Visual subcircuit-specific dysfunction and input-specific mispatterning in the superior colliculus of fragile X mice.

BACKGROUND: Sensory processing deficits are frequently co-morbid with neurodevelopmental disorders. For example, patients with fragile X syndrome (FXS), caused by a silencing of the FMR1 gene, exhibit impairments in visual function specific to the dorsal system, which processes motion information. However, the developmental and circuit mechanisms underlying this deficit remain unclear. Recently, the superior colliculus (SC), a midbrain structure regulating head and eye movements, has emerged as a model for dissecting visual circuit development and function. Previous studies have demonstrated a critical role for activity-dependent processes in the development of visual circuitry in the SC. Based on the known role of the FMR1 gene product in activity-dependent synaptic plasticity, we explored the function and organization of visual circuits in the SC of a mouse model of FXS (Fmr1-/y). METHODS: We utilized in vivo extracellular electrophysiology in combination with computer-controlled visual stimuli to determine the receptive field properties of visual neurons in the SC of control and Fmr1-/y mice. In addition, we utilized anatomical tracing methods to assess the organization of visual inputs to the SC and along the retinogeniculocortical pathway. RESULTS: Receptive fields of visual neurons in the SC of Fmr1-/y mice were significantly larger than those found in control animals, though their shape and structure were unaffected. Further, selectivity for direction of movement was decreased, while selectivity to axis of movement was unchanged. Interestingly, axis-selective (AS) neurons exhibited a specific hyperexcitability in comparison to AS neurons in control SC and to direction-selective (DS) neurons in both control and Fmr1-/y SC. Anatomical tracings revealed that retinocollicular, retinogeniculate, and geniculocortical projections were normally organized in the absence of Fmr1. However, projections from primary visual cortex (V1) to the SC were poorly refined. CONCLUSIONS: Fmr1 is required for the proper development of visual circuit organization and function in the SC. We find that visual dysfunction is heterogeneously manifested in a subcircuit-specific manner in Fmr1-/y mice, consistent with previous studies in human FXS patients. Further, we show a specific alteration of inputs to the SC from V1, but not the retina. Together, these data suggest that Fmr1 may function in distinct ways during the development of different visual subcircuits.

Visual Neurons in the Superior Colliculus Innervated by Islet2+ or Islet2- Retinal Ganglion Cells Display Distinct Tuning Properties.

Throughout the visual system, different subtypes of neurons are tuned to distinct aspects of the visual scene, establishing parallel circuits. Defining the mechanisms by which such tuning arises has been a long-standing challenge for neuroscience. To investigate this, we have focused on the retina's projection to the superior colliculus (SC), where multiple visual neuron subtypes have been described. The SC receives inputs from a variety of retinal ganglion cell (RGC) subtypes; however, which RGCs drive the tuning of different SC neurons remains unclear. Here, we pursued a genetic approach that allowed us to determine the tuning properties of neurons innervated by molecularly defined subpopulations of RGCs. In homozygous Islet2-EphA3 knock-in (Isl2EA3/EA3) mice, Isl2+ and Isl2- RGCs project to non-overlapping sub-regions of the SC. Based on molecular and anatomic data, we show that significantly more Isl2- RGCs are direction-selective (DS) in comparison with Isl2+ RGCs. Targeted recordings of visual responses from each SC sub-region in Isl2EA3/EA3 mice revealed that Isl2- RGC-innervated neurons were significantly more DS than those innervated by Isl2+ RGCs. Axis-selective (AS) neurons were found in both sub-regions, though AS neurons innervated by Isl2+ RGCs were more tightly tuned. Despite this segregation, DS and AS neurons innervated by Isl2+ or Isl2- RGCs did not differ in their spatial summation or spatial frequency (SF) tuning. Further, we did not observe alterations in receptive field (RF) size or structure of SC neurons innervated by Isl2+ or Isl2- RGCs. Together, these data show that innervation by Isl2+ and Isl2- RGCs results in distinct tuning in the SC and set the stage for future studies investigating the mechanisms by which these circuits are built.

Diversity among principal and GABAergic neurons of the anterior olfactory nucleus.

