Matthew T. Colonnese

Early Gamma Oscillations Synchronize Developing Thalamus and Cortex

Thalamic gamma rhythms help develop highly spatially and laminar-specific ascending cortical projections. During development, formation of topographic maps in sensory cortex requires precise temporal binding in thalamocortical networks. However, the physiological substrate for such synchronization is unknown. We report that early gamma oscillations (EGOs) enable precise spatiotemporal thalamocortical synchronization in the neonatal rat whisker sensory system. Driven by a thalamic gamma oscillator and initially independent of cortical inhibition, EGOs synchronize neurons in a single thalamic barreloid and corresponding cortical barrel and support plasticity at developing thalamocortical synapses. We propose that the multiple replay of sensory input in thalamocortical circuits during EGOs allows thalamic and cortical neurons to be organized into vertical topographic functional units before the development of horizontal binding in adult brain.

Development of hemodynamic responses and functional connectivity in rat somatosensory cortex

Functional magnetic resonance imaging (fMRI) is a valuable method for probing postnatal circuit refinement and plasticity. However, its use during early development has been hindered by uncertainty as to the nature of neurovascular coupling in young individuals. Here we used somatosensory stimulation in rats to determine age-related parameters of the blood oxygenation level–dependent (BOLD) signal from its apparent inception on postnatal day 13 to adulthood. By comparing fMRI measurements with electrophysiological recordings, we determined that the regional BOLD response in these animals undergoes a systematic decline in latency and growth in amplitude over this period. We found no evidence of negative BOLD at any age. Maturation of hemodynamic responses correlated with age-dependent increases in susceptibility to inhibition of carbonic anhydrase. With knowledge of the infant BOLD response characteristics, we showed that interhemispheric and higher-order cortical stimulus responses are enhanced during the first several weeks after birth.

“Slow Activity Transients” in Infant Rat Visual Cortex:A Spreading Synchronous Oscillation Patterned by Retinal Waves

A primary feature of the preterm infant electroencephalogram is the presence of large infra-slow potentials containing rapid oscillations called slow activity transients (SATs). Such activity has not been described in animal models, and their generative mechanisms are unknown. Here we use direct-current and multisite extracellular, as well as whole-cell, recording in vivo to demonstrate the existence of regularly repeating SATs in the visual cortex of infant rats before eye opening. Present only in absence of anesthesia, SATs at postnatal day 10–11 were identifiable as a separate group of long-duration (∼10 s) events that consisted of large (>1 mV) negative local-field potentials produced by the summation of multiple bursts of rapid oscillatory activity (15–30 Hz). SATs synchronized the vast majority of neuronal activity (87%) in the visual cortex before eye opening. Enucleation eliminated SATs, and their duration, interevent interval, and sub-burst structure matched those of phase III retinal waves recorded in vitro. Retinal waves, however, lacked rapid oscillations, suggesting that they arise centrally. Multielectrode recordings showed that SATs spread horizontally in cortex and synchronize activity at coactive locales via the rapid oscillations. SATs were clearly different from ongoing cortical activity, which was observable as a separate class of short bursts from postnatal day 9. Together, our data suggest that, in vivo, early cortical activity is primarily determined by peripheral inputs—retinal waves in visual cortex—that provide excitatory input, and by thalamocortical circuitry, which transforms this input to beta oscillations. We propose that the synchronous oscillations of SATs participate in the formation of visual circuitry.

Pentraxins Coordinate Excitatory Synapse Maturation and Circuit Integration of Parvalbumin Interneurons.

Circuit computation requires precision in the timing, extent, and synchrony of principal cell (PC) firing that is largely enforced by parvalbumin-expressing, fast-spiking interneurons (PVFSIs). To reliably coordinate network activity, PVFSIs exhibit specialized synaptic and membrane properties that promote efficient afferent recruitment such as expression of high-conductance, rapidly gating, GluA4-containing AMPA receptors (AMPARs). We found that PVFSIs upregulate GluA4 during the second postnatal week coincident with increases in the AMPAR clustering proteins NPTX2 and NPTXR. Moreover, GluA4 is dramatically reduced in NPTX2(-/-)/NPTXR(-/-) mice with consequent reductions in PVFSI AMPAR function. Early postnatal NPTX2(-/-)/NPTXR(-/-) mice exhibit delayed circuit maturation with a prolonged critical period permissive for giant depolarizing potentials. Juvenile NPTX2(-/-)/NPTXR(-/-) mice display reduced feedforward inhibition yielding a circuit deficient in rhythmogenesis and prone to epileptiform discharges. Our findings demonstrate an essential role for NPTXs in controlling network dynamics highlighting potential therapeutic targets for disorders with inhibition/excitation imbalances such as schizophrenia.

