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Rett syndrome (RTT) is a neurodevelopmental disorder that results from mutations in the X-linked gene for methyl-CpG-binding protein 2 ( MECP2). The underlying cellular mechanism for the sensory deficits in patients with RTT is largely unknown. This study used the Bird mouse model of RTT to investigate sensory thalamocortical synaptic transmission in the barrel cortex of Mecp2-null mice. Electrophysiological results showed an excitation/inhibition imbalance, biased toward inhibition, due to an increase in efficacy of postsynaptic GABAA receptors rather than alterations in inhibitory network and presynaptic release properties. Enhanced inhibition impaired the transmission of tonic sensory signals from the thalamus to the somatosensory cortex. Previous morphological studies showed an upregulation of NMDA receptors in the neocortex of both RTT patients and Mecp2-null mice at early ages [Blue ME, Naidu S, Johnston MV. Ann Neurol 45: 541–545, 1999; Blue ME, Kaufmann WE, Bressler J, Eyring C, O'Driscoll C, Naidu S, Johnston MV. Anat Rec (Hoboken) 294: 1624–1634, 2011]. Although AMPA and NMDA receptor-mediated excitatory synaptic transmission was not altered in the barrel cortex of Mecp2-null mice, extrasynaptic NMDA receptor-mediated responses increased markedly. These responses were blocked by memantine, suggesting that extrasynaptic NMDA receptors play an important role in the pathogenesis of RTT. The results suggest that enhancement of postsynaptic GABAA and extrasynaptic NMDA receptor-mediated responses may underlie impaired somatosensation and that pharmacological blockade of extrasynaptic NMDA receptors may have therapeutic value for RTT.

The whisker-sensory trigeminal central pathway of rodents is an established model for studies of activity-dependent neural plasticity. The first relay station of the pathway is the trigeminal principal nucleus (PrV), the ventral part of which receives sensory inputs mainly from the infraorbital branch of the maxillary trigeminal nerve (ION). Whisker-sensory afferents play an important role in the development of the morphological and physiological properties of PrV neurons. In neonates, deafferentation by ION transection leads to the disruption of whisker-related neural patterns (barrelettes) and cell death within a specific time window (critical period), as revealed by morphological studies. Whisker-sensory inputs control synaptic elimination, postsynaptic AMPA receptor trafficking, astrocyte-mediated synaptogenesis, and receptive-field characteristics of PrV cells, without a postnatal critical period. Sensory activity-dependent synaptic plasticity requires the activation of NMDA receptors and involves the participation of glia. However, the basic physiological properties of PrV neurons, such as cell type-specific ion channels, presynaptic terminal function, postsynaptic NMDA receptor subunit composition, and formation of the inhibitory circuitry, are independent of sensory inputs. Therefore, the first relay station of the whisker sensation is largely mature-like and functional at birth. Delineation of activity-dependent and activity-independent features of the postnatal PrV is important for understanding the development and functional characteristics of downstream trigeminal stations in the thalamus and neocortex. This mini review focuses on such features of the developing rodent PrV.

The purpose of the present study was to determine whether retinal activity can support long-term changes in synaptic strength in the developing dorsal lateral geniculate nucleus (LGN) of thalamus. To test for this we made use of a rodent in vitro explant preparation in which retinal afferents and the intrinsic circuitry of the LGN remain intact. We repetitively stimulated the optic tract with a tetanus protocol that approximated the temporal features of spontaneous retinal waves. We found the amplitude of extracellular field potentials evoked by retinal stimulation changed significantly after tetanus and that the polarity of these alterations was related to postnatal age. At a time when substantial pruning of retinal connections occurs (postnatal day 1 [P1] to P14), high-frequency stimulation led to an immediate and long-term depression (LTD). However, at times when pruning wanes and adultlike patterns of connectivity are stabilizing (P16 to P30), the identical form of stimulation produced a modest form of potentiation (long-term potentiation [LTP]). The LTD was unaffected by the bath application of γ-aminobutyric acid type A and N-methyl-d-aspartate receptor antagonists. However, both LTD and LTP were blocked by L-type Ca2+-channel antagonists. Thus the Ca2+ influx associated with L-type channel activation mediates the induction of synaptic plasticity and may signal the pruning and subsequent stabilization of developing retinogeniculate connections.

