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Spinal interneurons are critical modulators of motor circuit function. In the dorsal spinal cord, a set of interneurons called GABApre presynaptically inhibits proprioceptive sensory afferent terminals, thus negatively regulating sensory-motor signaling. Although deficits in presynaptic inhibition have been inferred in human motor diseases, including dystonia, it remains unclear whether GABApre circuit components are altered in these conditions. Here, we use developmental timing to show that GABApre neurons are a late Ptf1a-expressing subclass and localize to the intermediate spinal cord. Using a microarray screen to identify genes expressed in this intermediate population, we find the kelch-like family member Klhl14, implicated in dystonia through its direct binding with torsion-dystonia-related protein Tor1a. Furthermore, in Tor1a mutant mice in which Klhl14 and Tor1a binding is disrupted, formation of GABApre sensory afferent synapses is impaired. Our findings suggest a potential contribution of GABApre neurons to the deficits in presynaptic inhibition observed in dystonia.
Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.
In the rubber hand illusion, perceived hand ownership can be transferred to a rubber hand after synchronous visual and tactile stimulation. Perceived body ownership and self-other relation are foundational for development of self-awareness, imitation, and empathy, which are all affected in autism spectrum disorders (ASD). We examined the rubber hand illusion in children with and without ASD. Children with ASD were initially less susceptible to the illusion than the comparison group, yet showed the effects of the illusion after 6 minutes. Delayed susceptibility to the illusion may result from atypical multisensory temporal integration and/or an unusually strong reliance on proprioception. Children with ASD who displayed less empathy were significantly less likely to experience the illusion than those with more intact ability to express empathy. A better understanding of body representation in ASD may elucidate neural underpinnings of social deficits, thus informing future intervention approaches.
BACKGROUND - A weakened sense of self may contribute to psychotic experiences. Body ownership, one component of self-awareness, can be studied with the rubber hand illusion (RHI). Watching a rubber hand being stroked while one's unseen hand is stroked synchronously can lead to a sense of ownership over the rubber hand, a shift in perceived position of the real hand, and a limb-specific drop in stimulated hand temperature. We aimed to assess the RHI in schizophrenia using quantifiable measures: proprioceptive drift and stimulation-dependent changes in hand temperature.
METHODS - The RHI was elicited in 24 schizophrenia patients and 21 matched controls by placing their unseen hand adjacent to a visible rubber hand and brushing real and rubber hands synchronously or asynchronously. Perceived finger location was measured before and after stimulation. Hand temperature was taken before and during stimulation. Subjective strength of the illusion was assessed by a questionnaire.
RESULTS - Across groups, the RHI was stronger during synchronous stimulation, indicated by self-report and proprioceptive drift. Patients reported a stronger RHI than controls. Self-reported strength of RHI was associated with schizotypy in controls Proprioceptive drift was larger in patients, but only following synchronous stimulation. Further, we observed stimulation-dependent changes in skin temperature. During right hand stimulation, temperature dropped in the stimulated hand and rose in the unstimulated hand. Interestingly, induction of RHI led to an out-of-body experience in one patient, linking body disownership and psychotic experiences.
CONCLUSIONS - The RHI is quantitatively and qualitatively stronger in schizophrenia. These findings suggest that patients have a more flexible body representation and weakened sense of self, and potentially indicate abnormalities in temporo-parietal networks implicated in body ownership. Further, results suggest that these body ownership disturbances might be at the heart of a subset of the pathognomonic delusions of passivity.
GABAergic interneurons are key elements in neural coding, but the mechanisms that assemble inhibitory circuits remain unclear. In the spinal cord, the transfer of sensory signals to motor neurons is filtered by GABAergic interneurons that act presynaptically to inhibit sensory transmitter release and postsynaptically to inhibit motor neuron excitability. We show here that the connectivity and synaptic differentiation of GABAergic interneurons that mediate presynaptic inhibition is directed by their sensory targets. In the absence of sensory terminals these GABAergic neurons shun other available targets, fail to undergo presynaptic differentiation, and withdraw axons from the ventral spinal cord. A sensory-specific source of brain derived neurotrophic factor induces synaptic expression of the GABA synthetic enzyme GAD65--a defining biochemical feature of this set of interneurons. The organization of a GABAergic circuit that mediates presynaptic inhibition in the mammalian CNS is therefore controlled by a stringent program of sensory recognition and signaling.
A combination of neuroanatomical and electrophysiological techniques was used to study the effects of peripheral axotomy and regeneration of primary afferents on their central projections in the spinal cord. Individual regenerated afferent fibers were impaled with HRP-filled electrodes in the dorsal columns of alpha-chloralose-anesthetized cats and activated by current pulses delivered via the intracellular electrode. The resulting cord dorsum potentials (CDPs) were recorded at four rostrocaudal locations and HRP was iontophoretically injected into the fiber. Central distributions of boutons and CDPs were compared with peripheral receptor type to determine the accuracy of peripheral regeneration and the effects of central-peripheral mismatches. Reconstruction of the central projections of 13 individual afferents for which the adequate stimulus and CDPs had been recorded revealed many abnormalities. For example, unlike controls, four group I and II afferents with central projections typical of proprioceptors (concentrated in laminae V, VI, and VII) innervating either cutaneous or noncutaneous targets evoked measurable CDPs. Three other group II or A beta afferents innervating low-threshold mechanoreceptors with central terminations confined to the dorsal horn exhibited extensive collateralization in laminae I and II in addition to large numbers of terminals in laminae III-IV. These fibers activated central networks whose adaptation behavior was identical to those evoked by high-threshold mechanoreceptive afferents in controls. These results suggest that primary afferents and their central connections are capable of significant modifications following axotomy and regeneration. In addition, the anatomical studies indicate some reorganization in the laminar distribution of boutons as well as in bouton size.