association of Bcl-xL with mitochondria is linked to the onset of LTP in hippocampal CA1 neurons. Finally, we will determine if a low conductance ATP synthase c-subunit will reverse the effects of genetic Bcl- xL depletion, and will allow for the onset and/or maintenance of LTP.