Sensory deprivation studies in neonatal mammals, such as monocular eye closure, whisker trimming, and chemical blockade of the olfactory epithelium have revealed the importance of sensory inputs in brain wiring during distinct critical periods. But very few studies have paid attention to the effects of neonatal peripheral sensory nerve damage on synaptic wiring of the central nervous system (CNS) circuits. Peripheral somatosensory nerves differ from other special sensory afferents in that they are more prone to crush or severance because of their locations in the body. Unlike the visual and auditory afferents, these nerves show regenerative capabilities after damage. Uniquely, damage to a somatosensory peripheral nerve does not only block activity incoming from the sensory receptors but also mediates injury-induced neuro- and glial chemical signals to the brain through the uninjured central axons of the primary sensory neurons. These chemical signals can have both far more and longer lasting effects than sensory blockade alone. Here we review studies which focus on the consequences of neonatal peripheral sensory nerve damage in the principal sensory nucleus of the brainstem trigeminal complex.

Using intracellular recordings in an isolated (in vitro) rat brain stem preparation, we examined the synaptic responses of developing relay neurons in the dorsal lateral geniculate nucleus (LGN). In newborn rats, strong stimulation of the optic tract (OT) evoked excitatory postsynaptic potentials (EPSPs) that gave rise to a sustained (300–1,300 ms), slow-decaying (2+ channels. Synaptic activation of the plateau potential relied on N-methyl-d-aspartate (NMDA) receptor-mediated activity and the spatial and/or temporal summation of retinally evoked EPSPs. Inhibitory postsynaptic responses (IPSPs) did not prevent the expression of the plateau potential. However, GABAA receptor activity modulated the intensity of optic tract stimulation needed to evoke the plateau potential, while GABAB receptor activity affected its duration. Expression of the plateau potential was developmentally regulated, showing a much higher incidence at P1–2 (90%) than at P19–20 (1%). This was in part due to the fact that developing relay cells show a greater degree of spatial summation than their mature counterparts, receiving input from as many as 7–12 retinal ganglion cells. Early spontaneous retinal activity is also likely to trigger the plateau potential. Repetitive stimulation of optic tract in a manner that approximated the high-frequency discharge of retinal ganglion cells led to a massive temporal summation of EPSPs and the activation of a sustained depolarization (>1 min) that was blocked by L-type Ca2+ channel antagonists. These age-related changes in Ca2+ signaling may contribute to the activity-dependent refinement of retinogeniculate connections.

We examined whether the postsynaptic responses of cells in the principal sensory nucleus of the trigeminal nerve (PrV) are subject to long-term changes in synaptic strength, and if such changes were correlated the whisker-specific patterning during and just after the critical period for pattern formation. We used an in vitro brainstem preparation in which the trigeminal ganglion (TG) and PrV remained attached. By electrically activating TG afferents, we evoked large-amplitude extracellular field potentials. These responses were postsynaptic in origin and blocked by the glutamate antagonist, DNQX. At P1, a time when barrelettes are consolidating, high frequency stimulation of their afferents led to an immediate (1 min) and long-lasting (or =90 min) reduction (35%) in the amplitude of the evoked response. At P3-7, when the pattern of barrelettes have stabilized, the same form of tetanus led to an immediate and long-lasting increase (40%) in the amplitude of the response. Both forms of synaptic plasticity were mediated by the activation of L-type Ca(2+) channels. Application of the L-type channel blocker, nitrendipine, led to a complete blockade of any the tetanus induced changes. These associative processes may regulate the patterning and maintenance of whisker-specific patterns in the brainstem trigeminal nuclei.

1. Local inhibition in the deep layers of the superior colliculus plays a crucial role in sensorimotor integration. Using intracellular and extracellular recording techniques, we studied the organization of inhibitory circuits in the deep layers of the superior colliculus in anaesthetized rabbits. 2. We identified a new cell type in the deep superior colliculus that showed a characteristic burst response to stimulation of both the predorsal bundle and optic chiasm. The response had a jittering latency and failed to follow high frequency stimuli, indicating trans-synaptic (orthodromic) events. Moreover, the predorsal bundle stimulation-evoked orthodromic response could be made to collide with the response to a preceding stimulation of the optic chiasm, suggesting that burst-firing cells received excitatory inputs from the axonal collaterals of predorsal bundle-projecting cells. 3. Stimulation of the predorsal bundle could evoke an IPSP in predorsal bundle-projecting cells. The latency of the IPSP was 0.5-1.0 ms longer than the orthodromic response in burst-firing cells. Simultaneous recordings showed that the IPSP in predorsal bundle-projecting cells was preceded by a burst of extracellular spikes from burst-firing cells with short latency ( approximately 0.9 ms), indicating an inhibitory monosynaptic connection from burst-firing cells to predorsal bundle-projecting cells. 4. Burst-firing cells exhibited a prolonged depression after the predorsal bundle or optic chiasm stimulation due to an inhibitory postsynaptic potential. Latency analysis implies that burst-firing cells may form mutual inhibitory connections. 5. Together our results suggest that burst-firing cells and predorsal bundle-projecting cells form reciprocal excitatory and inhibitory connections and burst-firing cells may function as the recurrent inhibitory interneurons in the deep layers of the rabbit superior colliculus.

