Felch DL , Khakhalin AS , Aizenman CD .

T32 EY018080 NEI NIH HHS

	Figure 1. Multisensory integration in tectal neurons is dependent on interstimulus interval (ISI).(A) Diagram showing placement of the 'V' and 'HB' bipolar electrodes relative to tectal afferents and recording location. (B) Raw traces of cell-attached spikes generated during single and paired stimulation. Letters indicate times of stimulus presentation and modality of stimulus. (C) Example raster plots from two cells, one from a stages 44–46 animal (left) and one from a stages 48–49 animal (right) as a function of ISI. (D) Grouped data from both developmental groups. In a given cell, data are averaged over trials at each ISI, to determine the MSIn ratio. Plotted here is the population means of these trial-averaged MSIn ratios, at the ISI's tested. Error bars show +/– S.E.M. MSIn = (combined response – single response) / single response.DOI: http://dx.doi.org/10.7554/eLife.15600.002
	Figure 2. Developmental changes in temporal tuning and gain of MSI.(A, B) Histogram bars show the ISI that for each cell, exhibited maximal MSIn values. Notice that values cluster at shorter ISIs in the younger tadpoles. Older tadpoles are tuned to a broader range of ISIs. (C) Maximum MSIn ratios are compared across developmental stages, and show decrease in MSIn gain over development. Error bars indicate +/– S.E.M. (D) The identity of the ISI's responsible for the maximal response (and thus the maximum MSIn ratio) in each developmental group are compared. Error bars show interquartile range. *p<0.05. (E) MSIn-versus-ISI tuning curves from crossmodal pairs were aligned at their peak values, and then averaged across cells. Solid lines connect the population means. Shaded areas demarcate +/– S.E.M. Stage 48–49 cells are more narrowly tuned around their preferred ISI. MSIn = (combined response – single response) / single response.DOI: http://dx.doi.org/10.7554/eLife.15600.003
	Figure 3. Interaction between different modalities is mostly linear or sublinear.(A) Traces show examples of two possible outcomes of interactions between different modality responses. The upper traces show an example of sublinear summation, where the combined response evoked fewer spikes than the sum of the individual responses. The bottom example shows supralinear summation, where the combined response evokes more spikes than the sum of the individual responses. (B) For each cell, the maximum raw spike counts after paired stimulation (combined response) is plotted against the spike count predicted by the sum of adding individual modality responses. Dashed line represents the line of unity. Notice that most points cluster to the right of the dashed line, indicating a sublinear interaction. (C) Cumulative Frequency Distributions of Z-score values are plotted for the comparison between predicted and actual number of action potentials recorded after paired stimulation, in each cell. Vertical dashed lines indicate Z = +/–1.97, the point at which actual responses are +/–2 S.D.'s away from the respective predicted response. For greater detail on generation of the predicted responses and calculation of Z-scores, see Materials and methods. (D) Distribution of cells by interaction type shows few developmental differences.DOI: http://dx.doi.org/10.7554/eLife.15600.005
	Figure 4. Developmental changes in MSI do not simply reflect changes in network dynamics.(A) Grouped data showing enhancement of unisensory pairs at both developmental groups. In a given cell, data are averaged over multiple trials at each ISI, to determine the PPR. Plotted here is the population means of these trial-averaged PPR ratios, at the ISI's tested. Error bars show +/– S.E.M. (B) Histogram bars show the ISI that for each cell, exhibited maximal PPR values. Notice that values tend to cluster at shorter ISIs in both groups. (C) Maximum PPR ratios are compared across developmental stages, and show no change in PPR gain over development. Error bars indicate +/– S.E.M. (D) The identity of the ISI's at which maximal PPR occurred, separated by developmental group. Error bars show interquartile range. n. s. = not significant. (E) PPR-versus-ISI tuning curves from unimodal pairs were aligned at their peak values, and then averaged across cells. Since pairs were unisensory, only one direction is shown. Solid lines connect the population means. Shaded areas demarcate +/– S.E.M. Tuning for unisensory pairs does not change over development. PPR = (paired response – single response) / single response.DOI: http://dx.doi.org/10.7554/eLife.15600.006