Understanding the cellular components of neural circuits is an essential step in discerning regional function. The anterior olfactory nucleus (AON) is reciprocally connected to both the ipsi- and contralateral olfactory bulb (OB) and piriform cortex (PC), and, as a result, can broadly influence the central processing of odor information. While both the AON and PC are simple cortical structures, the regions differ in many ways including their general organization, internal wiring and synaptic connections with other brain areas. The present work used targeted whole-cell patch clamping to investigate the morphological and electrophysiological properties of the AON's two main neuronal populations: excitatory projection neurons and inhibitory interneurons. Retrograde fluorescent tracers placed into either the OB or PC identified projection neurons. Two classes were observed with different physiological signatures and locations (superficial and deep pyramidal neurons), suggesting the AON contains independent efferent channels. Transgenic mice in which GABA-containing cells expressed green fluorescent protein were used to assess inhibitory neurons. These cells were further identified as containing one or more of seven molecular markers including three calcium-binding proteins (calbindin, calretinin, parvalbumin) or four neuropeptides (somatostatin, vasoactive intestinal peptide, neuropeptide Y, cholecystokinin). The proportion of GABAergic cells containing these markers varied across subregions reinforcing notions that the AON has local functional subunits. At least five classes of inhibitory cells were observed: fast-spiking multipolar, regular-spiking multipolar, superficial neurogliaform, deep neurogliaform, and horizontal neurons. While some of these cell types are similar to those reported in the PC and other cortical regions, the AON also has unique populations. These studies provide the first examination of the cellular components of this simple cortical system.

The mouse olfactory peduncle.

The olfactory peduncle, the region connecting the olfactory bulb with the basal forebrain, contains several neural areas that have received relatively little attention. The present work includes studies that provide an overview of the region in the mouse. An analysis of cell soma size in pars principalis (pP) of the anterior olfactory nucleus (AON) revealed considerable differences in tissue organization between mice and rats. An unbiased stereological study of neuron number in the cell-dense regions of pars externa (pE) and pP of the AON of 3-, 12-, and 24-month-old mice indicated that pE has about 16,500 cells in 0.043 mm(3) and pP about 58,300 cells in 0.307 mm(3) . Quantitative Golgi studies of pyramidal neurons in pP suggested that mouse neurons are similar to although smaller than those of the rat. An immunohistochemical analysis demonstrated that all peduncular regions (pE, pP, the dorsal peduncular cortex, ventral tenia tecta, and anterior olfactory tubercle and piriform cortex) have cells that express either calbindin, calretinin, parvalbumin, somatostatin, vasoactive intestinal polypeptide, neuropeptide Y, or cholecystokinin (antigens commonly co-expressed by subspecies of γ-aminobutyric acid [GABA]ergic neurons), although the relative numbers of each cell type differ between zones. Finally, an electron microscopic comparison of the organization of myelinated fibers in lateral olfactory tract in the anterior and posterior peduncle indicated that the region is less orderly in mice than in rats. The results provide a caveat for investigators who generalize data between species, as both similarities and differences between the laboratory mouse and rat were observed.

Spatial distribution of neural activity in the anterior olfactory nucleus evoked by odor and electrical stimulation.

Several lines of evidence indicate that complex odorant stimuli are parsed into separate data streams in the glomeruli of the olfactory bulb, yielding a combinatorial "odotopic map." However, this pattern does not appear to be maintained in the piriform cortex, where stimuli appear to be coded in a distributed fashion. The anterior olfactory nucleus (AON) is intermediate and reciprocally interconnected between these two structures, and also provides a route for the interhemispheric transfer of olfactory information. The present study examined potential coding strategies used by the AON. Rats were exposed to either caproic acid, butyric acid, limonene, or purified air and the spatial distribution of Fos-immunolabeled cells was quantified. The two major subregions of the AON exhibited different results. Distinct odor-specific spatial patterns of activity were observed in pars externa, suggesting that it employs a topographic strategy for odor representation similar to the olfactory bulb. A spatially distributed pattern that did not appear to depend on odor identity was observed in pars principalis, suggesting that it employs a distributed representation of odors more similar to that seen in the piriform cortex.