Developmental period for N-methyl-D-aspartate (NMDA) receptor-dependent synapse elimination correlated with visuotopic map refinement.

During a short perinatal interval, N‐methyl‐D‐aspartate receptor (NMDAR) function is essential to a process in which spontaneous retinal waves focus retinal axon arbors in the superficial layers of the rodent superior colliculus (sSC). Here we provide evidence that this NMDAR‐dependent axonal refinement occurs through elimination of uncorrelated retinal synapses arising from disparate loci, rather than stabilization of topographically appropriate inputs. The density of synaptic release sites within fluorescently labeled retinal terminals was counted in double‐labeling experiments using confocal microscopy and antibodies against synaptophysin or synapsin‐1. Chronic NMDAR blockade from birth increased retinal axon synapse density at postnatal days (P) 6, 8, and 10, suggesting that NMDAR currents reduce synapse density during the refinement period. With assay at P14, after focal arborization has been established, the effect disappeared. Conversely, chronic NMDA treatment, known to induce functional synaptic depression in the sSC, decreased retinocollicular synapse density at P14, but not earlier, during the refinement period (P8). Thus during the development of retinocollicular topographic order, there is a period when NMDAR activity predominantly eliminates retinal axon synapses. We were able to extend this period by using retinal lesions to reduce synaptic density in a defined zone. Synapse density on intact retinocollicular axons sprouting into this zone was increased by NMDAR blockade, even when examined at P14. Thus, the period of NMDAR‐dependent synaptic destabilization is terminated by a factor related to the density and refinement of retinal arbors. J. Comp. Neurol. 494:738–751, 2006.

NMDA receptor currents suppress synapse formation on sprouting axons in vivo

NMDA receptors (NMDARs) play an important role in the structural maintenance and functional strength of synapses. The causal relationship between these anatomical and functional roles is poorly defined. Using quantitative confocal microscopy, synaptic vesicle immunoreactivity, and differential label of retinal projections, we measured axon volume and synapse density along ipsilateral retinal axons (ipsi axons) sprouting into the superficial visual layers of the superior colliculus (sSC) deafferented by a contralateral retinal lesion (a scotoma) 8 d earlier. When retinal lesions were made at postnatal day 6 (P6), glutamatergic synaptic currents on neurons within the scotoma were significantly reduced. Both ipsi axon sprouting and synapse density were increased by chronic d-AP-5 antagonism of NMDARs. Conversely, ipsi axon sprouting and synapse density were reduced by chronic exposure to the agonist, NMDA, known to functionally depress glutamate transmission in this system. After P11 lesions, however, NMDAR blockade had no effect on sprouting or synapse density. Developmental changes in NMDAR current kinetics could not account for this difference in the structural effects of NMDAR function. Also, synaptic current frequencies within the scotoma were not affected after the P11 lesions. The corticocollicular projection matures during the P11 survival interval and, as indicated by previous work, it is a source of competition for synaptic space and probably of maintained activity in the older sSC. Thus, our results suggest that during early development, NMDAR currents predominantly destabilize nascent synapses. As the neuropil matures, however, competition for synaptic space suppresses axon sprouting and synapse formation regardless of NMDAR function.

Auditory Stimuli Mimicking Ambient Sounds Drive Temporal ''Delta-Brushes'' in Premature Infants

In the premature infant, somatosensory and visual stimuli trigger an immature electroencephalographic (EEG) pattern, “delta-brushes,” in the corresponding sensory cortical areas. Whether auditory stimuli evoke delta-brushes in the premature auditory cortex has not been reported. Here, responses to auditory stimuli were studied in 46 premature infants without neurologic risk aged 31 to 38 postmenstrual weeks (PMW) during routine EEG recording. Stimuli consisted of either low-volume technogenic “clicks” near the background noise level of the neonatal care unit, or a human voice at conversational sound level. Stimuli were administrated pseudo-randomly during quiet and active sleep. In another protocol, the cortical response to a composite stimulus (“click” and voice) was manually triggered during EEG hypoactive periods of quiet sleep. Cortical responses were analyzed by event detection, power frequency analysis and stimulus locked averaging. Before 34 PMW, both voice and “click” stimuli evoked cortical responses with similar frequency-power topographic characteristics, namely a temporal negative slow-wave and rapid oscillations similar to spontaneous delta-brushes. Responses to composite stimuli also showed a maximal frequency-power increase in temporal areas before 35 PMW. From 34 PMW the topography of responses in quiet sleep was different for “click” and voice stimuli: responses to “clicks” became diffuse but responses to voice remained limited to temporal areas. After the age of 35 PMW auditory evoked delta-brushes progressively disappeared and were replaced by a low amplitude response in the same location. Our data show that auditory stimuli mimicking ambient sounds efficiently evoke delta-brushes in temporal areas in the premature infant before 35 PMW. Along with findings in other sensory modalities (visual and somatosensory), these findings suggest that sensory driven delta-brushes represent a ubiquitous feature of the human sensory cortex during fetal stages and provide a potential test of functional cortical maturation during fetal development.

