Optic Tract Stimulation Research Articles

Pattern of Driver-Like Input onto Neurons of the Mouse Ventral Lateral Geniculate Nucleus.

The ventral lateral geniculate nucleus (vLGN) is a retinorecipient region of thalamus that contributes to a number of complex visual behaviors. Retinal axons that target vLGN terminate exclusively in the external subdivision (vLGNe), which is also transcriptionally and cytoarchitectonically distinct from the internal subdivision (vLGNi). While recent studies shed light on the cell types and efferent projections of vLGNe and vLGNi, we have a crude understanding of the source and nature of the excitatory inputs driving postsynaptic activity in these regions. Here, we address this by conducting in vitro whole-cell recordings in acutely prepared thalamic slices and using electrical and optical stimulation techniques to examine the postsynaptic excitatory activity evoked by the activation of retinal or cortical layer V input onto neurons in vLGNe and vLGNi. Activation of retinal afferents by electrical stimulation of optic tract or optical stimulation of retinal terminals resulted in robust driver-like excitatory activity in vLGNe. Optical activation of corticothalamic terminals from layer V resulted in similar driver-like activity in both vLGNe and vLGNi. Using a dual-color optogenetic approach, we found that many vLGNe neurons received convergent input from these two sources. Both individual pathways displayed similar driver-like properties, with corticothalamic stimulation leading to a stronger form of synaptic depression than retinogeniculate stimulation. We found no evidence of convergence in vLGNi, with neurons only responding to corticothalamic stimulation. These data provide insight into the influence of excitatory inputs to vLGN and reveal that only neurons in vLGNe receive convergent input from both sources.

Differential Distribution of Ca2+ Channel Subtypes at Retinofugal Synapses.

Retinofugal synapses serve as models for understanding how sensory signals from the periphery are relayed to the brain. Past studies have focused primarily on understanding the postsynaptic glutamatergic receptor subtypes involved in signal transmission, but the mechanisms underlying glutamate release at presynaptic retinal terminals remains largely unknown. Here we explored how different calcium (Ca2+) channel subtypes regulate glutamatergic excitatory synaptic transmission in two principal retinorecipient targets, the dorsal lateral geniculate nucleus (dLGN) and superior colliculus (SC) of the mouse. We used an in vitro slice preparation to record the synaptic responses of dLGN and SC neurons evoked by the electrical stimulation of optic tract (OT) fibers before and during the application of selective Ca2+ channel blockers. We found that synaptic responses to paired or repetitive OT stimulation were highly sensitive to extracellular levels of Ca2+ and to selective antagonists of voltage gated Ca2+ channels, indicating that these channels regulate the presynaptic release of glutamate at retinal synapses in both dLGN and SC. Bath application of selective Ca2+ channel blockers revealed that P/Q-type Ca2+ channels primarily operate to regulate glutamate release at retinal synapses in dLGN, while N-type Ca2+ channels dominate release in the SC.

Refinement of Spatial Receptive Fields in the Developing Mouse Lateral Geniculate Nucleus Is Coordinated with Excitatory and Inhibitory Remodeling.

Receptive field properties of individual visual neurons are dictated by the precise patterns of synaptic connections they receive, including the arrangement of inputs in visual space and features such as polarity (On vs Off). The inputs from the retina to the lateral geniculate nucleus (LGN) in the mouse undergo significant refinement during development. However, it is unknown how this refinement corresponds to the establishment of functional visual response properties. Here we conducted in vivo and in vitro recordings in the mouse LGN, beginning just after natural eye opening, to determine how receptive fields develop as excitatory and feedforward inhibitory retinal afferents refine. Experiments used both male and female subjects. For in vivo assessment of receptive fields, we performed multisite extracellular recordings in awake mice. Spatial receptive fields at eye-opening were >2 times larger than in adulthood, and decreased in size over the subsequent week. This topographic refinement was accompanied by other spatial changes, such as a decrease in spot size preference and an increase in surround suppression. Notably, the degree of specificity in terms of On/Off and sustained/transient responses appeared to be established already at eye opening and did not change. We performed in vitro recordings of the synaptic responses evoked by optic tract stimulation across the same time period. These recordings revealed a pairing of decreased excitatory and increased feedforward inhibitory convergence, providing a potential mechanism to explain the spatial receptive field refinement.SIGNIFICANCE STATEMENT The development of precise patterns of retinogeniculate connectivity has been a powerful model system for understanding the mechanisms underlying the activity-dependent refinement of sensory systems. Here we link the maturation of spatial receptive field properties in the lateral geniculate nucleus (LGN) to the remodeling of retinal and inhibitory feedforward convergence onto LGN neurons. These findings should thus provide a starting point for testing the cell type-specific plasticity mechanisms that lead to refinement of different excitatory and inhibitory inputs, and for determining the effect of these mechanisms on the establishment of mature receptive fields in the LGN.

