In accordance with the proposed goals, we investigated the mechanisms and relevance of dendritic spikes and complex spike bursts (CSBs) in CA3PC functions.
We discovered that the propensity of CA3PCs to fire CSBs is highly heterogeneous and is regulated differently depending on the topographic position of cells within the area. We pinpointed two specific dendritic ion channel types whose region-specific activity partly explains the topographic modulation of CSB propensity. We uncovered that the synaptic input-output transformation rules triggering CSBs are non-uniform among CA3PCs: CSBs serve as an associative input pathway signal in regular spiking (RS) cells but can be triggered by any input type clustered in any individual dendritic branch in CSB-firing cells.
Using direct dendritic recordings we discovered that, unlike in other PC types, individual distal apical dendrites of CA3PCs can express two distinct spatiotemporal forms of dendritic Ca2+ spikes (a slow global and a novel fast compartmentalized type) and revealed that these distinct Ca2+ spike forms have opposing impacts on somatic firing, promoting either CSBs or strictly single action potentials, respectively.
We showed that the compound Ca2+ spike form, as measured at the soma, is also highly heterogeneous, and that a subpopulation of CA3PCs expresses dominantly short-duration Ca2+ spikes and cannot sustain prolonged CSBs under baseline conditions. Using pharmacological tools we characterized the ion channels underlying the variability of the dendritic Ca2+ spike forms. We discovered prominent regulation of the Ca2+ form by cholinergic neuromodulation, which prolongs Ca2+ spikes and promotes CSB firing, primarily in a subpopulation of CA3PCs. This mechanism may allow state-dependent, subtype-specific contribution of active dendrites to CA3PC computations.
We have established an in vivo (two-photon microscope combined with virtual reality) system for imaging hippocampal CA1 and CA3 PCs, developed software tools to program data acquisition protocols and monitor behavioral performance, and worked out spatial context discrimination training paradigms. In experiments in head-fixed mice navigating in various virtual spatial contexts, we have imaged the activity of populations of PCs or subcellular compartments of individual PCs and investigated the forms of dendritic activity and their roles in neuronal activity and tuning.
Using novel computational and experimental approaches we demonstrated how long-term synaptic plasticity depends on the spatial pattern of inputs as well as local and global dendritic integrative mechanisms in hippocampal neurons.
The results arising from the project have been presented at several prominent scientific conferences and in part have been published (or are in the process of publication) in prestigious neuroscience journals.
