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Bernstein Conference 2022 abstract. http://bernstein-conference.de

A balanced and fine-tuned ratio of neuronal excitation and inhibition is a prerequisite for information processing. In this issue of Neuron, He et al. (2022) reveal a causal link between reduced input to local somatostatin-expressing, MeCP2-negative O-LM interneurons in CA1 and long-term memory impairment in a mouse model of Rett syndrome.

Rewiring neural circuits by the formation and elimination of synapses is thought to be a key cellular mechanism of learning and memory in the mammalian brain. Dendritic spines are the postsynaptic structural component of excitatory synapses, and their experience-dependent plasticity has been extensively studied in mouse superficial cortex using two-photon microscopy in vivo. By contrast, very little is known about spine plasticity in the hippocampus, which is the archetypical memory center of the brain, mostly because it is difficult to visualize dendritic spines in this deeply embedded structure with sufficient spatial resolution. We developed chronic 2P-STED microscopy in mouse hippocampus, using a 'hippocampal window' based on resection of cortical tissue and a long working distance objective for optical access. We observed a two-fold higher spine density than previous studies and measured a spine turnover of ~40% within 4 days, which depended on spine size. We thus provide direct evidence for a high level of structural rewiring of synaptic circuits and new insights into the structure-dynamics relationship of hippocampal spines. Having established chronic super-resolution microscopy in the hippocampus in vivo, our study enables longitudinal and correlative analyses of nanoscale neuroanatomical structures with genetic, molecular and behavioral experiments.

Alzheimer's disease (AD) is characterized by synaptic dysfunction and progressive memory loss. The hippocampus is indispensable for memory processes and early affected by diseaseassociated pathology. It is still debated how in particular encoding and retrieval of memories is impaired in AD. Therefore, the current study investigated how individual neurons in the hippocampus encode a memory and whether this process is disturbed under AD-like conditions in a pre-clinical model. To achieve this goal a cutting-edge technology – twophoton in vivo imaging - was used to repetitively analyze the activity of neurons in the hippocampus throughout a hippocampus-dependent memory test. Initially, this study revealed two populations of hippocampal CAl neurons that differ in their long-term activity: a subset of neurons was continuously active over several days, whereas another population showed variable activity. The latter provided the population that responded to memory encoding as well as retrieval and hence, formed the cellular memory trace, also known as engram. Interestingly, network activity and engram formation under AD-like conditions (APP/PSl mice) was intact. However, a further analysis of neurons composing the "retrieval network" identified an additional neuronal ensemble in CAl that superimposed the memory trace suggesting a causal relationship of memory trace superimposition and memory impairment. Indeed, mimicking superimposition by artificial activation of a non-related memory trace coding a different context caused reduced memory performance in healthy mice and thus, presents a potential mechanism for impaired memory retrieval in APP/PSl mice. Furthermore, parvalbumin-expressing (PV+) interneurons in CAl were indispensable for successful memory encoding and retrieval in healthy mice. Their functional impairment represented a potential explanation of the observed engram superimposition in APP/PSl mice. Finally, a learningrelated loss of synaptic connections was discovered on dendrites of CAl pyramidal neurons in healthy mice suggesting a mechanism of synaptic selection important for encoding of new information. Learning-induced changes of synaptic connectivity were absent in APP/PSl mice indicating that synaptic connectivity deficits might be causally related to memory trace superimposition and ultimately memory impairment under AD-like conditions. Summarized, the present study provides a refinement of the engram's characteristics and furthermore, identifies a novel mechanism of memory impairment on the cellular and synaptic level in a mouse model of AD.

In vivo imaging represents a powerful tool to study microglia in their natural environment, which led to the discovery of their fine-process motility. Moreover, imaging of microglia in relation to blood vessels and neurons revealed important physiological and pathological functions. Up to now, microglia have been analyzed in superficial cortical areas of anesthetized mice. Despite the importance of the hippocampus for learning and memory, knowledge about microglia motility and interaction with neurons is scarce for this brain region. Moreover, the influence of anesthesia on microglia motility remains unknown. Here we present a novel technological approach to perform in vivo imaging of microglia and neurons in the hippocampus. This preparation will enable the recording of microglia motility in awake mice during learning and memory processes.