Excessive dopamine neurotransmission underlies psychotic episodes as observed in patients with some types of bipolar disorder and schizophrenia. The dopaminergic hypothesis was postulated after the finding that antipsychotics were effective to halt increased dopamine tone. However, there is little evidence for dysfunction within the dopaminergic system itself. Alternatively, it has been proposed that excessive afferent activity onto ventral tegmental area dopaminergic neurons, particularly from the ventral hippocampus, increase dopamine neurotransmission, leading to psychosis. Here, we show that selective dopamine D receptor deletion from parvalbumin interneurons in mouse causes an impaired inhibitory activity in the ventral hippocampus and a dysregulated dopaminergic system. Conditional mutant animals show adult onset of schizophrenia-like behaviors and molecular, cellular, and physiological endophenotypes as previously described from postmortem brain studies of patients with schizophrenia. Our findings show that dopamine D receptor expression on parvalbumin interneurons is required to modulate and limit pyramidal neuron activity, which may prevent the dysregulation of the dopaminergic system.
Understanding changes in brain rhythms provides useful information to predict the onset of a seizure and to localize its onset zone in epileptic patients. Brain rhythms dynamics in general, and phase-amplitude coupling in particular, are known to be drastically altered during epileptic seizures. However, the neural processes that take place before a seizure are not well understood. We analysed the phase-amplitude coupling dynamics of stereoelectroencephalography recordings (30 seizures, 5 patients) before and after seizure onset. Electrodes near the seizure onset zone showed higher phase-amplitude coupling. Immediately before the beginning of the seizure, phase-amplitude coupling dropped to values similar to the observed in electrodes far from the seizure onset zone. Thus, our results bring accurate information to detect epileptic events during pre-ictal periods and to delimit the zone of seizure onset in patients undergoing epilepsy surgery.
Tauopathies are neurodegenerative diseases caused by the abnormal metabolism of the microtubule associated protein Tau, which is highly expressed in neurons and critically involved in microtubule dynamics. In the adult human brain, the alternative splicing of exon 10 in tau pre-mRNA produces equal amounts of protein isoforms with either three (3 R) or four (4 R) microtubule binding domains. Imbalance in the 3 R : 4 R tau ratio is associated with primary tauopathies that develop atypical parkinsonism, such as Progressive Supranuclear Palsy and Corticobasal Degeneration. Yet, the development of effective therapies for those pathologies is an unmet goal.
Here we report motor coordination impairments in the htau mouse model of tauopathy which bear abnormal 3 R : 4 R tau isoforms contents, and contrariwise to TauKO mice, are unresponsive to L-DOPA. Preclinical-PET imaging, array tomography and electrophysiological analyses pointed the dorsal striatum as the candidate structure mediating such phenotypes. Indeed, local modulation of tau isoforms by RNA trans-splicing in the striata of adult htau mice, prevented motor coordination deficits and restored basal neuronal firing. Together, these results constitute readout that abnormal striatal tau-isoforms contents might lead to parkinsonian-like phenotypes and provide proof of concept that modulation of tau mis-splicing could be a plausible disease-modifying therapy for some primary tauopathies.
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