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.

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...

Acetylcholine release in the hippocampus plays a central role in the formation of new memory representations. An influential but largely untested theory proposes that memory formation requires acetylcholine to enhance responses in CA1 to new sensory information from entorhinal cortex whilst depressing inputs from previously encoded representations in CA3. Here, we show that excitatory inputs from entorhinal cortex and CA3 are depressed equally by synaptic release of acetylcholine in CA1. However, feedforward inhibition from entorhinal cortex exhibits greater depression than CA3 resulting in a selective enhancement of excitatory-inhibitory balance and CA1 activation by entorhinal inputs. Entorhinal and CA3 pathways engage different feedforward interneuron subpopulations and cholinergic modulation of presynaptic function is mediated differentially by muscarinic M3 and M4 receptors, respectively. Thus, our data support a role and mechanisms for acetylcholine to prioritise novel information inputs to CA1 during memory formation.

Acetylcholine release in the hippocampus plays a central role in the formation of new memory representations by facilitating synaptic plasticity. It is also proposed that memory formation requires acetylcholine to enhance responses in CA1 to new sensory information from entorhinal cortex whilst depressing inputs from previously encoded representations in CA3, but this influential theory has not been directly tested. Here, we show that excitatory inputs from entorhinal cortex and CA3 are depressed equally by synaptic release of acetylcholine in CA1. However, greater depression of feedforward inhibition from entorhinal cortex results in an overall enhancement of excitatory-inhibitory balance and CA1 activation. Underpinning the prioritisation of entorhinal inputs, entorhinal and CA3 pathways engage distinct feedforward interneuron subpopulations and depression is mediated differentially by presynaptic muscarinic M3 and M4 receptors respectively. These mechanisms enable acetylcholine to prioritise novel information inputs to CA1 during memory formation and suggest selective muscarinic targets for therapeutic intervention.

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