Biology subjects

Rodriguez Diaz, J. C.

Publications and source records attributed to Rodriguez Diaz, J. C..

2 recordsLinked to original sources

bioRxiv2024

Grin2a Hypofunction Disrupts Hippocampal Network Oscillations and E/I Balance Contributing to Cognitive Deficits

BackgroundN-methyl-D-aspartate (NMDA) receptors, particularly those containing the GluN2A subunit, play a critical role in hippocampal-dependent learning and memory. The GluN2A subunit, encoded by the Grin2a gene, is essential for maintaining cognitive function, including working memory. In this study, we explore how Grin2a mutations impair working memory and disrupt hippocampal network oscillations and E/I balance. MethodsGrin2a mutant mice were assessed for spatial working memory deficits using the 8-arm radial maze. We utilized multi-electrode arrays and whole-cell patch-clamp electrophysiology to evaluate network oscillation and synaptic inputs to pyramidal cells in ex vivo hippocampal slices. We performed an immunohistochemical analysis of hippocampal slices to evaluate changes in the abundance of GABAergic neurons. ResultsOur results demonstrate that Grin2a deficiency impairs spatial working memory and disrupts coupling of theta-gamma oscillations in the hippocampus. Moreover, Grin2a mutants express an overabundance of parvalbumin-expressing (PV+) interneurons that integrate into hippocampal circuits and destabilize excitatory/inhibitory (E/I) input to CA1 pyramidal neurons. ConclusionThis study highlights the critical role of GluN2A-containing NMDA receptors in maintaining hippocampal network synchrony. Impairments in network synchrony and E/I balance within the hippocampus may drive the cognitive deficits observed in Grin2a-related disorders such as schizophrenia, epilepsy, and intellectual disability.

neuroscience↗

bioRxiv2018

Ankyrin-G Regulates Forebrain Connectivity and Network Synchronization via Interaction with GABARAP

GABAergic circuits are critical for the synchronization and higher order function of brain networks, and defects in this circuitry are linked to neuropsychiatric diseases, including bipolar disorder, schizophrenia, and autism. Work in cultured neurons has shown that ankyrin-G plays a key role in the regulation of GABAergic synapses on the axon initial segment and somatodendritic domain of pyramidal neurons where it interacts directly with the GABAO_SCPCAPAC_SCPCAP receptor associated protein (GABARAP) to stabilize cell surface GABAO_SCPCAPAC_SCPCAP receptors. Here, we generated a knock-in mouse model expressing a mutation that abolishes the ankyrin-G/GABARAP interaction (Ank3 W1989R) to understand how ankyrin-G and GABARAP regulate GABAergic circuitry in vivo. We found that Ank3 W1989R mice exhibit a striking reduction in forebrain GABAergic synapses resulting in pyramidal cell hyperexcitability and disruptions in network synchronization. In addition, we identified changes in pyramidal cell dendritic spines and axon initial segments consistent with compensation for hyperexcitability. Finally, we identified the ANK3 W1989R variant in a family with bipolar disorder, suggesting a potential role of this variant in disease. Our results highlight the importance of ankyrin-G in regulating forebrain circuitry and provide novel insights into how ANK3 loss-of-function variants may contribute to human disease.

neuroscience↗