Rapid developmental emergence of stable depolarization during wakefulness by inhibitory balancing of cortical network excitability

The ability to generate behaviorally appropriate cortical network states is central to sensory perception and plasticity, but little is known about the timing and mechanisms of their development. I paired intracellular and extracellular recordings in the visual cortex of awake infant rats to determine the synaptic and circuit mechanisms regulating the development of a key network state, the persistent and stable subthreshold membrane potential (Vm) depolarization associated with wakefulness/alertness in cortical networks, called the “desynchronized” or “activated” state. Current-clamp recordings reveal that the desynchronized state is absent during the first 2 postnatal weeks, despite behavioral wakefulness. During this period, Vm remains at the resting membrane potential >80% of the time, regardless of behavioral state. Vm dynamics during spontaneous or light-evoked activity were highly variable, contained long-duration supratheshold plateau potentials, and high spike probability, suggesting an unstable and hyperexcitable early cortical network. Voltage-clamp recordings reveal that effective feedforward inhibition is absent at these early ages despite the presence of feedback inhibition. Stable membrane depolarization during wakefulness finally emerges 1–2 d before eye opening and is statistically indistinguishable from that in adults within days. Reduced cortical excitability, fast feedforward inhibition, and the slow cortical oscillation appear simultaneously with stable depolarization, suggesting that an absence of inhibitory balance during early development prevents the expression of the active state and hence a normal wakeful state in early cortex. These observations identify feedforward inhibition as a potential key regulator of cortical network activity development.

Disrupted Cortical State Regulation in a Rat Model of Fragile X Syndrome

Abstract Children with Fragile X syndrome (FXS) have deficits of attention and arousal. To begin to identify the neural causes of these deficits, we examined juvenile rats lacking the Fragile X mental retardation protein (FMR‐KO) for disruption of cortical activity related to attention and arousal. Specifically, we examined the switching of visual cortex between activated and inactivated states that normally occurs during movement and quiet rest, respectively. In both wild‐type and FMR‐KO rats, during the third and fourth postnatal weeks cortical activity during periods of movement was dominated by an activated state with prominent 18‐52 Hz activity. However, during quiet rest, when activity in wild‐type rats became dominated by the inactivated state (3‐9 Hz activity), FMR‐KO rat cortex abnormally remained activated, resulting in increased high‐frequency and reduced low‐frequency power during rest. Firing rate correlations revealed reduced synchronization in FMR‐KO rats, particularly between fast‐spiking interneurons, that developmentally precede cortical state defects. Together our data suggest that disrupted inhibitory connectivity impairs the ability of visual cortex to regulate exit from the activated state in a behaviorally appropriate manner, potentially contributing to disrupted attention and sensory processing observed in children with FXS by making it more difficult to decrease cortical drive by unattended stimuli.

An excitatory cortical feedback loop gates retinal wave transmission in rodent thalamus

Spontaneous retinal waves are critical for the development of receptive fields in visual thalamus (LGN) and cortex (VC). Despite a detailed understanding of the circuit specializations in retina that generate waves, whether central circuit specializations also exist to control their propagation through visual pathways of the brain is unknown. Here we identify a developmentally transient, corticothalamic amplification of retinal drive to thalamus as a mechanism for retinal wave transmission in the infant rat brain. During the period of retinal waves, corticothalamic connections excite LGN, rather than driving feedforward inhibition as observed in the adult. This creates an excitatory feedback loop that gates retinal wave transmission through the LGN. This cortical multiplication of retinal wave input ends just prior to eye-opening, as cortex begins to inhibit LGN. Our results show that the early retino-thalamo-cortical circuit uses developmentally specialized feedback amplification to ensure powerful, high-fidelity transmission of retinal activity despite immature connectivity. DOI: http://dx.doi.org/10.7554/eLife.18816.001