Input-specific maturation of NMDAR-mediated transmission onto parvalbumin-expressing interneurons in layers 2/3 of the visual cortex.

Parvalbumin-expressing (PV) GABAergic interneurons regulate local circuit dynamics. In terms of the excitation driving PV interneuron activity, the N-methyl-d-aspartate receptor (NMDAR)-mediated component onto PV interneurons tends to be smaller than that onto pyramidal neurons but makes a significant contribution to their physiology and development. In the visual cortex, PV interneurons mature during the critical period. We hypothesize that during the critical period, the NMDAR-mediated signaling and functional properties of glutamatergic synapses onto PV interneurons are developmentally regulated. We therefore compared the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)- and NMDAR-mediated synaptic responses before (postnatal days 15-20, P15-P20), during (P25-P40), and after (P50-P60) the visual critical period. AMPAR miniature excitatory postsynaptic currents (mEPSCs) showed a developmental decrease in frequency, whereas NMDAR mEPSCs were absent or showed extremely low frequencies throughout development. For evoked responses, we consistently saw a NMDAR-mediated component, suggesting pre- or postsynaptic differences between evoked and spontaneous neurotransmission. Evoked responses showed input-specific developmental changes. For intralaminar inputs, the NMDAR-mediated component significantly decreased with development. This resulted in adult intralaminar inputs almost exclusively mediated by AMPARs, suited for the computation of synaptic inputs with precise timing, and likely having NMDAR-independent forms of plasticity. In contrast, interlaminar inputs maintained a stable NMDAR-mediated component throughout development but had a shift in the AMPAR paired-pulse ratio from depression to facilitation. Adult interlaminar inputs with facilitating AMPAR responses and a substantial NMDAR component would favor temporal integration of synaptic responses and could be modulated by NMDAR-dependent forms of plasticity. NEW & NOTEWORTHY We show for the first time input-specific developmental changes in the N-methyl-d-aspartate receptor component and short-term plasticity of the excitatory drive onto layers 2/3 parvalbumin-expressing (PV) interneurons in the visual cortex during the critical period. These developmental changes would lead to functionally distinct adult intralaminar and interlaminar glutamatergic inputs that would engage PV interneuron-mediated inhibition differently.

Dissecting the determinants of light sensitivity in amphioxus microvillar photoreceptors: possible evolutionary implications for melanopsin signaling.

Melanopsin, a photopigment related to the rhodopsin of microvillar photoreceptors of invertebrates, evolved in vertebrates to subserve nonvisual light-sensing functions, such as the pupillary reflex and entrainment of circadian rhythms. However, vertebrate circadian receptors display no hint of a microvillar specialization and show an extremely low light sensitivity and sluggish kinetics. Recently in amphioxus, the most basal chordate, melanopsin-expressing photoreceptors were characterized; these cells share salient properties with both rhabdomeric photoreceptors of invertebrates and circadian receptors of vertebrates. We used electrophysiology to dissect the gain of the light-transduction process in amphioxus and examine key features that help outline the evolutionary transition toward a sensor optimized to report mean ambient illumination rather than mediating spatial vision. By comparing the size of current fluctuations attributable to single photon melanopsin isomerizations with the size of single-channels activated by light, we concluded that the gain of the transduction cascade is lower than in rhabdomeric receptors. In contrast, the expression level of melanopsin (gauged by measuring charge displacements during photo-induced melanopsin isomerization) is comparable with that of canonical visual receptors. A modest amplification in melanopsin-using receptors is therefore apparent in early chordates; the decrease in photopigment expression-and loss of the anatomical correlates-observed in vertebrates subsequently enabled them to attain the low photosensitivity tailored to the role of circadian receptors.

Gabrb3 is required for the functional integration of pyramidal neuron subtypes in the somatosensory cortex.