Absence of plateau potentials in dLGN cells leads to a breakdown in retinogeniculate refinement.

The link between neural activity and the refinement of projections from retina to the dorsal lateral geniculate nucleus (dLGN) of thalamus is based largely on studies that disrupt presynaptic retinogeniculate activity. Postsynaptic mechanisms responsible for implementing the activity-dependent remodeling in dLGN remain unknown. We tested whether L-type Ca(2+) channel activity in the form of synaptically evoked plateau potentials in dLGN cells is needed for remodeling by using a mutant mouse that lacks the ancillary β3 subunit and, as a consequence, has highly reduced L-type channel expression and attenuated L-type Ca(2+) currents. In the dLGNs of β3-null mice, glutamatergic postsynaptic activity evoked by optic tract stimulation was normal, but plateau potentials were rarely observed. The few plateaus that were evoked required high rates of retinal stimulation, but were still greatly attenuated compared with those recorded in age-matched wild-type mice. While β3-null mice exhibit normal stage II and III retinal waves, their retinogeniculate projections fail to segregate properly and dLGN cells show a high degree of retinal convergence even at late postnatal ages. These structural and functional defects were also accompanied by a reduction in CREB phosphorylation, a signaling event that has been shown to be essential for retinogeniculate axon segregation. Thus, postsynaptic L-type Ca(2+) activity plays an important role in mediating the refinement of the retinogeniculate pathway.

Nuclei-specific differences in nerve terminal distribution, morphology, and development in mouse visual thalamus.

BackgroundMouse visual thalamus has emerged as a powerful model for understanding the mechanisms underlying neural circuit formation and function. Three distinct nuclei within mouse thalamus receive retinal input, the dorsal lateral geniculate nucleus (dLGN), the ventral lateral geniculate nucleus (vLGN), and the intergeniculate nucleus (IGL). However, in each of these nuclei, retinal inputs are vastly outnumbered by nonretinal inputs that arise from cortical and subcortical sources. Although retinal and nonretinal terminals associated within dLGN circuitry have been well characterized, we know little about nerve terminal organization, distribution and development in other nuclei of mouse visual thalamus.ResultsImmunolabeling specific subsets of synapses with antibodies against vesicle-associated neurotransmitter transporters or neurotransmitter synthesizing enzymes revealed significant differences in the composition, distribution and morphology of nonretinal terminals in dLGN, vLGN and IGL. For example, inhibitory terminals are more densely packed in vLGN, and cortical terminals are more densely distributed in dLGN. Overall, synaptic terminal density appears least dense in IGL. Similar nuclei-specific differences were observed for retinal terminals using immunolabeling, genetic labeling, axonal tracing and serial block face scanning electron microscopy: retinal terminals are smaller, less morphologically complex, and more densely distributed in vLGN than in dLGN. Since glutamatergic terminal size often correlates with synaptic function, we used in vitro whole cell recordings and optic tract stimulation in acutely prepared thalamic slices to reveal that excitatory postsynaptic currents (EPSCs) are considerably smaller in vLGN and show distinct responses following paired stimuli. Finally, anterograde labeling of retinal terminals throughout early postnatal development revealed that anatomical differences in retinal nerve terminal structure are not observable as synapses initially formed, but rather developed as retinogeniculate circuits mature.ConclusionsTaken together, these results reveal nuclei-specific differences in nerve terminal composition, distribution, and morphology in mouse visual thalamus. These results raise intriguing questions about the different functions of these nuclei in processing light-derived information, as well as differences in the mechanisms that underlie their unique, nuclei-specific development.