Neonatal damage to the trigeminal nerve leads to “reactive synaptogenesis” in the brain stem sensory trigeminal nuclei. In vitro models of brain injury-induced synaptogenesis have implicated an important role for astrocytes. In this study we tested the role of astrocyte function in reactive synaptogenesis in the trigeminal principal nucleus (PrV) of neonatal rats following unilateral transection of the infraorbital (IO) branch of the trigeminal nerve. We used electrophysiological multiple input index analysis (MII) to estimate the number of central trigeminal afferent fibers that converge onto single barrelette neurons. In the developing PrV, about 30% of afferent connections are eliminated within 2 postnatal weeks. After neonatal IO nerve damage, multiple trigeminal inputs (2.7 times that of the normal inputs) converge on single barrelette cells within 3–5 days; they remain stable up to the second postnatal week. Astrocyte proliferation and upregulation of astrocyte-specific proteins (GFAP and ALDH1L1) accompany reactive synaptogenesis in the IO nerve projection zone of the PrV. Pharmacological blockade of astrocyte function, purinergic receptors, and thrombospondins significantly reduced or eliminated reactive synaptogenesis without changing the MII in the intact PrV. GFAP immunohistochemistry further supported these electrophysiological results. We conclude that immature astrocytes, purinergic receptors, and thrombospondins play an important role in reactive synaptogenesis in the peripherally deafferented neonatal PrV.

One of the major consequences of neonatal infraorbital nerve damage is irreversible morphological reorganization in the principal sensory nucleus (PrV) of the trigeminal nerve in the brainstem. We used the voltage-clamp technique to study synaptic transmission in the normal and the denervated PrV of neonatal rats in anin vitrobrainstem preparation. Most of the synapses in the PrV are already functional at birth. Three days after peripheral deafferentation, functional synapses become silent, lacking AMPA receptor-mediated currents. Without sensory inputs from the whiskers, silent synapses persist through the second postnatal week, indicating that the maintenance of AMPA receptor function depends on sensory inputs. High-frequency (50 Hz) electrical stimulation of the afferent pathway, which mimics sensory input, restores synaptic function, whereas low-frequency (1 Hz) stimulation has no effect. Application of glycine, which promotes AMPA receptor exocytosis, also restores synaptic function. Therefore, normal synaptic function in the developing PrV requires incoming activity via sensory afferents and/or enhanced AMPA receptor exocytosis. Sensory deprivation most likely results in AMPA receptor endocytosis and/or lateral diffusion to the extrasynaptic membrane.

The advent of transgenic mice has made the developing retinogeniculate pathway a model system for targeting potential mechanisms that underlie the refinement of sensory connections. However, a detailed characterization of the form and function of this pathway is lacking. Here we use a variety of anatomical and electrophysiological techniques to delineate the structural and functional changes occurring in the lateral geniculate nucleus (LGN) of dorsal thalamus of the C57/BL6 mouse. During the first two postnatal weeks there is an age-related recession in the amount of terminal space occupied by retinal axons arising from the two eyes. During the first postnatal week, crossed and uncrossed axons show substantial overlap throughout most of the LGN. Between the first and second week retinal arbors show significant pruning, so that by the time of natural eye opening (P12–14) segregation is complete and retinal projections are organized into distinct eye-specific domains. During this time of rapid anatomical rearrangement, LGN cells could be readily distinguished using immunocytochemical markers that stain for NMDA receptors, GABA receptors, L-type Ca2+channels, and the neurofilament protein SMI-32. Moreover, the membrane properties and synaptic responses of developing LGN cells are remarkably stable and resemble those of mature neurons. However, there are some notable developmental changes in synaptic connectivity. At early ages, LGN cells are binocularly responsive and receive input from as many as 11 different retinal ganglion cells. Optic tract stimulation also evokes plateau-like depolarizations that are mediated by the activation of L-type Ca2+channels. As retinal inputs from the two eyes segregate into nonoverlapping territories, there is a loss of binocular responsiveness, a decrease in retinal convergence, and a reduction in the incidence of plateau potentials. These data serve as a working framework for the assessment of phenotypes of genetically altered strains as well as provide some insight as to the molecular mechanisms underlying the refinement of retinogeniculate connections.

