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Compartment-specific tuning of dendritic feature selectivity by intracellular Ca2+ release

Justin K. O’Hare,Kevin C. Gonzalez,Stephanie Herrlinger,Y. Hirabayashi,Victoria L. Hewitt,Heike Blockus,Miklos Szoboszlay,Sebi V. Rolotti,T. Geiller,Adrian Negrean,Vikas Chelur,F. Polleux,A. Losonczy

Published 2022 in Science

ABSTRACT

Dendritic calcium signaling is central to neural plasticity mechanisms that allow animals to adapt to the environment. Intracellular calcium release (ICR) from the endoplasmic reticulum has long been thought to shape these mechanisms. However, ICR has not been investigated in mammalian neurons in vivo. We combined electroporation of single CA1 pyramidal neurons, simultaneous imaging of dendritic and somatic activity during spatial navigation, optogenetic place field induction, and acute genetic augmentation of ICR cytosolic impact to reveal that ICR supports the establishment of dendritic feature selectivity and shapes integrative properties determining output-level receptive fields. This role for ICR was more prominent in apical than in basal dendrites. Thus, ICR cooperates with circuit-level architecture in vivo to promote the emergence of behaviorally relevant plasticity in a compartment-specific manner. Description Calcium release and neuronal plasticity What is the role of intracellular calcium release from the endoplasmatic reticulum in neuronal signal processing and in the formation of hippocampal place fields? O’Hare et al. used single-cell viral delivery techniques, optogenetics, and in vivo calcium imaging to simultaneously record dendritic and somatic activity of area CA1 pyramidal neurons. Increasing intracellular calcium release increased spatial tuning in apical and, to a lesser extent, in basal CA1 pyramidal cell dendrites. This activity in turn changed place cell responses during learning and memory storage. Intracellular calcium release in concert with circuit-level anatomical features thus shapes and promotes somatic feature selectivity in vivo. —PRS Intracellular calcium release orchestrates subcellular, cellular, and circuit architecture to shape learning in the hippocampus. INTRODUCTION Synaptic plasticity, the process by which neurons adjust the strengths of their thousands of inputs, allows animals to adapt to their environment. Decades of research have established Ca2+ as a central mediator of synaptic plasticity. Historically, most investigations into the role of Ca2+ in plasticity have focused on its influx through voltage-gated channels that open when synaptic input depolarizes a neuron. However, a large body of in vitro research suggests that an alternate source of Ca2+ may also play a potent role in shaping plasticity: the endoplasmic reticulum (ER). The ER stores Ca2+ in vast quantities within a cell and can release this store in response to strong synaptic input through intracellular Ca2+ release (ICR). The ER is therefore poised to shape the magnitude and spatial distribution of Ca2+ during plasticity induction. Despite its potential role in synaptic plasticity, ICR has never been investigated in mammalian neurons in vivo. RATIONALE To test whether ICR participates in experience-dependent plasticity, we focused on pyramidal neurons of hippocampal area CA1 (CA1PNs). CA1PNs receive excitatory inputs from multiple afferent circuits, carrying complementary streams of information about an animal’s environment that impinge onto distinct compartments of the CA1PN dendritic arbor. As an animal explores a new environment, CA1PNs integrate these inputs to form spatially tuned receptive fields known as place fields that manifest as a neuron firing when an animal occupies a particular location. Recent work has characterized an in vivo plasticity mechanism driving place field formation: behavioral time-scale plasticity (BTSP). BTSP is initiated by a large, prolonged dendritic depolarization (plateau potential) that ultimately potentiates synaptic inputs received during a seconds-long time window corresponding to the time of plateau onset. Here, we used CA1PNs and BTSP as a model system to test whether ICR participates in the experience-dependent emergence of feature selectivity. We implemented a series of tools based on single-cell electroporation allowing us to (i) manipulate the cytosolic impact of ICR at single-cell resolution using conditional gene deletion, (ii) optogenetically induce place cells, and (iii) image somatic and dendritic Ca2+ dynamics simultaneously during spatial navigation. RESULTS The gene Pdzd8 encodes a recently identified ER-mitochondrial tethering protein that, when deleted, leads to unrestricted ICR. We found that Pdzd8 deletion in single adult CA1PNs in vivo substantially increased the level of spatial co-tuning observed in their apical dendrites relative to the soma of CA1 place cells, a phenomenon not observed in basal dendrites, which were already highly co-tuned with the soma in control CA1PNs. Maximizing ICR leads to more-stable retention of place cell spatial tuning over time and alters the integrative properties of their apical dendrites to shape output-level receptive fields. CONCLUSION ICR plays a key and previously uncharacterized role in shaping the dendritic integration properties of CA1PNs during the emergence of feature selectivity. Therefore, ICR cooperates with circuit-level architecture in vivo to promote the emergence of behaviorally relevant forms of plasticity in a compartment-specific manner. ICR shapes receptive fields important for spatial navigation. We tested the role of ICR in neuronal feature selectivity by genetically ablating contact sites between ER and mitochondria (Mito) in single pyramidal neurons of hippocampal area CA1 in vivo. Increasing the impact of ICR on cytoplasmic Ca2+ altered integrative properties in apical dendrites, widening and stabilizing “place fields” over time. Illustration by Matteo Farinella

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