Presynaptic forms of long-term plasticity in the mammalian hippocampus

Abstract

Long-term, activity-dependent changes in synaptic efficacy at excitatory and inhibitory neurons contribute to hippocampal-dependent forms of learning and memory. While much is known about the cellular and molecular mechanisms taking place in postsynaptic compartments during long-term plasticity, far less is understood about the role of presynaptic signaling, in particular at inhibitory synapses, during long-term plasticity. To investigate presynaptic inhibitory function, I performed electrophysiological recordings in acute hippocampal marine brain slices combined with selective pharmacological and genetic manipulations. I discovered and characterized the induction and expression mechanism of a novel form of long-term depression of synaptic transmission expressed specifically at presynaptic inhibitory interneurons. This plasticity is induced by postsynaptic CA1 pyramidal cell theta-burst firing that mimics in vivo activity and is mediated by the retrograde actions of endogenous cannabinoids (eCBs). Since eCBs are found throughout the brain at inhibitory and excitatory synapses, this form of long-term presynaptic plasticity may be a general mode by which single neurons fine-tune their presynaptic inputs in a manner that depends solely on their postsynaptic activity. To extend what is known about the molecular mechanisms occurring in presynaptic terminals during long-term plasticity, I performed paired recordings between interneurons and CA1 pyramidal cells and found that eCB-mediated long-term depression of inhibition requires presynaptic protein synthesis. I also participated in two collaborative projects investigating presynaptic function. Rab3B is a vesicle-associated G protein enriched at hippocampal inhibitory synapses. I established that Rab3B is required for eCB-mediated, long-term plasticity at inhibitory synapses. In addition, Rab3B is important for hippocampal-dependent forms of learning and memory. Synaptotagmin-12 is a calcium-insensitive vesicle-associated protein that can be phosphorylated by protein kinase A (PKA). I found that synaptotagmin-12 is dispensable for eCB-mediated inhibitory long-term plasticity, which is known to require presynaptic PKA signaling, but is essential for presynaptic, PKA-dependent long-term plasticity at the mossy fiber-to-CA3 pyramidal cell synapse. Collectively, this research provides new mechanistic insight into normal presynaptic function and informs future studies exploring hippocampal-dependent forms of learning and memory.