The spine apparatus (SA), an endoplasmic reticulum-related organelle present in a subset of mature dendritic spines, plays a key role in postsynaptic development and has been implicated in various neurological disorders. However, the molecular mechanisms that dictate SA localization at selected synapses are poorly understood. Here, we identify a novel postsynaptic signaling complex comprising the GPCR-like receptor GPR158 and a largely uncharacterized phospholipase C (PLC), PLCXD2, that controls SA abundance. Sparse genetic manipulations in vivo demonstrate that in the absence of GPR158, unrestrained PLCXD2 activity impedes postsynaptic SA incorporation and hampers dendritic spine maturation. Finally, we show that extracellular heparan sulfate proteoglycan (HSPG) binding modulates the GPR158-PLCXD2 interaction. Thus, our findings uncover a novel molecular mechanism through which cell-surface localized GPR158 cell-autonomously signals via PLCXD2 to control postsynaptic SA content and the proper maturation of dendritic spines.

Alzheimer’s disease (AD) patients suffer from severe comorbidities including depression and movement disorders which could arise from dysfunctional dopamine release from subcortical areas. Dopamine is tonically released throughout the brain to maintain homeostatic functions. This tonic activity, governed by spontaneous pacemaker activity, can be modulated to release more or less of the neurotransmitter in response to internal and environmental stimuli. In the 3xTg-AD model, mice largely failed to learn a dopamine dependent behavioral task. To probe potential physiological determinates, we used patch clamp electrophysiology in 3xTg-AD brain slices. We show that altered balance between intrinsic, excitatory, and inhibitory signals drive dopamine neurons into a hyperexcitable state. At late pathological stages, global inhibitory input decreases in frequency, with no apparent pre-synaptic alteration. In contrast, excitatory input appears to robustly increase in both amplitude and frequency. Interestingly, paired pulse ratio experiments suggest a shift in the glutamate release probability in the 3xTg-AD mice. In addition to a move toward heightened synaptic excitation, dopamine neurons also exhibit an intrinsic shift towards hyperexcitability described by increased spontaneous firing and response to somatic current injection. Leveraging Patch-seq and pharmacology, we determined the increase in cell-autonomous hyperexcitability is caused by excessive calmodulin phosphorylation of plasmalemmal calcium activated potassium channels. Inhibition of the responsible kinase, CK2, completely ameliorates excessive firing of DA neurons in 3xTg mice, providing the first step toward a potential disease-modifying intervention. Taken together, dopamine neurons in the 3xTg-AD model intrinsically and extrinsically boost their excitability, driven in part by druggable targets.

Neocortical interneurons are spectacularly diverse, yet little is known about how dendritic operations contribute to their functional diversity. Using two-photon glutamate uncaging and patch-clamp recordings, we observed two different modes of dendritic integration in parvalbumin and somatostatin positive interneurons (PV-INs and SST-INs). PV-INs display low NMDA receptors (NMDAR) density and perform sublinear integration of quasi-synchronous inputs while SST-INs perform supralinear NMDAR-dependent dendritic integration. Interestingly, differences in dendritic integration were coupled to distinct spatial organization of synapses along their dendritic trees. While synapse density is relatively uniform for SST-INs dendrites, it strongly decreases with distance from soma for PV-INs. According to model simulations, the combination of these dendritic properties endows PV- and SST-INs with different strategies for optimizing signal transmission in thin dendritic structures and leads to distinct processing of temporal features in both input and output signals. Finally, in agreement with model predictions, in vivo recordings in the primary visual cortex confirmed the role of NMDAR-dependent dendritic integration in shaping the functional features of SST-INs. Our work reveals a diversity of dendritic properties across interneurons that might greatly contribute to their specific function in neocortical circuits.