Social play behavior shapes the development of prefrontal inhibition in a region-specific manner

Experience-dependent organization of neuronal connectivity is critical for brain development. We recently demonstrated the importance of social play behavior for the developmental fine-tuning of inhibitory synapses in the medial prefrontal cortex in rats. When these effects of play experience occur and if this happens uniformly throughout the prefrontal cortex is currently unclear. Here we report important temporal and regional heterogeneity in the impact of social play on the development of excitatory and inhibitory neurotransmission in the medial prefrontal cortex and the orbitofrontal cortex. We recorded in layer 5 pyramidal neurons from juvenile (postnatal day (P)21), adolescent (P42), and adult (P85) rats after social play deprivation (between P21 and P42). The development of these prefrontal cortex subregions followed different trajectories. On P21, inhibitory and excitatory synaptic input was higher in the orbitofrontal cortex than in the medial prefrontal cortex. Social play deprivation did not affect excitatory currents, but reduced inhibitory transmission in both medial prefrontal cortex and orbitofrontal cortex. Intriguingly, the reduction occurred in the medial prefrontal cortex during social play deprivation, whereas the reduction in the orbitofrontal cortex only became manifested after social play deprivation. These data reveal a complex interaction between social play experience and the specific developmental trajectories of prefrontal subregions

Molecular and Electrophysiological Characterization of GFP-Expressing CA1 Interneurons in GAD65-GFP Mice

The use of transgenic mice in which subtypes of neurons are labeled with a fluorescent protein has greatly facilitated modern neuroscience research. GAD65-GFP mice, which have GABAergic interneurons labeled with GFP, are widely used in many research laboratories, although the properties of the labeled cells have not been studied in detail. Here we investigate these cells in the hippocampal area CA1 and show that they constitute ∼20% of interneurons in this area. The majority of them expresses either reelin (70±2%) or vasoactive intestinal peptide (VIP; 15±2%), while expression of parvalbumin and somatostatin is virtually absent. This strongly suggests they originate from the caudal, and not the medial, ganglionic eminence. GFP-labeled interneurons can be subdivided according to the (partially overlapping) expression of neuropeptide Y (42±3%), cholecystokinin (25±3%), calbindin (20±2%) or calretinin (20±2%). Most of these subtypes (with the exception of calretinin-expressing interneurons) target the dendrites of CA1 pyramidal cells. GFP-labeled interneurons mostly show delayed onset of firing around threshold, and regular firing with moderate frequency adaptation at more depolarized potentials

Correction:How the COVID-19 pandemic highlights the necessity of animal research (vol 30, pg R1014, 2020)

(Current Biology 30, R1014–R1018; September 21, 2020) As a result of an author oversight in the originally published version of this article, a number of errors were introduced in the author list and affiliations. First, the middle initials were omitted from the names of several authors. Second, the surname of Dr. van Dam was mistakenly written as “Dam.” Third, the first name of author Bernhard Englitz was misspelled as “Bernard” and the surname of author B.J.A. Pollux was misspelled as “Pullox.” Finally, Dr. Keijer's first name was abbreviated rather than written in full. These errors, as well as various errors in the author affiliations, have now been corrected online

Structural plasticity of GABAergic axons is regulated by network activity and GABAA receptor activation

Coordinated changes at excitatory and inhibitory synapses are essential for normal brain development and function. It is well established that excitatory neurons undergo structural changes, but our knowledge about inhibitory structural plasticity is rather scarce. Here we present a quantitative analysis of the dynamics of GABAergic boutons in the dendritic region of the hippocampal CA1 area using time-lapse two-photon imaging in organotypic hippocampal cultures from GAD65-GFP mice. We show that ~20% of inhibitory boutons are not stable. They are appearing, disappearing and reappearing at specific locations along the inhibitory axon and reflect immature or incomplete synapses. Furthermore, we observed that persistent boutons show large volume fluctuations over several hours, suggesting that presynaptic content of inhibitory synapses is not constant. Our data show that inhibitory boutons are highly dynamic structures and suggest that inhibitory axons are continuously probing potential locations for inhibitory synapse formation by redistributing presynaptic material along the axon.In addition, we found that neuronal activity affects the exploratory dynamics of inhibitory axons. Blocking network activity rapidly reduces the number of transient boutons, whereas enhancing activity reduces the number of persistent inhibitory boutons, possibly reflecting enhanced competition between boutons along the axon. The latter effect requires signaling through GABAA receptors. We propose that activity-dependent regulation of bouton dynamics contributes to inhibitory synaptic plasticity

The postnatal GABA shift: A developmental perspective

GABA is the major inhibitory neurotransmitter that counterbalances excitation in the mature brain. The inhibitory action of GABA relies on the inflow of chloride ions (Cl−), which hyperpolarizes the neuron. In early development, GABA signaling induces outward Cl− currents and is depolarizing. The postnatal shift from depolarizing to hyperpolarizing GABA is a pivotal event in brain development and its timing affects brain function throughout life. Altered timing of the postnatal GABA shift is associated with several neurodevelopmental disorders. Here, we argue that the postnatal shift from depolarizing to hyperpolarizing GABA represents the final shift in a sequence of GABA shifts, regulating proliferation, migration, differentiation, and finally plasticity of developing neurons. Each developmental GABA shift ensures that the instructive role of GABA matches the circumstances of the developing network. Sensory input may be a crucial factor in determining proper timing of the postnatal GABA shift. A developmental perspective is necessary to interpret the full consequences of a mismatch between connectivity, activity and GABA signaling during brain development

Activity-dependent adaptations in inhibitory axons

Synaptic connections in our brains change continuously and throughout our lifetime. Despite ongoing synaptic changes, a healthy balance between excitation and inhibition is maintained by various forms of homeostatic and activity-dependent adaptations, ensuring stable functioning of neuronal networks. In this review we summarize experimental evidence for activity-dependent changes occurring in inhibitory axons, in cultures as well as in vivo. Axons form many presynaptic terminals, which are dynamic structures sharing presynaptic material along the axonal shaft. We discuss how internal (e.g. vesicle sharing) and external factors (e.g. binding of cell adhesion molecules or secreted factors) may affect the formation and plasticity of inhibitory synapses

Single Synapse LTP : A Matter of Context?

The most commonly studied form of synaptic plasticity is long-term potentiation (LTP). Over the last 15 years, it has been possible to induce structural and functional LTP in dendritic spines using two-photon glutamate uncaging, allowing for studying the signaling mechanisms of LTP with single synapse resolution. In this review, we compare different stimulation methods to induce single synapse LTP and discuss how LTP is expressed. We summarize the underlying signaling mechanisms that have been studied with high spatiotemporal resolution. Finally, we discuss how LTP in a single synapse can be affected by excitatory and inhibitory synapses nearby. We argue that single synapse LTP is highly dependent on context: the choice of induction method, the history of the dendritic spine and the dendritic vicinity crucially affect signaling pathways and expression of single synapse LTP