Salaka, R. J.; Chapman, E. R.

The hippocampal CA3 subfield is central to associative learning and memory consolidation. The principal cells of the CA3, pyramidal neurons, execute these functions by generating hypersynchronous bursts that feed forward to the CA1. Extensive recurrent collateral connections within the CA3 neuron population 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 synaptic vesicle (SV) release 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 spontaneous excitatory network activity remain unanswered. Using whole-cell recordings in disinhibited acute hippocampal slices obtained from juvenile Doc2- and Syt7- knockout (KO) mice (P15-21), we report increased CA3 burst generation without changes in spontaneous excitatory postsynaptic current (sEPSC) frequency or amplitude. Moreover, the intrinsic properties of CA3 pyramidal neurons, such as the resting membrane potential, firing rate and input resistance, are unchanged. We propose that this novel burst phenotype in Doc2- and Syt7- KO mice is unrelated to changes in SV release but might be mediated by changes in neuropeptide release from DCVs. Regardless of the underlying mechanisms, this work reveals that both proteins act to regulate network activity. The hippocampal CA3 subfield is central to associative learning and memory consolidation. The principal cells of the CA3, pyramidal neurons, execute these functions by generating hypersynchronous bursts that feed forward to the CA1. Extensive recurrent collateral connections within the CA3 neuron population 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 synaptic vesicle (SV) release 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 spontaneous excitatory network activity remain unanswered. Using whole-cell recordings in disinhibited acute hippocampal slices obtained from juvenile Doc2- and Syt7- knockout (KO) mice (P15-21), we report increased CA3 burst generation without changes in spontaneous excitatory postsynaptic current (sEPSC) frequency or amplitude. Moreover, the intrinsic properties of CA3 pyramidal neurons, such as the resting membrane potential, firing rate and input resistance, are unchanged. We propose that this novel burst phenotype in Doc2- and Syt7- KO mice is unrelated to changes in SV release but might be mediated by changes in neuropeptide release from DCVs. Regardless of the underlying mechanisms, this work reveals that both proteins act to regulate network activity.