	Figure 5. Inhibitory blockade broadens tuning window and enhances gain of MSI.(A) Grouped data from stage 48–9 tadpoles in control condition and in the presence of GABAA receptor blocker PTX. In a given cell, data are averaged over trials at each ISI, to determine the MSI ratio. Plotted here are the population means of these trial-averaged MSIn ratios, at each ISI tested. Error bars show +/– S.E.M. (B) Histogram bars show the ISI at which each cell exhibited maximal MSIn values in control and PTX groups. Notice that PTX shifts the preferred ISI values to shorter intervals. (C) Maximum MSIn ratios are compared across control and PTX conditions, and show increase in MSI gain with inhibitory blockade. Error bars indicate +/– S.E.M. (D) The identity of the ISI's responsible for the maximal response (and thus the maximum MSI ratio) in control and PTX groups are compared. Error bars show interquartile range. *p<0.05. (E) MSI-versus-ISI tuning curves from crossmodal pairs were aligned at their peak values, and then averaged across cells. Solid lines connect the population means. Shaded areas demarcate +/– S.E.M. PTX treated cells are more broadly tuned around their preferred ISI. (F) For each cell, the maximum raw spike counts after paired stimulation (combined response) is plotted against the spike count predicted by the linear sum of individual modality responses. Dashed line represents the line of unity. Notice that in PTX treated group most points cluster to the left of the dashed line. (C) Cumulative Frequency Distributions of Z-score values are plotted for the comparison between predicted and actual number of action potentials recorded after paired stimulation, in each cell. Vertical dashed lines indicate Z = +/–1.97, the point at which actual responses are +/–2 S.D.'s away from the respective predicted response. For greater detail on generation of the predicted responses and calculation of Z-scores, see Materials and methods. Z-scores in the PTX treated group are significantly shifted toward the right (p<0.0001, Kolmogorov-Smirnov test).DOI: http://dx.doi.org/10.7554/eLife.15600.007
	Figure 6. Crossmodal responses have faster onset latencies than single unimodal responses across groups, but inhibitory blockade slows response onset times.(A, B, C) Plot of response onset times for single responses and crossmodal responses at multiple ISIs for all experimental groups. For each paired ISI, as well as the appropriate control stimulus (left axis), the. 25,. 50 (median), and. 75 quartiles of post-stimulus times for all first spikes are plotted on the bottom axis. Dashed lines connect 0.25 and 0.75 quartile values, and solid lines connect. 50 quartile (median) values. (D) Comparison of response onset times of paired vs. unpaired responses shows that across conditions, cross modal responses occur faster than single modality responses. (E) Comparison between paired response onset times across groups shows that while there is no significant speeding up of the response over development, picrotoxin delays onset times. Bars indicate median values, error bars show the IQR. *p< 0.05DOI: http://dx.doi.org/10.7554/eLife.15600.008
	Figure 7. Multisensory responses have a greater inhibitory to excitatory ratio in older animals.(A) Sample excitatory (red) and inhibitory (blue) synaptic conductances recorded at different ISIs. S1 and S2 show timing of the individual modality responses (V and HB, respectively in this example). (B) Plot of crossmodal enhancement of excitatory synaptic conductances as a function of ISI at both developmental stages. Notice that excitation becomes relatively less enhanced in the older tadpoles. (C) Plot of crossmodal enhancement of inhibitory synaptic conductances as a function of ISI at both developmental stages. Notice that there is no developmental change in the amount of inhibitory enhancement. P value determined from 2-way ANOVA. (D) Plot of maximum excitatory and inhibitory enhancement for each cell. Dotted line represents linear fit for each developmental group. p value determined by an F-Test and compares both fits. Notice that older cells exhibit relatively more inhibitory than excitatory enhancement.DOI: http://dx.doi.org/10.7554/eLife.15600.009

Akerman, Depolarizing GABAergic conductances regulate the balance of excitation to inhibition in the developing retinotectal circuit in vivo. 2006, Pubmed, Xenbase

Akerman, Depolarizing GABAergic conductances regulate the balance of excitation to inhibition in the developing retinotectal circuit in vivo. 2006, Pubmed , Xenbase
Alvarado, Multisensory versus unisensory integration: contrasting modes in the superior colliculus. 2007, Pubmed
Baum, Behavioral, perceptual, and neural alterations in sensory and multisensory function in autism spectrum disorder. 2015, Pubmed
Behrend, Neural responses to water surface waves in the midbrain of the aquatic predator Xenopus laevis laevis. 2006, Pubmed , Xenbase
Bell, A neuroprotective role for polyamines in a Xenopus tadpole model of epilepsy. 2011, Pubmed , Xenbase
Bergan, Visual modulation of auditory responses in the owl inferior colliculus. 2009, Pubmed
Binns, Importance of NMDA receptors for multimodal integration in the deep layers of the cat superior colliculus. 1996, Pubmed
Ciarleglio, Multivariate analysis of electrophysiological diversity of Xenopus visual neurons during development and plasticity. 2015, Pubmed , Xenbase
Deeg, Development of multisensory convergence in the Xenopus optic tectum. 2009, Pubmed , Xenbase
Dong, Visual avoidance in Xenopus tadpoles is correlated with the maturation of visual responses in the optic tectum. 2009, Pubmed , Xenbase
Dong, A competition-based mechanism mediates developmental refinement of tectal neuron receptive fields. 2012, Pubmed , Xenbase