In the rodent brain stem trigeminal complex, select sets of neurons form modular arrays or “barrelettes,” that replicate the patterned distribution of whiskers and sinus hairs on the ipsilateral snout. These cells detect the patterned input from the trigeminal axons that innervate the whiskers and sinus hairs. Other brain stem trigeminal cells, interbarrelette neurons, do not form patterns and respond to multiple whiskers. We examined the membrane properties and synaptic responses of morphologically identified barrelette and interbarrelette neurons in the principal sensory nucleus (PrV) of the trigeminal nerve in early postnatal rats shortly after whisker-related patterns are established. Barrelette cell dendritic trees are confined to a single barrelette, whereas the dendrites of interbarrelette cells span wider territories. These two cell types are distinct from smaller GABAergic interneurons. Barrelette cells can be distinguished by a prominent transient A-type K+ current ( I A) and higher input resistance. On the other hand, interbarrelette cells display a prominent low-threshold T-type Ca2+ current ( I T) and lower input resistance. Both classes of neurons respond differently to electrical stimulation of the trigeminal tract. Barrelette cells show either a monosynaptic excitatory postsynaptic potential (EPSP) followed by a large disynaptic inhibitory postsynaptic potential (IPSP) or just simply a disynaptic IPSP. Increasing stimulus intensity produces little change in EPSP amplitude but leads to a stepwise increase in IPSP amplitude, suggesting that barrelette cells receive more inhibitory input than excitatory input. This pattern of excitation and inhibition indicates that barrelette cells receive both feed-forward and lateral inhibition. Interbarrelette cells show a large monosynaptic EPSP followed by a small disynaptic IPSP. Increasing stimulus intensity leads to a stepwise increase in EPSP amplitude and the appearance of polysynaptic EPSPs, suggesting that interbarrelette cells receive excitatory inputs from multiple sources. Taken together, these results indicate that barrelette and interbarrelette neurons can be identified by their morphological and functional attributes soon after whisker-related pattern formation in the PrV.

The retinocollicular pathway undergoes activity-dependent refinement during postnatal development, which results in the precise retinotopic order seen in adults. This process is NMDA- and nitric oxide-dependent. Recent studies have shown that L-type Ca2+ channels may also play a role in synaptic plasticity, but such channel activity has not previously been reported in the developing superior colliculus (SC). Here we report the presence of a postsynaptic plateau potential mediated by L-type Ca2+ channels using whole-cell current clamp of the SC in an isolated brainstem preparation of rats. Seventy percent of SC neurons showed these potentials as early as postnatal day 0 (P0)-P2. The potential was blocked by nitrendipine and/or APV and facilitated by bicuculline, showing that the channel is activated by NMDA receptor-mediated EPSPs and deactivated by GABAA receptor-mediated IPSPs. Blockade of L-type Ca2+ channels also diminished long-term depression, which we could induce in the retinocollicular pathway in neonatal animals. The incidence of plateau potentials decreased to 39% of neurons by P10-P14, suggesting that L-type calcium channels may contribute to retinocollicular pathway refinement in the developing SC.

The synaptic organization in the lateral geniculate nucleus of the albino rabbit was studied with an intracellular recording technique. A disynaptic IPSP from the cortex and a trisynaptic IPSP from the optic nnerve could be recorded from both fast and slow relay cells. These IPSPs are most likely mediated by a common recurrent inhibitory pathaway. No evidence for a feed-forward inhibitory pathway to the relay cells was obtained.

Intracellular recordings from slow relay cells in the rabbit lateral geniculate nucleus demonstrated that the slow cells, just like the fast ones, receive a monosynaptic EPSP and a trisynaptic IPSP from the optic nerve. The IPSP is most likely mediated by interleurones activated by recurrent collaterals of the relay cell axon. In slow relay cells, both the EPSP and the IPSP from the optic nerve are brought about via the same group of slowly-conducting fibers. No mutual inhibition between the fast and the slow conducting system was observed in the rabbit lateral geniculate nucleus.

In the monocular segment of the rabbit lateral geniculate nucleus, relay cells responded exclusively to the contralateral optic input with an EPSP-IPSP sequence. The ipsilateral optic input could neither evoke PSPs nor facilitate the PSPs from the contralateral eye, indicating the absence of binocular inhibition in the segment.