Interplay of synaptic and backpropagating signals in neurogliaform dendrites
Inhibitory interneurons are conventionally thought to support precise timing of neural activity and regulation of circuit excitability, whilst principal neurons are the main locus of synaptic plasticity. Recent evidence for long-term potentiation (LTP) at glutamatergic synapses on GABAergic interneurons calls for close attention to the sub-cellular phenomena that underlie the induction of plasticity in aspiny dendrites. Neurogliaform interneurons, in particular, exhibit large NMDA receptor-mediated currents, robust Hebbian LTP and pronounced supralinear summation of glutamatergic signals converging on dendritic compartments. Unlike pyramidal neurons, however, dendritic supralinearity in interneurons operates independently of sodium channels. Here we investigate the principles governing supralinear synaptic integration and how it interacts with backpropagating action potentials in the context of synaptic plasticity. We developed a biophysically realistic, multi-compartmental model of a murine hippocampal neurogliaform interneuron, with dendritic architecture and ion channel densities tuned to match ex vivo recordings. The interaction of synaptic inputs and action potential were validated with patch-clamp electrophysiology and two-photon imaging of dendritic calcium-dependent fluorescence transients. We show that, whether simulated glutamatergic excitatory postsynaptic potentials are clustered on a dendritic fragment or dispersed across the entire arbor, they summate supralinearly as assessed from the calculated somatic voltage response. Clustered inputs however induce more pronounced local depolarizations and calcium transients than dispersed inputs. Action potentials generated at the soma backpropagate throughout the dendritic arbor but are attenuated at branch points. Coincident synaptic input and backpropagating action potentials relieve this attenuation, further enhance dendritic depolarizations, and greatly potentiate calcium influx via NMDA receptors. Despite differences in dendritic anatomy and in the roles of sodium channels, the interplay of orthodromic and antidromic voltage propagation and resultant calcium signal amplification exhibits remarkable similarities between neurogliaform interneurons and principal cells. Author summaryLearning and memory are believed to rely in large part on the brains ability to strengthen excitatory connections among principal cells. Potentiation of excitation must however be balanced by inhibition. Our study focuses on a key player in this balancing act: the neurogliaform interneuron, which exerts a powerful inhibition of the apical dendrites of principal neurons in the cortex and hippocampus. Recent work has revealed that both principal neurons and neurogliaform interneurons amplify coincident excitatory signals in their extensively branching dendrites. Key to the induction of synaptic potentiation is the coincidence of orthodromic depolarization arising from synapses and action potentials generated at or near the cell body. We asked how these electrical signals interact, using a blend of computer simulations and experimental manipulations. Unlike principal neurons, neurogliaform interneurons are devoid of dendritic spines, and voltage-gated sodium channels are dispensable for boosting of synaptic depolarization. Nevertheless, the core principle that coincident orthodromic and antidromic signals leads to widespread depolarization spreading throughout the dendritic arbor is conserved between these neurons. The conclusions of this work shed light not only on healthy brain function but also on common disorders such as epilepsy and schizophrenia, which abnormal dendritic function has been implicated.