Foxe, Severe multisensory speech integration deficits in high-functioning school-aged children with Autism Spectrum Disorder (ASD) and their resolution during early adolescence. 2015, Pubmed
Gaze, The evolution of the retinotectal map during development in Xenopus. 1974, Pubmed , Xenbase
Graybiel, Anatomical organization of retinotectal afferents in the cat: an autoradiographic study. 1975, Pubmed
Hillock, Binding of sights and sounds: age-related changes in multisensory temporal processing. 2011, Pubmed
Hiramoto, Convergence of multisensory inputs in Xenopus tadpole tectum. 2009, Pubmed , Xenbase
Jiang, Two cortical areas mediate multisensory integration in superior colliculus neurons. 2001, Pubmed
Khakhalin, GABAergic transmission and chloride equilibrium potential are not modulated by pyruvate in the developing optic tectum of Xenopus laevis tadpoles. 2012, Pubmed , Xenbase
Khakhalin, Excitation and inhibition in recurrent networks mediate collision avoidance in Xenopus tadpoles. 2014, Pubmed , Xenbase
Knudsen, Visual instruction of the neural map of auditory space in the developing optic tectum. 1991, Pubmed
Knudsen, Instructed learning in the auditory localization pathway of the barn owl. 2002, Pubmed
Knudsen, Auditory and visual maps of space in the optic tectum of the owl. 1982, Pubmed
Lowe, Organisation of lateral line and auditory areas in the midbrain of Xenopus laevis. 1986, Pubmed , Xenbase
Lowe, Single-unit study of lateral line cells in the optic tectum of Xenopus laevis: evidence for bimodal lateral line/optic units. 1987, Pubmed , Xenbase
Markram, The intense world theory - a unifying theory of the neurobiology of autism. 2010, Pubmed
May, The mammalian superior colliculus: laminar structure and connections. 2006, Pubmed
Meredith, Interactions among converging sensory inputs in the superior colliculus. 1983, Pubmed
Meredith, Spatial determinants of multisensory integration in cat superior colliculus neurons. 1996, Pubmed
Meredith, Determinants of multisensory integration in superior colliculus neurons. I. Temporal factors. 1987, Pubmed
Miller, Relative unisensory strength and timing predict their multisensory product. 2015, Pubmed
Miraucourt, GABA expression and regulation by sensory experience in the developing visual system. 2012, Pubmed , Xenbase
Pouille, Enforcement of temporal fidelity in pyramidal cells by somatic feed-forward inhibition. 2001, Pubmed
Pratt, Development and spike timing-dependent plasticity of recurrent excitation in the Xenopus optic tectum. 2008, Pubmed , Xenbase
Pratt, Homeostatic regulation of intrinsic excitability and synaptic transmission in a developing visual circuit. 2007, Pubmed , Xenbase
Priebe, Inhibition, spike threshold, and stimulus selectivity in primary visual cortex. 2008, Pubmed
Roberts, Responses of hatchling Xenopus tadpoles to water currents: first function of lateral line receptors without cupulae. 2009, Pubmed , Xenbase
Rowland, A model of the neural mechanisms underlying multisensory integration in the superior colliculus. 2007, Pubmed
Rowland, Multisensory integration shortens physiological response latencies. 2007, Pubmed
Shen, Inhibition to excitation ratio regulates visual system responses and behavior in vivo. 2011, Pubmed , Xenbase
Skaliora, Functional topography of converging visual and auditory inputs to neurons in the rat superior colliculus. 2004, Pubmed
Stanford, Evaluating the operations underlying multisensory integration in the cat superior colliculus. 2005, Pubmed
Stein, The neural basis of multisensory integration in the midbrain: its organization and maturation. 2009, Pubmed
Stein, Multisensory integration: current issues from the perspective of the single neuron. 2008, Pubmed
Straznicky, The development of the tectum in Xenopus laevis: an autoradiographic study. 1972, Pubmed , Xenbase
Tao, Activity-dependent matching of excitatory and inhibitory inputs during refinement of visual receptive fields. 2005, Pubmed , Xenbase
Wallace, Development of multisensory neurons and multisensory integration in cat superior colliculus. 1997, Pubmed
Wallace, Onset of cross-modal synthesis in the neonatal superior colliculus is gated by the development of cortical influences. 2000, Pubmed
Wallace, The development of cortical multisensory integration. 2006, Pubmed
Wallace, Early experience determines how the senses will interact. 2007, Pubmed
Wallace, Converging influences from visual, auditory, and somatosensory cortices onto output neurons of the superior colliculus. 1993, Pubmed
Wehr, Balanced inhibition underlies tuning and sharpens spike timing in auditory cortex. 2003, Pubmed
Wu, Maturation of a central glutamatergic synapse. 1996, Pubmed , Xenbase
Xu, Incorporating cross-modal statistics in the development and maintenance of multisensory integration. 2012, Pubmed
Yu, Multisensory plasticity in adulthood: cross-modal experience enhances neuronal excitability and exposes silent inputs. 2013, Pubmed
Yu, Initiating the development of multisensory integration by manipulating sensory experience. 2010, Pubmed
Zittlau, Horseradish peroxidase study of tectal afferents in Xenopus laevis with special emphasis on their relationship to the lateral-line system. 1988, Pubmed , Xenbase