Biology subjects

Purisic, E.

Publications and source records attributed to Purisic, E..

3 recordsLinked to original sources

bioRxiv2026

GluD1 Modulates GluN2B-containing NMDAR Function and Plasticity at Subicular Synapses

Dysregulation of the delta-type glutamate receptor GluD1 and N-methyl-D-aspartate receptors (NMDARs) is implicated in neuropsychiatric disorders including schizophrenia and intellectual disability, and GluD1 modulates NMDAR response in hippocampal neurons. However, the precise mechanisms by which GluD1 influences specific NMDAR subtypes remain undefined, representing a critical gap given the reliance of synaptic plasticity and cognition on NMDAR composition. GluN2A- and GluN2B-containing NMDARs are essential for synaptic long-term potentiation (LTP) and contextual learning and memory. Here, we used CRISPR/Cas9 to generate GluD1 knockout (KO) in cultured hippocampal neurons and observed a selective decrease in GluN2B-containing NMDAR responses. In acute hippocampal slices, GluD1 KO similarly reduced GluN2B-containing NMDAR currents at ventral CA1[->]subiculum synapses and impaired LTP at these synapses. In vivo, region-specific GluD1 deficiency in the ventral subiculum disrupted long-term contextual memory, indicating a critical role for GluD1 in cognitive processes. These findings demonstrate that GluD1 is indispensable for preserving GluN2B-containing NMDAR function, synaptic plasticity, and memory, providing molecular insight into how GluD1 regulates NMDAR subtypes implicated in synaptic dysfunction in neuropsychiatric disorders. Understanding this mechanism will guide the development of therapeutic strategies that selectively target GluD1-dependent modulation of NMDAR subtypes in brain disease.

neuroscience↗

bioRxiv2024

Bipolar and schizophrenia risk gene AKAP11 encodes an autophagy receptor coupling the regulation of PKA kinase network homeostasis to synaptic transmission

Human genomic studies have identified protein-truncating variants in AKAP11 associated with both bipolar disorder (BD) and schizophrenia (SCZ), implicating a shared disease mechanism driven by loss-of-function. AKAP11, a protein kinase A (PKA) adaptor, plays a key role in degrading the PKA-RI complex through selective autophagy. However, the neuronal functions of AKAP11 and the impact of its loss-of-function remains largely uncharacterized. Through multi-omics approaches, cell biology, and electrophysiology analysis in mouse models and human induced neurons, we delineated a central role of AKAP11 in coupling PKA kinase network regulation to synaptic transmission. Loss of AKAP11 distorted compartment-specific PKA and GSK3/{beta} activities and impaired cellular functions that significantly overlap with pathways associated with BD and SCZ. Moreover, we identified interactions between AKAP11, the PKA-RI adaptor SPHKAP, and the ER-resident autophagy-related proteins VAPA/B, which co-adapt and mediate PKA-RI complex degradation in neurons. Notably, AKAP11 deficiency impaired neurotransmission, providing key insights into the mechanism underlying AKAP11-associated psychiatric diseases.

neuroscience↗

bioRxiv2023

Egr1 is a sex-specific regulator of neuronal chromatin, synaptic plasticity, and behaviour

Sex differences are found in brain structure and function across species, and across brain disorders in humans1-3. The major source of brain sex differences is differential secretion of steroid hormones from the gonads across the lifespan4. Specifically, ovarian hormones oestrogens and progesterone are known to dynamically change structure and function of the adult female brain, having a major impact on psychiatric risk5-7. However, due to limited molecular studies in female rodents8, very little is still known about molecular drivers of female-specific brain and behavioural plasticity. Here we show that overexpressing Egr1, a candidate oestrous cycle-dependent transcription factor9, induces sex-specific changes in ventral hippocampal neuronal chromatin, gene expression, and synaptic plasticity, along with hippocampus-dependent behaviours. Importantly, Egr1 overexpression mimics the high-oestrogenic phase of the oestrous cycle, and affects behaviours in ovarian hormone-depleted females but not in males. We demonstrate that Egr1 opens neuronal chromatin directly across the sexes, although with limited genomic overlap. Our study not only reveals the first sex-specific chromatin regulator in the brain, but also provides functional evidence that this sex-specific gene regulation drives neuronal gene expression, synaptic plasticity, and anxiety- and depression-related behaviour. Our study exemplifies an innovative sex-based approach to studying neuronal gene regulation1 in order to understand sex-specific synaptic and behavioural plasticity and inform novel brain disease treatments.

neuroscience↗