Neurons in the mammalian central nervous system communicate with each other via synapses. The dendrites of cells that receive excitatory glutamatergic input are highly complex structures, and covered in tiny membranous protuberances called dendritic spines. Spines house the postsynaptic density and associated protein machinery that constitutes the post-synaptic side of the synapse. These include receptors for neurotransmitters, voltage-activated ion channels, scaffolding proteins, calcium (Ca) sensors, and many other signaling molecules. The regulation of synapses, which occurs in part by adjusting the postsynaptic responses to glutamate release, is thought to underlie higher-order processes such as learning and memory. However, understanding how the action and regulation of proteins in the dendritic spine contributes to synaptic function and plasticity is a major challenge in modern neuroscience. In this thesis, we investigated two major mechanisms of post-synaptic regulation at the CA3 to CA1 synapse in the mouse hippocampus.

Dendritic spines are separated from their parent dendrites by a thin, ∼0.1 micron long neck – a morphological feature that intuitively suggests it might function to limit the transmission of electrical and biochemical signals. To elucidate the role of the spine neck in regulating synaptic signals, we use spatiotemporally controlled stimulation to generate calcium signals within the spine head and/or neighboring dendrite. By comparing these measurements we demonstrate that spines create specialized electrical signaling compartments, which has at least two functional consequences. First, this allows for the selective activation of voltage-gated calcium channels within the spine head. Second, voltage changes in the spine head arising from compartmentalization shape the time course of synaptically evoked calcium influx such that it is biphasic.

Within the hippocampus, activation of muscarinic cholinergic receptors enhance synaptic transmission and forms of long-term potentiation, but the mechanism of modulations has remained unclear. By directly stimulating spines via 2-photon uncaging of glutamate, we found that excitatory post-synaptic potentials and Ca transients are increased by muscarinic stimulation; however, this was not due to direct modulation of glutamate receptors. Instead, mAChRs activation reduces the Ca sensitivity of small conductance Ca-activated potassium (SK) channels that are found in the spine, resulting in increased synaptic potentials and Ca transients. Thus, muscarinic modulation regulates synaptic transmission by tuning the activity of non-glutamatergic post-synaptic ion channels.