Changes in the modulation of retinocollicular transmission through group III mGluRs long after an increase in intraocular pressure in a rat model of glaucoma

Metabotropic glutamate receptors (mGluRs) have been shown to be involved in the modulation of retinocollicular neurotransmission. In glaucoma, retinal ganglion cells (RGCs) degenerate, which may have an implication on this transmission as the superior colliculus is their major central target in the much-used rodent models of the disease. We have investigated this using an in vitro slice preparation of the superior colliculus by eliciting field excitatory postsynaptic potentials (fEPSPs) through optic tract stimulation in a rat ocular hypertension model of glaucoma. Application of the group III mGluR agonist L-AP4 reduced the peak amplitude of the fEPSP in superior colliculus slices through presynaptic mechanisms as previously shown in our lab. At 3 and 16 weeks after surgery, there were no significant differences in the effect of L-AP4 on fEPSP peak amplitude in the superior colliculus slices receiving input from the glaucomatous eyes [elevated intraocular pressure (IOP)] compared to those with input from the unoperated eyes (normal IOP). However, at 32 weeks, the fEPSP peak amplitude was reduced to a significantly greater degree during L-AP4 application in the elevated IOP slices compared to normal IOP slices. At all time points, there were no significant changes in the baseline amplitudes of fEPSPs or the stimulus intensities required to evoke fEPSPs. These results suggest that the modulation of synaptic transmission through group III mGluRs on RGC terminals to the superior colliculus is changed at later stages due to RGC degeneration through IOP elevation. These changes may be compensatory changes possibly through plasticity in the RGC terminals of surviving cells, which may be due to increases in the numbers of group III mGluRs. This result may have implications on further treatment studies carried out using these models of glaucoma as changes in the central visual system may need to be considered along with the retinal changes that occur.

Requirements for synaptically evoked plateau potentials in relay cells of the dorsal lateral geniculate nucleus of the mouse

In developing cells of the mouse dorsal lateral geniculate nucleus (dLGN), synaptic responses evoked by optic tract (OT) stimulation give rise to long-lasting, high-amplitude depolarizations known as plateau potentials. These events are mediated by L-type Ca2+ channels and occur during early postnatal life, a time when retinogeniculate connections are remodelling. To better understand the relationship between L-type activity and dLGN development we used an in vitro thalamic slice preparation which preserves the retinal connections and intrinsic circuitry in dLGN and examined how synaptic responses evoked by OT stimulation lead to the activation of plateau potentials. By varying the strength and temporal frequency of OT stimulation we identified at least three factors that contribute to the developmental regulation of plateau activity: the degree of retinal convergence, the temporal pattern of retinal stimulation and the emergence of feed-forward inhibition. Before natural eye opening (postnatal day 14), the excitatory synaptic responses of relay cells receiving multiple retinal inputs summated in both the spatial and temporal domains to produce depolarizations sufficient to activate L-type activity. After eye opening, when inhibitory responses are fully developed, plateau activity was rarely evoked even with high temporal rates of OT stimulation. When the bulk of this inhibition was blocked by bath application of bicuculline, the incidence of plateau activity increased significantly. We also made use of a transgenic mouse that lacks the β3 subunit of the L-type Ca2+ channel. These mutants have far fewer membrane-bound Ca2+ channels and attenuated L-type activity. In β3 nulls, L-type plateau activity was rarely observed even at young ages when plateau activity prevails. Thus, in addition to the changing patterns of synaptic connectivity and retinal activity, the expression of L-type Ca2+ channels is a requisite component in the manifestation of plateau activity.

Cortical visual evoked potentials recorded after optic tract near field stimulation during GPi-DBS in non-cooperative patients

Object Neurophysiologic monitoring during deep brain stimulation (DBS) interventions in the globus pallidus internum (Gpi) for the treatment of Parkinson's disease or primary dystonia is generally based upon microelectrode recordings (MER); moreover, MER request sophisticated technology and high level trained personnel for a reliable monitoring. Recordings of cortical visual evoked potentials (CVEPs) obtained after stimulation of the optic tract may be a potential option to MER; since optic tract lies just beneath the best target for Gpi DBS, changes in CVEPs during intraoperative exploration may drive a correct electrode positioning. Patients and methods Cortical VEPs from optic tract stimulation (OT C-CEPs) have been recorded in seven patients during GPi-DBS for the treatment of Parkinson's disease and primary dystonia under general sedation. OT C-VEPs were obtained after near-field monopolar stimulation of the optic tract; recording electrodes were at the scalp. Cortical responses after optic tract versus standard visual stimulation were compared. Results After intraoperative near-field OT stimulation a biphasic wave, named N40–P70, was detected in all cases. N40–P70 neither change in morphology nor in latency at different depths, but increased in amplitude approaching the optic tract. The electrode tip was positioned just 1 mm above the point where OT-CVEPs showed the larger amplitude. No MERs were obtained in these patients; OT CVEPs were the only method to detect the Gpi before positioning the electrodes. Conclusions OT CVEPs seem to be as reliable as MER to detail the optimal target in Gpi surgery: in addition they are less expensive, faster to perform and easier to decode.