Dysfunction of gamma-aminobutyric acid (GABA)ergic circuits is strongly associated with neurodevelopmental disorders. However, it is unclear how genetic predispositions impact circuit assembly. Using in vivo two-photon and widefield calcium imaging in developing mice, we show that Gabrb3, a gene strongly associated with autism spectrum disorder (ASD) and Angelman syndrome (AS), is enriched in contralaterally projecting pyramidal neurons and is required for inhibitory function. We report that Gabrb3 ablation leads to a developmental decrease in GABAergic synapses, increased local network synchrony, and long-lasting enhancement in functional connectivity of contralateral-but not ipsilateral-pyramidal neuron subtypes. In addition, Gabrb3 deletion leads to increased cortical response to tactile stimulation at neonatal stages. Using human transcriptomics and neuroimaging datasets from ASD subjects, we show that the spatial distribution of GABRB3 expression correlates with atypical connectivity in these subjects. Our studies reveal a requirement for Gabrb3 during the emergence of interhemispheric circuits for sensory processing.

The Role of Inhibitory Interneurons in Circuit Assembly and Refinement Across Sensory Cortices.

Sensory information is transduced into electrical signals in the periphery by specialized sensory organs, which relay this information to the thalamus and subsequently to cortical primary sensory areas. In the cortex, microcircuits constituted by interconnected pyramidal cells and inhibitory interneurons, distributed throughout the cortical column, form the basic processing units of sensory information underlying sensation. In the mouse, these circuits mature shortly after birth. In the first postnatal week cortical activity is characterized by highly synchronized spontaneous activity. While by the second postnatal week, spontaneous activity desynchronizes and sensory influx increases drastically upon eye opening, as well as with the onset of hearing and active whisking. This influx of sensory stimuli is fundamental for the maturation of functional properties and connectivity in neurons allocated to sensory cortices. In the subsequent developmental period, spanning the first five postnatal weeks, sensory circuits are malleable in response to sensory stimulation in the so-called critical periods. During these critical periods, which vary in timing and duration across sensory areas, perturbations in sensory experience can alter cortical connectivity, leading to long-lasting modifications in sensory processing. The recent advent of intersectional genetics, in vivo calcium imaging and single cell transcriptomics has aided the identification of circuit components in emergent networks. Multiple studies in recent years have sought a better understanding of how genetically-defined neuronal subtypes regulate circuit plasticity and maturation during development. In this review, we discuss the current literature focused on postnatal development and critical periods in the primary auditory (A1), visual (V1), and somatosensory (S1) cortices. We compare the developmental trajectory among the three sensory areas with a particular emphasis on interneuron function and the role of inhibitory circuits in cortical development and function.

The light-sensitive conductance of melanopsin-expressing Joseph and Hesse cells in amphioxus.

Two types of microvillar photoreceptors in the neural tube of amphioxus, an early chordate, sense light via melanopsin, the same photopigment as in "circadian" light detectors of higher vertebrates. Because in amphioxus melanopsin activates a G(q)/phospholipase C cascade, like phototransduction in arthropods and mollusks, possible commonalities in the photoconductance were investigated. Unlike other microvillar photoreceptors, reversal of the photocurrent can only be attained upon replacement of extracellular Na(+). In addition to Na(+), Ca(2+) is also permeant, as indicated by the fact that (a) in normal ionic conditions the photocurrent remains inward at V(m) > E(Na); (b) in Na-free solution a small residual inward photocurrent persists at V(m) near resting level, provided that Ca is present; and (c) V(rev) exhibits a modest shift with [Ca](o) manipulations. The unusual reversal is accounted for by an uncommonly low permeability of the light-dependent channels to K(+), as [K](o) only marginally affects the photocurrent amplitude and its reversal. Lanthanum and ruthenium red (RuR), two TRP channel antagonists, reversibly suppress the response to photostimulation of moderate intensity; therefore, the melanopsin-initiated cascade may recruit ion channels of the same family as those of rhabdomeric photoreceptors. With brighter lights, blockage declines, so that both La(3+) and RuR induce a right shift in the sensitivity curve without a reduction of its asymptote. Nonetheless, an effect on the transduction cascade, rather than the channels, was ruled out on the basis of the voltage dependency of the blockade and the lack of effects of intracellular application of the same substances. The mechanisms of action of these antagonists thus entail a state-dependent blockade, with a higher affinity for the channel in the closed conformation. Collectively, the results indicate a kinship of the light-sensitive channels of amphioxus with those of invertebrate rhabdomeric visual cells and support the representation of this lineage of photoreceptors among chordates.