Increased CA3 burst activity in Doc2α and Syt7 knockout mice

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 (Doc2) 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, Doc2 is a sensor for miniature neurotransmission, whereas Syt7 is involved in synaptic facilitation and SV replenishment. Both Doc2 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 {degrees}C and 1.2 mM Ca2+) in acute hippocampal slices obtained from juvenile (P15-21) KO mice lacking Doc2, 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 Doc2- 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 Doc2 and Syt7 act to regulate network activity.