Biology subjects

Meira, T.

Publications and source records attributed to Meira, T..

2 recordsLinked to original sources

bioRxiv2019

Coding of social novelty in the hippocampal CA2 region and its disruption and rescue in a mouse model of schizophrenia

The hippocampal CA2 region is essential for social memory and has been implicated in neuropsychiatric disorders. However, little is known about how CA2 neural activity encodes social interactions and how this coding is altered in disease. We recorded from CA2 pyramidal neurons as mice engaged in social interactions and found that while CA2 failed to stably represent spatial location, CA2 activity encoded contextual changes and novel social stimuli. In the Df(16)A+/- mouse model of the human 22q11.2 microdeletion, a major schizophrenia risk factor, CA2 activity showed a surprising increase in spatial coding while failing to encode social novelty, consistent with the social memory deficit in these mice. Previous work has shown that CA2 pyramidal neurons are hyperpolarized in Df(16)A+/- mice, likely as a result of upregulation of TREK-1 K+ current. We found that administration of a TREK-1 antagonist rescued the social memory deficits and restored normal CA2 coding properties in Df(16)A+/- mice, supporting a crucial role for CA2 in the encoding of novel social stimuli and social dysfunction.

neuroscience↗

bioRxiv2018

Endo-lysosomal sorting and degradation of Tau mediates glucocorticoid-driven hippocampalmalfunction

Emerging studies implicate Tau as an essential mediator of neuronal atrophy and cognitive impairment in Alzheimers disease (AD), yet the factors that precipitate Tau dysfunction in AD are poorly understood. Chronic environmental stress and elevated glucocorticoids (GC), the major stress hormones, are associated with increased risk of AD, and have been shown to trigger intracellular Tau accumulation and downstream Tau-dependent neuronal dysfunction. However, the mechanisms through which stress and GC disrupt Tau clearance and degradation in neurons remain unclear. Here, we demonstrate that Tau undergoes degradation via endolysosomal sorting in a pathway requiring the small GTPase Rab35 and the endosomal sorting complex required for transport (ESCRT) machinery. Furthermore, we find that GC impair Tau degradation by decreasing Rab35 levels, and that AAV-mediated expression of Rab35 in the hippocampus rescues GC-induced Tau accumulation and related neurostructural deficits. These studies indicate that the Rab35/ESCRT pathway is essential for Tau clearance and part of the mechanism through which GC precipitate brain pathology.

neuroscience↗