Biology subjects

Chavez, A. E.

Publications and source records attributed to Chavez, A. E..

4 recordsLinked to original sources

bioRxiv2026

EXECUTIVE DYSFUNCTIONS IN THE EAAT3 OVEREXPRESSING MOUSE MODEL OF COMPULSIVE BEHAVIOR

Executive functions are a set of cognitive processes that regulate behavior and adapt responses to changing demands. Impairments in these processes are common in various neuropsychiatric conditions, including obsessive-compulsive disorder. Mice overexpressing the neuronal glutamate transporter EAAT3 in the forebrain (EAAT3glo/CaMKII) exhibit increased compulsive behaviors and synaptic alterations relevant to OCD. However, whether EAAT3 overexpression affects executive functioning across multiple cognitive domains has not been studied. Using operant conditioning and visuospatial learning tasks, we evaluated the performance of EAAT3glo/CaMKII mice across three behavioral domains commonly associated with executive function: cognitive flexibility, working memory, and inhibitory control. EAAT3glo/CaMKII mice showed impaired cognitive flexibility in both operant extinction and reversal learning. EAAT3glo/CaMKII mice also failed to acquire the Trial-unique, delayed nonmatching-to-location task, suggesting impaired working memory, and showed increased impulsivity in the five-choice serial reaction time task, as evidenced by elevated premature responses. Perseverative responses, response accuracy, and attentional performance were unaffected in EAAT3glo/CaMKII mice. Collectively, these findings suggest that EAAT3 overexpression in forebrain neurons is associated with a cognitive profile characterized by difficulties in flexibility and task acquisition, alongside increased impulsivity, while attentional performance and motivational measures remain intact in a model of compulsive behavior.

animal behavior and cognition↗

bioRxiv2026

Neuronal glutamate transporter EAAT3 regulates hippocampal GABAergic plasticity and reversal learning

Long-term depression (LTD) is a form of synaptic plasticity implicated in tasks involving the modification or elimination of previously learned information. While glial glutamate transporters can control the strength of synaptic plasticity, much less is known about the contribution of the neuronal glutamate transporter EAAT3 in controlling hippocampal LTD and learning processes. Here, we report that overexpression of EAAT3 in principal neurons, but not in GABAergic interneurons, impairs heterosynaptic GABAergic synaptic plasticity (iLTD) and homosynaptic excitatory LTD in the hippocampus. LTD impairments can be reversed by inhibiting EAAT3 or by a brief exogenous activation of mGluR during LTD induction, suggesting that, by limiting glutamate spillover between neighboring synapses, EAAT3 contributes to setting the strength of different forms of hippocampal LTD. Moreover, mice overexpressing EAAT3 in principal neurons, but not in GABAergic interneurons, display impaired reversal learning, a phenotype that can be rescued by blocking EAAT3 in vivo. Together, these findings reveal that, by controlling the strength of hippocampal LTD, EAAT3 contributes to cognitive flexibility required for processing new information.

neuroscience↗

bioRxiv2021

Retrograde adenosine/A2A receptor signaling mediates presynaptic hippocampal LTP and facilitates epileptic seizures

Retrograde signaling at the synapse is a fundamental way by which neurons communicate and neuronal circuit function is fine-tuned upon activity. While long-term changes in neurotransmitter release commonly rely on retrograde signaling, the mechanisms remain poorly understood. Here, we identified adenosine/A2A receptor (A2AR) as a novel retrograde signaling pathway underlying presynaptic long-term potentiation (LTP) at a hippocampal excitatory circuit critically involved in memory and epilepsy. Transient burst activity of a single dentate granule cell induced LTP of mossy cell synaptic inputs, a BDNF/TrkB-dependent form of plasticity that facilitates seizures. Postsynaptic TrkB activation released adenosine from granule cells, uncovering a non-conventional BDNF/TrkB signaling mechanism. Moreover, presynaptic A2ARs were necessary and sufficient for LTP. Lastly, seizure induction released adenosine in a TrkB-dependent manner, while removing A2ARs or TrkB from the dentate gyrus had anti-convulsant effects. By mediating presynaptic LTP, adenosine/A2AR retrograde signaling may modulate dentate gyrus-dependent learning and promote epileptic activity. HighlightsO_LIPostsynaptic firing induces presynaptic LTP at mossy cell to granule cell synapses C_LIO_LIPostsynaptic TrkB activation induces adenosine release from granule cells C_LIO_LIPresynaptic adenosine A2A receptors are necessary and sufficient to induce LTP C_LIO_LIAdenosine/A2AR signaling within the dentate gyrus is pro-convulsant C_LI In BriefNasrallah et al. report a novel retrograde signaling pathway at hippocampal synapses that involves postsynaptic TrkB-dependent release of adenosine and the activation of presynaptic A2A receptors. This pathway mediates presynaptic long-term potentiation at a key hippocampal excitatory synapse and can also promote epileptic seizures.

neuroscience↗

bioRxiv2021

Euchromatin factors HULC and Set1C affect heterochromatin organization for mating-type switching in fission yeast Schizosaccharomyces pombe

Mating-type (P or M) of fission yeast Schizosaccharomyces pombe is determined by the transcriptionally active mat1 cassette and is switched by gene conversion using a donor, either mat2 or mat3, located in an adjacent heterochromatin region (mating-type switching; MTS). In the process, heterochromatic donors of genetic information are selected based on the P or M cell type and on the action of two recombination enhancers, SRE2 promoting the use of mat2-P and SRE3 promoting the use of mat3-M, leading to replacement of the content of the expressed mat1 cassette. Recently, we found that the histone H3K4 methyltransferase complex Set1C participates in donor selection, raising the question of how a complex best known for its effects in euchromatin controls recombination in heterochromatin. Here, we report that the histone H2BK119 ubiquitin ligase complex HULC functions with Set1C in MTS, as mutants in the shf1, brl1, brl2 and rad6 genes showed defects similar to Set1C mutants and belonged to the same epistasis group as set1{Delta}. Moreover, using H3K4R and H2BK119R histone mutants and a Set1-Y897A catalytic mutant indicated that ubiquitylation of histone H2BK119 by HULC and methylation of histone H3K4 by Set1C are functionally coupled in MTS. Cell-type biases in MTS in these mutants suggested that HULC and Set1C inhibit the use of the SRE3 recombination enhancer in M cells, thus favoring SRE2 and mat2-P. Consistently, imbalanced switching in the mutants was traced to compromised association of the directionality factor Swi6 with the recombination enhancers in M cells. Based on their known effects at other chromosomal locations, we speculate that HULC and Set1C might control nucleosome mobility and strand invasion near the SRE elements. In addition, we uncovered distinct effects of HULC and Set1C on histone H3K9 methylation and gene silencing, consistent with additional functions in the heterochromatic domain.

genetics↗