Synaptic and dendritic architecture of different types of hippocampal somatostatin interneurons.

GABAergic inhibitory neurons fundamentally shape the activity and plasticity of cortical circuits. A major subset of these neurons contains somatostatin (SOM); these cells play crucial roles in neuroplasticity, learning, and memory in many brain areas including the hippocampus, and are implicated in several neuropsychiatric diseases and neurodegenerative disorders. Two main types of SOM-containing cells in area CA1 of the hippocampus are oriens-lacunosum-moleculare (OLM) cells and hippocampo-septal (HS) cells. These cell types show many similarities in their soma-dendritic architecture, but they have different axonal targets, display different activity patterns in vivo, and are thought to have distinct network functions. However, a complete understanding of the functional roles of these interneurons requires a precise description of their intrinsic computational properties and their synaptic interactions. In the current study we generated, analyzed, and make available several key data sets that enable a quantitative comparison of various anatomical and physiological properties of OLM and HS cells in mouse. The data set includes detailed scanning electron microscopy (SEM)-based 3D reconstructions of OLM and HS cells along with their excitatory and inhibitory synaptic inputs. Combining this core data set with other anatomical data, patch-clamp electrophysiology, and compartmental modeling, we examined the precise morphological structure, inputs, outputs, and basic physiological properties of these cells. Our results highlight key differences between OLM and HS cells, particularly regarding the density and distribution of their synaptic inputs and mitochondria. For example, we estimated that an OLM cell receives about 8,400, whereas an HS cell about 15,600 synaptic inputs, about 16% of which are GABAergic. Our data and models provide insight into the possible basis of the different functionality of OLM and HS cell types and supply essential information for more detailed functional models of these neurons and the hippocampal network.

Amyloid ß induces interneuron-specific changes in the hippocampus of APPNL-F mice.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline and amyloid-beta (Aß) depositions generated by the proteolysis of amyloid precursor protein (APP) in the brain. In APPNL-F mice, APP gene was humanized and contains two familial AD mutations, and APP-unlike other mouse models of AD-is driven by the endogenous mouse APP promoter. Similar to people without apparent cognitive dysfunction but with heavy Aß plaque load, we found no significant decline in the working memory of adult APPNL-F mice, but these mice showed decline in the expression of normal anxiety. Using immunohistochemistry and 3D block-face scanning electron microscopy, we found no changes in GABAA receptor positivity and size of somatic and dendritic synapses of hippocampal interneurons. We did not find alterations in the level of expression of perineuronal nets around parvalbumin (PV) interneurons or in the density of PV- or somatostatin-positive hippocampal interneurons. However, in contrast to other investigated cell types, PV interneuron axons were occasionally mildly dystrophic around Aß plaques, and the synapses of PV-positive axon initial segment (AIS)-targeting interneurons were significantly enlarged. Our results suggest that PV interneurons are highly resistant to amyloidosis in APPNL-F mice and amyloid-induced increase in hippocampal pyramidal cell excitability may be compensated by PV-positive AIS-targeting cells. Mechanisms that make PV neurons more resilient could therefore be exploited in the treatment of AD for mitigating Aß-related inflammatory effects on neurons.

Median raphe controls acquisition of negative experience in the mouse.

Adverse events need to be quickly evaluated and memorized, yet how these processes are coordinated is poorly understood. We discovered a large population of excitatory neurons in mouse median raphe region (MRR) expressing vesicular glutamate transporter 2 (vGluT2) that received inputs from several negative experience-related brain centers, projected to the main aversion centers, and activated the septohippocampal system pivotal for learning of adverse events. These neurons were selectively activated by aversive but not rewarding stimuli. Their stimulation induced place aversion, aggression, depression-related anhedonia, and suppression of reward-seeking behavior and memory acquisition-promoting hippocampal theta oscillations. By contrast, their suppression impaired both contextual and cued fear memory formation. These results suggest that MRR vGluT2 neurons are crucial for the acquisition of negative experiences and may play a central role in depression-related mood disorders.