Synaptic development of the mouse dorsal lateral geniculate nucleus

The dorsal lateral geniculate nucleus (dLGN) of the mouse has emerged as a model system in the study of thalamic circuit development. However, there is still a lack of information regarding how and when various types of retinal and nonretinal synapses develop. We examined the synaptic organization of the developing mouse dLGN in the common pigmented C57/BL6 strain, by recording the synaptic responses evoked by electrical stimulation of optic tract axons, and by investigating the ultrastructure of identified synapses. At early postnatal ages (<P12), optic tract evoked responses were primarily excitatory. The full complement of inhibitory responses did not emerge until after eye opening (>P14), when optic tract stimulation routinely evoked an excitatory postsynaptic potential/inhibitory postsynaptic potential (EPSP/IPSP) sequence, with the latter having both a GABA(A) and GABA(B) component. Electrophysiological and ultrastructural observations were consistent. At P7, many synapses were present, but synaptic profiles lacked the ultrastructural features characteristic of the adult dLGN, and little gamma-aminobutyric acid (GABA) could be detected by using immunocytochemical techniques. In contrast, by P14, GABA staining was robust, mature synaptic profiles of retinal and nonretinal origin were easily distinguished, and the size and proportion of synaptic contacts were similar to those of the adult. The emergence of nonretinal synapses coincides with pruning of retinogeniculate connections, and the transition of retinal activity from spontaneous to visually driven. These results indicate that the synaptic architecture of the mouse dLGN is similar to that of other higher mammals, and thus provides further support for its use as a model system for visual system development.

Cholinergic modulation of non- N-methyl- d-aspartic acid glutamatergic transmission in the chick ventral lateral geniculate nucleus

Neurotransmission between glutamatergic terminals of retinal ganglion cells and principal neurons of the ventral lateral geniculate nucleus (LGNv) was examined with patch clamp recordings in chick brain slices during electrical stimulation of the optic tract. Since muscarinic and nicotinic receptors are present in high densities in LGNv, the present study examined possible roles of both receptors in modulating retinogeniculate transmission. During whole-cell recordings from LGNv neurons, acetylcholine (ACh, 100 μM) caused an initial increase in amplitudes of optic tract-evoked non- N-methyl- d-aspartic acid (NMDA) glutamatergic postsynaptic currents (PSCs). This increase was unchanged when 1 μM atropine was present, indicating that this initial enhancement of PSCs was due entirely to activation of nicotinic receptors. However, during washout of ACh the amplitudes of evoked PSCs became significantly decreased by 40.4±5.0% for several minutes before recovering to their original amplitudes, an effect blocked by 1 μM atropine. Exogenously applied muscarine (10 μM) markedly depressed optic tract-evoked PSCs, and this decrease in amplitude was blocked by atropine. In a second set of experiments, we examined effects of releasing endogenous ACh prior to optic tract stimulation. This was accomplished by stimulation of the lateral portion of LGNv via a separate conditioning electrode. Following a brief train of low intensity conditioning stimuli, non-NMDA glutamatergic PSCs evoked by optic tract stimulation were potentiated. However, at higher conditioning stimulus intensities the PSCs were markedly decreased compared with control, and this decrease was partially blocked by atropine (1 μM). Neither ACh nor muscarine altered amplitudes of PSCs elicited by exogenously applied glutamate. Muscarine significantly reduced the frequency but not the amplitudes of miniature PSCs, consistent with a presynaptic location for muscarinic receptors mediating these effects. Thus while activation of nicotinic receptors potentiates retinogeniculate transmission, activation of muscarinic receptors mediates depression of transmission, demonstrating a complex cholinergic modulation of sensory information in LGNv.

