Role of Electrotonic Coupling in the Olivocerebellar System

The level of electrotonic coupling in the inferior olive is higher than in any other brain region. Connexin36 is the main protein that forms the olivary gap junctions. Yet, the functional role of electrotonic coupling in the cerebellar motor control remains to be determined. In this thesis mice that lack coupling among their olivary neurons were subjected to classical eyeblink conditioning. Cx36 deficient mice showed impaired learning-dependent timing in that they were not able to fix the timing of their conditioned responses at the moment when the unconditioned stimulus is about to occur. The timing of spike activities generated in the olive of coupling- deficient mice was abnormal in that their latencies in response to the unconditioned stimulus were inconsistent and that their overall synchrony was reduced. Whole cell recordings of olivary neurons in vivo showed that these different spiking activities over time result in part from altered interaction! s with their subthreshold oscillations. These results, combined with analysis of olivary activities in a computer simulation of the cerebellar system, suggest that electrotonic coupling among olivary neurons is necessary for proper synchronous oscillations in the inferior olive, which in turn determine the pace of the olivary responses necessary for learning-dependent timing in cerebellar motor control

GATA3 haploinsufficiency causes a rapid deterioration of distortion product otoacoustic emissions (DPOAEs) in mice

Human HDR (hypoparathyroidism, deafness and renal dysplasia)-syndrome is caused by haploinsufficiency of zinc-finger transcription factor GATA3. The hearing loss due to GATA3 haploinsufficiency has been shown to be peripheral in origin, but it is unclear to what extent potential aberrations in the outer hair cells (OHCs) contribute to this disorder. To further elucidate the pathophysiological mechanism underlying the hearing defect in HDR-syndrome, we investigated the OHCs in heterozygous Gata3-knockout mice at both the functional and morphological level. While the signal-to-noise ratios of distortion product otoacoustic emissions (DPOAE) in wild type mice did not change significantly during the first half-year of live, those in the heterozygous Gata3 mice decreased dramatically. In addition, both light microscopic and transmission electron microscopic analyses showed that the number of OHCs containing vacuoles was increased in the mutants. Together, these findings indicate that outer hair cell malfunctioning plays a major role in the hearing loss in HDR-syndrome

Modulation of murine olivary connexin 36 gap junctions by PKA and CaMKII

The inferior olive (IO) is a nucleus located in the brainstem and it is part of the olivo-cerebellar loop. This circuit plays a fundamental role in generation and acquisition of coherent motor patterns and it relies on synchronous activation of groups of Purkinje cells (PC) in the cerebellar cortex. IO neurons integrate their intrinsic oscillatory activity with excitatory inputs coming from the somatosensory system and inhibitory feedback coming from the cerebellar nuclei. Alongside these chemical synaptic inputs, IO neurons are coupled to one another via connexin 36 (Cx36) containing gap junctions (GJs) that create a functional syncytium between neurons. Communication between olivary neurons is regulated by these GJs and their correct functioning contributes to coherent oscillations in the IO and proper motor learning. Here, we explore the cellular pathways that can regulate the coupling between olivary neurons. We combined in vitroelectrophysiology and immunohistochemistry (IHC) on mouse acute brain slices to unravel the pathways that regulate olivary coupling. We found that enhancing the activity of the protein kinase A (PKA) pathway and blocking the Ca2+/calmodulin-dependent protein kinase II (CaMKII) pathway can both down-regulate the size of the coupled network. However, these two kinases follow different mechanisms of action. Our results suggest that activation of the PKA pathway reduces the opening probability of the Cx36 GJs, whereas inhibition of the CaMKII pathway reduces the number of Cx36 GJs. The low densities of Cx36 proteins and electrical synapses in βCaMKII knock-out mice point towards an essential role for this protein kinase in regulating the density of GJs in the IO. Thus, the level of olivary coupling is a dynamic process and regulated by a variety of enzymes modulating GJs expression, docking and activity

The Meta VCI Map consortium for meta-analyses on strategic lesion locations for vascular cognitive impairment using lesion-symptom mapping: design and multicenter pilot study

Introduction: The Meta VCI Map consortium performs meta-analyses on strategic lesion locations for vascular cognitive impairment using lesion-symptom mapping. Integration of data from different cohorts will increase sample sizes, to improve brain lesion coverage and support comprehensive lesion-symptom mapping studies. Methods: Cohorts with available imaging on white matter hyperintensities or infarcts and cognitive testing were invited. We performed a pilot study to test the feasibility of multicenter data processing and analysis and determine the benefits to lesion coverage. Results: Forty-seven groups have joined Meta VCI Map (stroke n = 7800 patients; memory clinic n = 4900; population-based n = 14,400). The pilot study (six ischemic stroke cohorts, n = 878) demonstrated feasibility of multicenter data integration (computed tomography/magnetic resonance imaging) and achieved marked improvement of lesion coverage. Discussion: Meta VCI Map will provide new insights into the relevance of vascular lesion location for cognitive dysfunction. After the successful pilot study, further projects are being prepared. Other investigators are welcome to join

Contribution of CYLN2 and GTF2IRD1 to neurological and cognitive symptoms in Williams Syndrome

Williams Syndrome (WS, [MIM 194050]) is a disorder caused by a hemizygous deletion of 25-30 genes on chromosome 7q11.23. Several of these genes including those encoding cytoplasmic linker protein-115 (CYLN2) and general transcription factors (GTF2I and GTF2IRD1) are expressed in the brain and may contribute to the distinct neurological and cognitive deficits in WS patients. Recent studies of patients with partial deletions indicate that hemizygosity of GTF2I probably contributes to mental retardation in WS. Here we investigate whether CYLN2 and GTF2IRD1 contribute to the motoric and cognitive deficits in WS. Behavioral assessment of a new patient in which STX1A and LIMK1, but not CYLN2 and GTF2IRD1, are deleted showed that his cognitive and motor coordination functions were significantly better than in typical WS patients. Comparative analyses of gene specific CYLN2 and GTF2IRD1 knockout mice showed that a reduced size of the corpus callosum as well as deficits in motor coordination and hippocampal memory formation may be attributed to a deletion of CYLN2, while increased ventricle volume can be attributed to both CYLN2 and GTF2IRD1. We conclude that the motor and cognitive deficits in Williams Syndrome are caused by a variety of genes and that heterozygous deletion of CYLN2 is one of the major causes responsible for such dysfunctions