Mercier, Marion S; Magloire, Vincent; Cornford, Jonathan H; Kullmann, Dimitri M; (2022) Long-term potentiation in neurogliaform interneurons modulates excitation-inhibition balance in the temporoammonic pathway. Journal of Physiology , 600 (17) pp. 4001-4017. 10.1113/JP282753.

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Abstract

Apical dendrites of pyramidal neurons integrate information from higher-order cortex and thalamus, and gate signalling and plasticity at proximal synapses. In the hippocampus, neurogliaform cells and other interneurons located within stratum lacunosum-moleculare mediate powerful inhibition of CA1 pyramidal neuron distal dendrites. Is the recruitment of such inhibition itself subject to use-dependent plasticity, and if so, what induction rules apply? Here we show that interneurons in mouse stratum lacunosum-moleculare exhibit Hebbian NMDA receptor-dependent long-term potentiation (LTP). Such plasticity can be induced by selective optogenetic stimulation of afferents in the temporoammonic pathway from the entorhinal cortex, but not by equivalent stimulation of afferents from the thalamic nucleus reuniens. We further show that theta-burst patterns of afferent firing induces LTP in neurogliaform interneurons identified using neuron-derived neurotrophic factor (Ndnf)-Cre mice. Theta-burst activity of entorhinal cortex afferents led to an increase in disynaptic feed-forward inhibition, but not monosynaptic excitation, of CA1 pyramidal neurons. Activity-dependent synaptic plasticity in stratum lacunosum-moleculare interneurons thus alters the excitation-inhibition balance at entorhinal cortex inputs to the apical dendrites of pyramidal neurons, implying a dynamic role for these interneurons in gating CA1 dendritic computations. Abstract figure legend Hebbian LTP of excitatory transmission onto interneurons located within hippocampal stratum lacunosum moleculare (SLM) can be induced by electrical stimulation protocols involving pairing of pre-and post-synaptic activity. Using Ndnf-Cre mice, we show that hippocampal neurogliaform (NGF) cells express this form of LTP. These cells receive glutamatergic afferents from both the nucleus reuniens of the thalamus and the entorhinal cortex (EC), but selective optogenetic activation of either set of fibers reveals LTP at EC inputs only. Using an optogenetic theta-burst stimulation (OptoTBS) protocol to stimulate EC fibers in a physiologically relevant way, we show that NGF interneuron LTP translates to an increase in disynaptic inhibition onto CA1 pyramidal cell distal dendrites. Monosynaptic EC-CA1 pyramidal cell inputs do not undergo equivalent potentiation, leading to a net decrease in the excitation/inhibition (E/I) ratio of this pathway.

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