Distinct Roles of Metabotropic Glutamate Receptor Activation on Inhibitory Signaling in the Ventral Lateral Geniculate Nucleus

The ventral lateral geniculate nucleus (vLGN) has been implicated in numerous functions including circadian rhythms, brightness discrimination, pupillary light reflex, and other visuomotor functions. The contribution of inhibitory mechanisms in the regulation of vLGN neuron excitability remains unexplored. We examined the actions of metabotropic glutamate receptor (mGluR) activation on the intrinsic excitability and inhibitory synaptic transmission in different lamina of vLGN. Activation of mGluRs exerts distinct pre- and postsynaptic actions in vLGN neurons. In the lateral magnocellular subdivision of vLGN (vLGNl), the general mGluR agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD) enhanced the frequency of GABA(A) receptor-mediated spontaneous inhibitory postsynaptic currents (sIPSC) that persisted in the presence of sodium channel blocker tetrodotoxin (TTX) in a subpopulation of neurons (TTX insensitive). This increase is attributed to the increased output of dendritic GABA release from vLGN interneurons. In contrast, in the medial subdivision of vLGN (vLGNm), the mGluR agonist-mediated increase in sIPSC frequency was completely blocked by TTX. The selective Group I mGluR agonist (RS)-3,5-dihydroxyphenylglycine (DHPG) increased sIPSC frequency, whereas the selective Group II mGluR agonist (2R, 4R)-4-aminopyrrolidine-2,4-dicarboxylate (APDC) significantly decreased sIPSC frequency in vLGNl neurons. Optic tract stimulation also produced an mGluR-dependent increase in sIPSC frequency in vLGNl neurons. In contrast, we were unable to synaptically evoke alterations in sIPSC activity in vLGNm neurons. In addition to these presynaptic actions, DHPG depolarized both vLGNl and vLGNm neurons. In vLGN interneurons, mGluR activation produced opposing actions: APDC hyperpolarized the membrane potential, whereas DHPG produced a membrane depolarization. The present findings demonstrate diverse actions of mGluRs on vLGN neurons localized within different vLGN lamina. Considering these different lamina are coupled with distinct functional roles, thus these diverse actions may be involved in distinctive forms of visual and visuomotor information processing.

Active Dendritic Conductances Dynamically Regulate GABA Release from Thalamic Interneurons

Inhibitory interneurons in the dorsal lateral geniculate nucleus (dLGN) process visual information by precisely controlling spike timing and by refining the receptive fields of thalamocortical (TC) neurons. Previous studies indicate that dLGN interneurons inhibit TC neurons by releasing GABA from both axons and dendrites. However, the mechanisms controlling GABA release are poorly understood. Here, using simultaneous whole-cell recordings from interneurons and TC neurons and two-photon calcium imaging, we find that synchronous activation of multiple retinal ganglion cells (RGCs) triggers sodium spikes that propagate throughout interneuron axons and dendrites, and calcium spikes that invade dendrites but not axons. These distinct modes of interneuron firing can trigger both a rapid and a sustained component of inhibition onto TC neurons. Our studies suggest that active conductances make LGN interneurons flexible circuit-elements that can shift their spatial and temporal properties of GABA release in response to coincident activation of functionally related subsets of RGCs.

Metabotropic Glutamate Receptors Differentially Regulate GABAergic Inhibition in Thalamus

Thalamic interneurons and thalamic reticular nucleus (TRN) neurons provide inhibitory innervation of thalamocortical cells that significantly influence thalamic gating. The local interneurons in the dorsal lateral geniculate nucleus (dLGN) give rise to two distinct synaptic outputs: classical axonal and dendrodendritic. Activation of metabotropic glutamate receptors (mGluRs) by agonists or optic tract stimulation increases the output of these presynaptic dendrites leading to increased inhibition of thalamocortical neurons. The present study was aimed to evaluate the actions of specific mGluRs on inhibitory GABA-mediated signaling. We found that the group I mGluR (mGluR(1,5)) agonist (RS)-3,5-dihydroxyphenylglycine (DHPG) or optic tract stimulation produced a robust increase in spontaneous IPSCs (sIPSCs) in thalamocortical neurons that was attenuated by the selective mGluR(5) antagonist 2-methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP). In contrast, the group II mGluR (mGluR(2,3)) agonists (2R, 4R)-4-aminopyrrolidine-2,4-dicarboxylate (APDC) or (2S,2'R,3'R)-2-(2'3'-dicarboxycyclopropyl)glycine (DCG-IV) suppressed the frequency of sIPSCs. In addition, mGluR(1,5) agonist DHPG produced depolarizations and mGluR(2/3) agonists APDC or L-CCG-I [(2S,1'S,2'S)-2-(carboxycyclopropyl)glycine] produced hyperpolarizations in dLGN interneurons. Furthermore, the enhanced sIPSC activity by optic tract stimulation was reduced when paired with corticothalamic fiber stimulation. The present data indicate that activation of specific mGluR subtypes differentially regulates inhibitory activity via different synaptic pathways. Our results suggest that activation of specific mGluR subtypes can upregulate or downregulate inhibitory activity in thalamic relay neurons, and these actions likely shape excitatory synaptic integration and thus regulate information transfer through thalamocortical circuits.

