The formation and maintenance of spatial representations within hippocampal cell assemblies is strongly dictated by patterns of inhibition from diverse interneuron populations. Although it is known that inhibitory synaptic strength is malleable, induction of long-term plasticity at distinct inhibitory synapses and its regulation of hippocampal network activity is not well understood. Here, we show that inhibitory synapses from parvalbumin and somatostatin expressing interneurons undergo long-term depression and potentiation respectively (PV-iLTD and SST-iLTP) during physiological activity patterns. Both forms of plasticity rely on T-type calcium channel activation to confer synapse specificity but otherwise employ distinct mechanisms. Since parvalbumin and somatostatin interneurons preferentially target perisomatic and distal dendritic regions respectively of CA1 pyramidal cells, PV-iLTD and SST-iLTP coordinate a reprioritisation of excitatory inputs from entorhinal cortex and CA3. Furthermore, circuit-level modelling reveals that PV-iLTD and SST-iLTP cooperate to stabilise place cells while facilitating representation of multiple unique environments within the hippocampal network.

SummaryActivity-dependent synaptic plasticity is critical for cortical circuit refinement. The synaptic homeostasis hypothesis suggests that synaptic connections are strengthened during wake and downscaled during sleep; however, it is not obvious how the same plasticity rules could explain both outcomes. Using whole-cell recordings and optogenetic stimulation of presynaptic input in urethane-anesthetized mice, which exhibit slow-wave-sleep (SWS)-like activity, we show that synaptic plasticity rules are gated by cortical dynamics in vivo. While Down states support conventional spike timing-dependent plasticity, Up states are biased toward depression such that presynaptic stimulation alone leads to synaptic depression, while connections contributing to postsynaptic spiking are protected against this synaptic weakening. We find that this novel activity-dependent and input-specific downscaling mechanism has two important computational advantages: (1) improved signal-to-noise ratio, and (2) preservation of previously stored information. Thus, these synaptic plasticity rules provide an attractive mechanism for SWS-related synaptic downscaling and circuit refinement.

22The formation and maintenance of spatial representations within hippocampal cell assemblies 23 is strongly dictated by patterns of inhibition from diverse interneuron populations. Although it 24 is known that inhibitory synaptic strength is malleable, induction of long-term plasticity at 25 distinct inhibitory synapses and its regulation of hippocampal network activity is not well 26 understood. Here, we show that inhibitory synapses from parvalbumin and somatostatin 27 expressing interneurons undergo long-term depression and potentiation respectively (PV-iLTD 28 and SST-iLTP) during physiological activity patterns. Both forms of plasticity rely on T-type 29 calcium channel activation to confer synapse specificity but otherwise employ distinct 30 mechanisms. Since parvalbumin and somatostatin interneurons preferentially target 31 perisomatic and distal dendritic regions respectively of CA1 pyramidal cells, PV-iLTD and 32 SST-iLTP coordinate a reprioritisation of excitatory inputs from entorhinal cortex and CA3. 33 Furthermore, circuit-level modelling reveals that PV-iLTD and SST-iLTP cooperate to 34 stabilise place cells while facilitating representation of multiple unique environments within 35 the hippocampal network.36 37 38 39 Keywords 40 Hippocampus, inhibition, plasticity, parvalbumin, somatostatin, LTD, LTP, STDP T-type 41 calcium channel. 42 102 term inhibitory plasticity have profound effects on the output of CA1 pyramidal neurons and 103use computational modelling to demonstrate that these plasticity rules can provide a 104 mechanism by which hippocampal place fields can remain stable over time whilst flexibly 105 encoding location in multiple environments. 106 Results 107Divergent inhibitory plasticity at PV and SST synapses 108 To achieve subtype specific control of inhibitory interneurons, we selectively activated either 109 PV or SST interneurons by expressing the light-activated cation channel channelrhodopsin-2 110 (ChR2) in a cre-dependent manner using mice that expressed cre recombinase under control of 111 the promoter for either the parvalbumin gene (PV-cre) or somatostatin gene (SST-cre) crossed 112 with mice expressing cre-dependent ChR2 (PV-ChR2 and SST-ChR2 mice; methods). 113Immunohistochemisty confirmed that ChR2 expression was highest in the Stratum Pyramidal 114 (SP) and Stratum Oriens (SO) layers for PV-ChR2 mice with cell bodies principally located in 115 SP (Figure 1A). Conversely, ChR2 expression was highest in the SO and Stratum Lacunosum 116 Moleculare (SLM) layers for SST-ChR2 mice with cell bodies principally located in SO 117 (Figure 1B). These expression profiles are consistent with the established roles of PV and SST 118 interneurons providing perisomatic and dendritic inhibition respectively (Booker and Vida, 119 2018; Klausberger and Somogyi, 2008; Pelkey et al., 2017). To further confirm the spatially 120 distinct inhibitory targets, we recorded interneuron subtype-specific inhibitory currents onto 121 CA1 pyramidal neurons by activating ChR2 with 470nm blue light (Figu...