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The development, maturation, and plasticity of neural circuits are strongly influenced by experience and the interaction of an individual with their environment can have a long-lasting effect on cognitive function. Using an enriched environment (EE) paradigm, we have recently demonstrated that enhancing social, physical, and sensory activity during the pre-weaning time in mice led to an increase of inhibitory and excitatory synapses in the dentate gyrus (DG) of the hippocampus. The structural plasticity induced by experience may affect information processing in the circuit. The DG performs pattern separation, a computation that enables the encoding of very similar and overlapping inputs into dissimilar outputs. In the presented study, we have tested the hypothesis that an EE in juvenile mice will affect DG's functions that are relevant for pattern separation: the decorrelation of the inputs from the entorhinal cortex (EC) and the recruitment of the principal excitatory granule cell (GC) during behavior. First, using a novel slice electrophysiology protocol, we found that the transformation of the incoming signal from the EC afferents by individual GC is moderately affected by EE. We further show that EE does not affect behaviorally induced recruitment of principal excitatory GC. Lastly, using the novel object recognition task, a hippocampus-dependent memory test, we show that the ontogeny of this discrimination task was similar among the EE mice and the controls. Taken together, our work demonstrates that pre-weaning enrichment moderately affects DG function., (© 2022. The Author(s).)

The majority of mouse and human genes are subject to alternative cleavage and polyadenylation (APA), which most often leads to the expression of two or more alternative length 3' untranslated region (3'-UTR) mRNA isoforms. In neural tissues, there is enhanced expression of APA isoforms with longer 3'-UTRs on a global scale, but the physiological relevance of these alternative 3'-UTR isoforms is poorly understood. Calmodulin 1 ( Calm1) is a key integrator of calcium signaling that generates short ( Calm1-S ) and long ( Calm1-L ) 3'-UTR mRNA isoforms via APA. We found Calm1-L expression to be largely restricted to neural tissues in mice including the dorsal root ganglion (DRG) and hippocampus, whereas Calm1-S was more broadly expressed. smFISH revealed that both Calm1-S and Calm1-L were subcellularly localized to neural processes of primary hippocampal neurons. In contrast, cultured DRG showed restriction of Calm1-L to soma. To investigate the in vivo functions of Calm1-L , we implemented a CRISPR-Cas9 gene editing strategy to delete a small region encompassing the Calm1 distal poly(A) site. This eliminated Calm1-L expression while maintaining expression of Calm1-S Mice lacking Calm1-L ( Calm1 ΔL/ΔL ) exhibited disorganized DRG migration in embryos, and reduced experience-induced neuronal activation in the adult hippocampus. These data indicate that Calm1-L plays functional roles in the central and peripheral nervous systems., (© 2020 Bae et al.; Published by Cold Spring Harbor Laboratory Press for the RNA Society.)

Functional NMDA and AMPA ionotropic glutamate receptors are expressed in embryonic hippocampal glutamatergic pyramidal neurons prior to synapse formation but their function and mechanisms of action are still unclear. At the same time, these neurons develop their calbindin-D(28k) phenotype through an activity-dependent NT-3 autocrine loop. Using single-neuron microcultures, we show here that immature pyramidal neurons spontaneously secreted glutamate and that chronic blockade of either NMDA or AMPA receptors down-regulated the number of calbindin-D(28k)-positive pyramidal neurons without affecting neuronal survival. This antagonistic effect of glutamate ionotropic receptors was mimicked by anti-TrkC antibodies and reversed by the application of NT-3. Similar results were obtained in ex vivo embryonic hippocampal slice cultures. Moreover, glutamate receptor blockade inhibited the generation of spontaneous sodium-driven action potentials which, in turn, regulate both the endogenous secretion of NT-3 and the calbindin-D(28k) phenotype acquisition. Altogether, these results suggest an unexpected role for glutamate in the development of the physiological and biochemical properties of hippocampal pyramidal neurons and support the idea that glutamate may underlie an activity-dependent mode of differentiation prior to synapse formation.