A two-dimensional population density approach to modeling the dLGN/PGN network

The interaction of two populations of integrate-and-fire-or-burst neurons representing thalamocortical cells from the dorsal lateral geniculate nucleus (dLGN) and thalamic reticular cells from the perigeniculate nucleus (PGN) is studied here using a population density approach. A two-dimensional probability density function that evolves according to a time-dependent advection-reaction equation gives the distribution of cells in each population over the membrane potential ( v ) and de-inactivation level ( h ) of the low-threshold Ca 2 + current I T . The response of the dLGN/PGN network is studied for optic tract stimulation protocols of different amplitude, duty cycle, and frequency.

Depression of retinogeniculate synaptic transmission by presynaptic D2‐like dopamine receptors in rat lateral geniculate nucleus

Extraretinal projections onto neurons in the dorsal lateral geniculate nucleus (dLGN) play an important role in modifying sensory information as it is relayed from the visual thalamus to neocortex. The dLGN receives dopaminergic innervation from the ventral tegmental area; however, the role of dopamine in synaptic transmission in dLGN has not been explored. In the present study, whole cell recordings were obtained to examine the actions of dopamine on glutamatergic synaptic transmission. Dopamine (2-100 microm) strongly suppressed excitatory synaptic transmission in dLGN relay neurons that was evoked by optic tract stimulation and mediated by both N-methyl-d-aspartate and non-N-methyl-d-aspartate glutamate receptors. In contrast, dopamine did not alter inhibitory synaptic transmission arising from either dLGN interneurons or thalamic reticular nucleus neurons. The suppressive action of dopamine on excitatory synaptic transmission was mimicked by the D(2)-like dopamine receptor agonist bromocriptine (2-25 microm) but not by the D(1)-like receptor agonist SKF38393 (10-25 microm). In addition, the dopamine-mediated suppression was antagonized by the D(2)-like receptor antagonist sulpiride (10-20 microm) but not by the D(1)-like receptor antagonist SCH23390 (5-25 microm). The dopamine-mediated decrease in evoked excitatory postsynaptic current amplitude was accompanied by an increase in the magnitude of paired-pulse depression. Furthermore, dopamine also reduced the frequency but not the amplitude of miniature excitatory postsynaptic currents. Taken together, these data suggest that dopamine may act presynaptically to regulate the release of glutamate at the retinogeniculate synapse and modify transmission of visual information in the dLGN.

Intracellular and current source density analyses of somatosensory input to the optic tectum of the frog

This is the first report of current source density (CSD) and intracellular analyses of non-optic processing in the frog optic tectum. Sciatic nerve stimulation was used to test for somatosensory input to the optic tectum. To demonstrate the distribution of somatosensory input, field potentials were recorded from the whole surface of both tecta. Two components were observed. An early component was found in the whole area, but a late component was detected only in medial and caudal regions of the contralateral tectum. The effect of different stimulus intensity suggested that the optic tectum receives mainly the tactile sensation with fast conducting, low threshold level afferents from the sciatic nerve. The result of CSD analysis suggests that somatosensory afferents terminate on the tectal neurons with vertically expanding dendrites at the medial site of the contralateral optic tectum where the late component was found. Intracellular recordings demonstrated postsynaptic potentials in the middle and deeper layers, which is consistent with results from mammalian superior colliculus in earlier studies. Additional stimulation of the optic tract demonstrated that some somatosensory neurons had bimodal responses. The responses of those in the middle layers appeared to participate in avoidance behavior, based upon previous CSD analysis of the tectum using optic tract stimulation. All somatosensory responses elicited in these neurons were IPSPs. The findings imply that the somatosensory input to the optic tectum gives a suppressive effect on avoidance behavior. A somatosensory effect on prey-catching behavior could not be found in the present small number of intracellular data.

Structural and functional composition of the developing retinogeniculate pathway in the mouse

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.

