Mechanisms and functional implications of long-term synaptic plasticity in striatum and network plasticity in hippocampus

Synaptic plasticity is the phenomenon that occurs when a brief signal causes a long-lasting change in the size of the postsynaptic response to a presynaptic action potential. In this thesis I focus on addressing the mechanistic basis of synaptic plasticity in the striatum. Two questions I address are: (1) what are the mechanisms by which these synapses make the effects of a brief signal long-lasting? and (2) is plasticity at these synapses associative and specific? To address these questions I used an in vitro slice preparation containing striatum and incoming excitatory axons from cortex and thalamus. The predominant form of long-term synaptic depression (LTD) at excitatory synapses onto striatal medium spiny neurons occurs when endogenous cannabinoids bind to presynaptic CB1 receptors and cause a decrease in the probability of transmitter release. I found that LTD due to CB1 or adenosine A1 receptor activation requires action potentials/Ca2+ channels, whereas short-term depression by GABAB receptor activation is due to direct inhibition of the transmitter release machinery and is independent of action potentials and Ca2+ channels.; A key feature of Hebbian learning rules for associative learning is synapse specificity. I studied independent sets of synapses onto single striatal neurons to examine synapse specificity during striatal LTD. I found that LTD is specific to active presynaptic sites, as inactive terminals do not undergo LTD even when exposed to high levels of cannabinoids. This synapse specificity is achieved by a requirement for coincident presynaptic Ca2+ influx and cannabinoid binding.; Finally, I studied a different type of plasticity in a different brain region, neurogenesis of neural stem/progenitor cells from the adult hippocampus. Neuron turnover has been observed in the adult mammalian dentate gyrus, and experimental evidence suggests that this turnover is involved in hippocampal function. We found that neural activtiy is sensed by NMDA receptors and L-type Ca2+ channels on the stem/progenitor cells and causes increased neurogenesis. I also studied the effects of activity-dependent neuron turnover in a computer model of a Hebbian neural network and found that neuron turnover enhances the storage of new memories as well as the clearance of old memories.