Year: 2026
Type: preprint
Abstract: ABSTRACT The hippocampal CA3 subfield is central to associative learning and memory consolidation. CA3 pyramidal neurons execute these functions by generating hypersynchronous bursts that feed forward to the CA1. Extensive recurrent collateral connections within CA3 are crucial for the generation of this burst activity. Double C2 domain-containing protein α (Doc2α) and synaptotagmin 7 (Syt7) are high-affinity calcium sensors implicated in asynchronous release (AR) of neurotransmitter and in the exocytosis of dense-core vesicles (DCVs). Additionally, Doc2α is a sensor for miniature neurotransmission, whereas Syt7 is involved in synaptic facilitation and SV replenishment. Both Doc2α and Syt7 are expressed in the hippocampus, but their potential roles in spontaneously bursting networks, like CA3, remain unanswered. Using whole-cell recordings at near physiological conditions (33-34 °C and 1.2 mM Ca 2+ ) in acute hippocampal slices obtained from juvenile (P15-21) KO mice lacking Doc2α, Syt7, or both proteins, we report no changes in spontaneous inhibitory or excitatory postsynaptic current frequency or amplitude in CA1 pyramidal neurons. However, there was a marked increase in burst activity, originating in CA3, in all three KO conditions; this was not due to changes in AR or the intrinsic properties of CA3 pyramidal neurons. We propose that this novel burst phenotype in Doc2α- and Syt7-KO mice is unrelated to changes in neurotransmitter release but might be mediated by changes in neuropeptide release from DCVs in the CA3 subfield, or along upstream pathways. Regardless of the underlying mechanisms, this work reveals that both Doc2α and Syt7 act to regulate network activity. KEY FINDINGS Hippocampal CA3 burst activity is critical for associative learning and memory consolidation Doc2α and Syt7 are high-affinity Ca 2+ sensors with similar kinetic properties and are expressed in the hippocampus Doc2α and Syt7 support various modes of neurotransmitter release and presynaptic plasticity Both Doc2α and Syt7 are also involved in the exocytosis of dense-core vesicles in neuroendocrine cells Loss of Doc2α and Syt7 results in increased CA3 burst activity without changing AR or the intrinsic properties of CA3 neurons Our results suggest a novel role for Doc2α and Syt7 in regulating CA3 burst activity GRAPHICAL ABSTRACT The hippocampal CA3 subfield forms an extensive recurrent collateral network enabling the generation of hypersynchronous bursts. In knockout (KO) mice lacking Doc2α, Syt7, or both proteins, there is an increase in CA3 burst activity. In this study, we hypothesize that this increase is likely due to alterations in dense-core vesicle-mediated control of burst activity.
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7167514805