The early developmental period is characterized by a high degree of plasticity and, consequently, is very sensitive to environmental factors, such as early life stressors (ELS). Exposure to ELS is known to increase risk to psychopathologies such as depression and anxiety disorders later in life . At a cellular level, alterations in the migration and integration of GABAergic interneurons (INs) in cortical circuits have emerged as a key processes involved in the vulnerability to psychiatric disorders . In humans and rodents, ELS interacts with genes regulating the serotonin system to increase risk to stress-related disorders . In addition, ELS is associated to a variety of epigenetic methylation changes in blood DNA from patients displaying a high loading of ELS . Here, we aimed to investigate the role of the ionotropic serotonin 3A receptor (5-HT3AR) at a genetic and epigenetic level in rodent and human models of early-life stress. We will first present data indicating that the 5-HT3AR is specifically expressed in a subset of cortical INs derived from the caudal ganglionic eminence (CGE) and controls early steps of cortical circuit assembly . Interestingly, the migration, transcriptional programs and positioning of 5-HT3AR expressing interneuron subtypes were found to be dysregulated in pathological models of early-life serotonin dysregulation. At a behavioral level, we found that ELS interacts with the 5-HTR3A to modulate social behaviors. Finally, we will present human data indicating that childhood adversity significantly impacts the methylation status of the promoter region of the human 5-HT3AR in an allele-specific manner. Taken together, this presentation will highlight the importance of the serotonin system in early life development and psychopathology with a special focus on the role of the 5-HT3AR in cortical interneuron development.

There are more than 30 distinct types of mammalian retinal ganglion cells, each sensitive to different features of the visual environment. In rabbit retina, they can be grouped into four classes according to their morphology and stratification of their dendrites in the inner plexiform layer (IPL). The goal of this study was to describe the synaptic inputs to one type of Class IV ganglion cell, the third member of the sparsely branched Class IV cells (SB3). One cell of this type was partially reconstructed in a retinal connectome developed using automated transmission electron microscopy (ATEM). It had slender, relatively straight dendrites that ramify in the sublamina a of the IPL. The dendrites of the SB3 cell were always postsynaptic in the IPL, supporting its identity as a ganglion cell. It received 29% of its input from bipolar cells, a value in the middle of the range for rabbit retinal ganglion cells studied previously. The SB3 cell typically received only one synapse per bipolar cell from multiple types of presumed OFF bipolar cells; reciprocal synapses from amacrine cells at the dyad synapses were infrequent. In a few instances, the bipolar cells presynaptic to the SB3 ganglion cell also provided input to an amacrine cell presynaptic to the ganglion cell. There was apparently no crossover inhibition from narrow-field ON amacrine cells. Most of the amacrine cell inputs were from axons and dendrites of GABAergic amacrine cells, likely providing inhibitory input from outside the classical receptive field.

Feedback is a ubiquitous feature of neural circuits in the mammalian central nervous system (CNS). Analogous to pure electronic circuits, neuronal feedback provides either a positive or negative influence on the output of upstream components/neurons. Although the particulars (i.e., connectivity, physiological encoding/processing/signaling) of circuits in higher areas of the brain are often unclear, the inner retina proves an excellent model for studying both the anatomy and physiology of feedback circuits within the functional context of visual processing. Inner retinal feedback to bipolar cells is almost entirely mediated by a single class of interneurons, the amacrine cells. Although this might sound like a simple circuit arrangement with an equally simple function, anatomical, molecular, and functional evidence suggest that amacrine cells represent an extremely diverse class of CNS interneurons that contribute to a variety of retinal processes. In this review, I classify the amacrine cells according to their anatomical output synapses and target cell(s) (i.e., bipolar cells, ganglion cells, and/or amacrine cells) and discuss specifically our current understandings of amacrine cell-mediated feedback and output to bipolar cells on the synaptic, cellular, and circuit levels, while drawing connections to visual processing.

It is increasingly clear that spinal reflex systems cannot be described in terms of simple and constant reflex actions. The extensive convergence of segmental and descending systems onto spinal interneurons suggests that spinal interneurons are not relay systems but rather form a crucial component in determining which muscles are activated during voluntary and reflex movements. The notion that descending systems simply modulate the gain of spinal interneuronal pathways has been tempered by the observation that spinal interneurons gate and distribute descending control to specific motoneurons. Spinal reflex systems are complex but current approaches will continue to provide insight into motor systems. During movement, several neural mechanisms act to reduce the functional complexity of motor systems by inhibiting some of the parallel reflex pathways available to segmental afferents and descending systems. The flexion reflex system is discussed as an example of the flexibility of spinal interneuron systems and as a useful conceptual construct. Examples are provided of the kinds of experiments that can be developed using current approaches to spinal interneuronal systems.

Although a tremendous honour, it is with great sadness that this review is dedicated to Mircea's memory. Mircea has been, not only an inspiration throughout my career, but a generous and supportive friend whose kindly, incisive criticism has been a constant reminder that what we study in vitro must eventually be understood in the context of the whole system. Quoting from the Preface to his elegant monograph ‘The evolution of work on extremely simplified preparations has reached the point where some investigators are not shy to jump from single-cell properties to global brain functions, such as arousal and sleep, paroxysmal events of the epileptic type, and even conscious thinking.’ (Steriade, 2001). Bearing in mind that the properties both of single neurons and the connections between them might vary in different brain states and in different phases of cortical rhythms, in this review I summarize studies of the local circuitry of the thalamo-recipient layers 4 and 6 focussing on results obtained with dual intracellular recordings and biocytin-labelling in adult neocortical slices.