Synaptically Released and Exogenous ACh Activates Different Nicotinic Receptors to Enhance Evoked Glutamatergic Transmission in the Lateral Geniculate Nucleus

The effects of activation of nicotinic acetylcholine receptors (nAChRs) on glutamatergic transmission in the ventral lateral geniculate nucleus (LGNv) were examined in chick brain slices. Whole cell recordings showed that monosynaptic postsynaptic currents (PSCs) evoked in LGNv neurons by optic tract stimulation were blocked by glutamate receptor antagonists. Exogenously applied nicotine (0.5 microM), choline (1 mM), or acetylcholine (ACh, 100 microM) markedly increased (>3-fold) these evoked PSCs. Potentiation by ACh was dose-dependent and did not desensitize during a 5-min application. In a second set of experiments, the effect of releasing endogenous ACh by stimulating the lateral portion of the LGNv through a separate conditioning electrode before optic tract stimulation was examined. Conditioning stimulation trains increased PSCs by an average of 5.2-fold, an effect dependent on both the intensity and number of conditioning pulses. This increase in PSC amplitude was most likely caused by released ACh activating alpha6- and/or alpha3-containing nAChRs because it was blocked by 100 nM alpha-conotoxin MII, 100 nM dihydro-beta-erythroidine (DHbetaE), and 0.1-1.0 microM methyllycaconitine (MLA). In contrast, exogenously applied ACh increased PSC amplitude by activating a pharmacologically different population of nAChRs because this effect was inhibited by 100 nM alpha-bungarotoxin, 50 nM MLA, and a high concentration (30 microM) of DHbetaE, indicating that alpha7- and/or alpha8-containing receptors were involved. The results are consistent with a model whereby alpha6- and/or alpha3-containing nAChRs on retinal ganglion cell nerve terminals are located preferentially at cholinergic synapses, whereas alpha7- and/or alpha8-containing receptors are primarily extrasynaptic.

Timing and Specificity of Feed-Forward Inhibition within the LGN

Local interneurons provide feed-forward inhibition from retinal ganglion cells (RGCs) to thalamocortical (TC) neurons, but questions remain regarding the timing, magnitude, and functions of this inhibition. Here, we identify two types of inhibition that are suited to play distinctive roles. We recorded excitatory and inhibitory postsynaptic currents (EPSCs/IPSCs) in TC neurons in mouse brain slices and activated individual RGC inputs. In 34% of TC neurons, we identified EPSCs and IPSCs with identical thresholds that were tightly correlated, indicating activation by the same RGC. Such "locked" IPSCs occurred 1 ms after EPSC onset. The remaining neurons had only "nonlocked" inhibition, in which EPSCs and IPSCs had different thresholds, indicating activation by different RGCs. Nonlocked inhibition may refine receptive fields within the LGN by providing surround inhibition. In contrast, dynamic-clamp recordings suggest that locked inhibition improves the precision of synaptically evoked responses in individual TC neurons by eliminating secondary spikes.

Modulation of retino-collicular transmission by Group III metabotropic glutamate receptors at different ages during development

Group III metabotropic glutamate receptors (especially mGlu4, mGlu7, mGlu8) are thought to be involved in modulating visual processing in the adult superior colliculus, a major termination site of retinal input in the rodent brain. We have investigated this role by making field EPSP recordings in response to optic tract stimulation in superior colliculus slices taken from rats aged from P14 to P180. Application of the Group III agonist L-AP4 at a concentration (10 μM) effective to activate mGlu4 and mGlu8 receptors, but not mGlu7 receptors, resulted in reductions of the field EPSP in all ages, although the effect was greatest in slices taken from P14 rats. Increasing the L-AP4 concentration to 100 μM so as to also activate mGlu7 receptors resulted in further field EPSP reductions. Similar reductions were seen in the combined presence of the GABA antagonists picrotoxin and CGP55845A, indicating a lack of involvement of GABAergic mechanisms in the action of L-AP4. Pairing of optic tract stimuli (20 ms separation) resulted in paired-pulse depression at all ages. L-AP4 was found to reduce paired-pulse depression at both 10 μM and 100 μM in slices from all ages of rat. The results of this study suggest that mGlu4/mGlu8 and mGlu7 receptors modulate retino-tectal transmission via a presynaptic mechanism, and that these effects are greatest in young animals. This is the first demonstration of a functional change in Group III receptor effect with aging, and this would be consistent with developmental regulation of these receptors.