ABSTRACT
A strong GABAergic tone imposes sparse levels of activity in the dentate gyrus of the hippocampus. This balance is challenged by the addition of new granule cells (GCs) with high excitability. How developing GCs integrate within local inhibitory networks remains unknown. We used optogenetics to study synaptogenesis between new GCs and GABAergic interneurons expressing parvalbumin (PV-INs) and somatostatin (SST-INs). PV-INs target the soma, and synapses become mature after 6 weeks. This transition is accelerated by exposure to an enriched environment. PV-INs exert efficient control of GC spiking and participate in both feedforward and feedback loops, a mechanism that would favor lateral inhibition and sparse coding. SST-INs target the dendrites, and synapses mature after 8 weeks. Outputs from GCs onto PV-INs develop faster than those onto SST-INs. Our results reveal a long-lasting transition wherein adult-born neurons remain poorly coupled to inhibition, which might enhance activity-dependent plasticity of input and output synapses.
Subject(s)
Aging/metabolism , Cytoplasmic Granules/metabolism , Interneurons/metabolism , Parvalbumins/metabolism , Somatostatin/metabolism , Animals , GABAergic Neurons/metabolism , HEK293 Cells , Humans , Mice , Neural Inhibition , Neurogenesis , Neuronal Plasticity , Subcellular Fractions/metabolism , Synapses/metabolismABSTRACT
Newly generated dentate granule cells (GCs) are relevant for input discrimination in the adult hippocampus. Yet, their precise contribution to information processing remains unclear. To address this question, it is essential to develop approaches to precisely label entire cohorts of adult-born GCs. In this work, we used genetically modified mice to allow conditional expression of tdTomato (Tom) in adult-born GCs and characterized their development and functional integration. Ascl1(CreERT2);CAG(floxStopTom) and Glast(CreERT2);CAG(floxStopTom) mice resulted in indelible expression of Tom in adult neural stem cells and their lineage upon tamoxifen induction. Whole-cell recordings were performed to measure intrinsic excitability, firing behavior, and afferent excitatory connectivity. Developing GCs were also staged by the expression of early and late neuronal markers. The slow development of adult-born GCs characterized here is consistent with previous reports using retroviral approaches that have revealed that a mature phenotype is typically achieved after 6-8 weeks. Our findings demonstrate that Ascl1(CreERT2) and Glast(CreERT2) mouse lines enable simple and reliable labeling of adult-born GC lineages within restricted time windows. Therefore, these mice greatly facilitate tagging new neurons and manipulating their activity, required for understanding adult neurogenesis in the context of network remodeling, learning, and behavior. SIGNIFICANCE STATEMENT: Our study shows that Ascl1(CreERT2) and Glast(CreERT2) mice lines can be used to label large cohorts of adult-born dentate granule cells with excellent time resolution. Neurons labeled in this manner display developmental and functional profiles that are in full agreement with previous findings using thymidine analogs and retroviral labeling, thus providing an alternative approach to tackle fundamental questions on circuit remodeling. Because of the massive neuronal targeting and the simplicity of this method, genetic labeling will contribute to expand research on adult neurogenesis.
Subject(s)
Action Potentials/physiology , Basic Helix-Loop-Helix Transcription Factors/metabolism , Dentate Gyrus/cytology , Excitatory Amino Acid Transporter 1/metabolism , Neurogenesis/physiology , Neurons/physiology , Action Potentials/drug effects , Animals , Animals, Newborn , Basic Helix-Loop-Helix Transcription Factors/genetics , Calbindin 1/metabolism , Computer Simulation , Estrogen Antagonists/pharmacology , Excitatory Amino Acid Transporter 1/deficiency , Excitatory Postsynaptic Potentials/drug effects , Excitatory Postsynaptic Potentials/genetics , Female , In Vitro Techniques , Integrases/genetics , Integrases/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Models, Neurological , Nerve Tissue Proteins/metabolism , Neurogenesis/drug effects , Neurons/classification , Neurons/drug effects , RNA, Untranslated/genetics , RNA, Untranslated/metabolism , Tamoxifen/pharmacologyABSTRACT
Throughout the adult life of all mammals including humans, new neurons are incorporated to the dentate gyrus of the hippocampus. During a critical window that lasts about two weeks, adult-born immature neurons are more excitable and plastic than mature ones, and they respond to a wider range of inputs. In apparent contradiction, new neurons have been shown to be crucial to solve behavioral tasks that involve the discrimination of very similar situations, which would instead require high input specificity. We propose that immature neurons are initially unspecific because their task is to identify novel elements inside a high dimensional input space. With maturation, they would specialize to represent details of these novel inputs, favoring discrimination.
Subject(s)
Dentate Gyrus/physiology , Memory/physiology , Nerve Net/physiology , Neural Networks, Computer , Neurogenesis/physiology , Neurons/physiology , Adult , Animals , Dentate Gyrus/cytology , Humans , Neurons/cytologyABSTRACT
Developing granule cells (GCs) of the adult dentate gyrus undergo a critical period of enhanced activity and synaptic plasticity before becoming mature. The impact of developing GCs on the activity of preexisting dentate circuits remains unknown. Here we combine optogenetics, acute slice electrophysiology, and in vivo chemogenetics to activate GCs at different stages of maturation to study the recruitment of local target networks. We show that immature (4-week-old) GCs can efficiently drive distal CA3 targets but poorly activate proximal interneurons responsible for feedback inhibition (FBI). As new GCs transition toward maturity, they reliably recruit GABAergic feedback loops that restrict spiking of neighbor GCs, a mechanism that would promote sparse coding. Such inhibitory loop impinges only weakly in new cohorts of young GCs. A computational model reveals that the delayed coupling of new GCs to FBI could be crucial to achieve a fine-grain representation of novel inputs in the dentate gyrus.