Mice

Small conductance Ca2+-activated K+ (SK) channels are expressed throughout brain regions important for long-term memory. They constrain the intrinsic excitability of neurons by enhancing afterhyperpolarization, shape glutamatergic synaptic potentials and limit induction of NMDA receptor-dependent synaptic plasticity. Behaviorally, SK channels modulate learning and memory encoding. It is hypothesized that SK channels influence cognitive symptoms of psychosis including executive functioning, working memory, and selective attention. Theories of psychosis currently posit that symptoms of psychosis are a result of dopaminergic hyperfunction, and glutamatergic dysregulation which can be induced following administration of the NMDA receptor antagonist, ketamine. Initial experiments confirmed that sub-chronic treatment with KET produced significant impairment of object recognition memory, trace fear memory, and latent inhibition compared to SAL mice. A comparison of ketamine dosing regimens revealed the necessity for sub-chronic/chronic dosing on a consistent schedule with a wash out period, to obtain long-lasting attention and memory impairment. These experiments revealed for the first time that sub-chronic KET treatment elicited a new phenotype in male C57BL/6J mice: audible vocalizations. KET mice emitted audible vocalizations within 10 min of receiving KET injections, and vocalizations were detected up to 30 min after injection. Experiments conducted to determine the efficacy of SK channel agonists and antagonists on SK channels to modulate attention and memory in the ketamineinduced model of psychosis in C57BL/6J mice demonstrated for the first time that the SK2 channel activator, CyPPA, significantly reduced memory impairment and decreased the attention deficit of KET mice. A new method of analysis for trace fear conditioning freezing responses permitted a more accurate measurement of the ability of mice to discriminate the predicted delivery of shock during trace versus CS intervals. The application of the novel analytical method further demonstrated that KET mice failed to accurately discriminate these intervals, due to their impaired attention and acquisition of the trace conditioned response. This study examined the efficacy of SK channel drugs to rescue cognitive impairments in a pharmacological mouse model of schizophrenia. The results indicate that SK2 subunit activators and blockers, may provide a new therapeutic treatment for memory impairment and attention deficits seen in schizophrenic disorders.

Previous research revealed that episodic memories are more likely to be consolidated if something novel occurs in relative temporal proximity to the original learned event (Dunsmoor, Murty, Davachi, & Phelps, 2015). Further, research conducted with rodents has revealed that novel contextual exposure following encoding of a spatial memory in a food-motivated task results in enhanced consolidation of that spatial memory (Takeuchi, Duszkiewics, Sonneborn et al., 2016). The present study sought to examine the influence of novel context exposure on non-spatial object memory in adult female and male C57BL/6J mice when novel context exposure follows encoding of object memory under two memory strength training protocols. Results revealed that regardless of memory strength or gender, subjects exposed to a novel context following encoding of object memory exhibited greater exploration of the novel object when assessed 23.5 h later. Thus, novel context exposure significantly enhanced the consolidation of recently encoded object memory. As novel context exposure has been shown to increase dopamine release in the hippocampus, these results are consistent with the theory of synaptic tag and capture, whereby activated dopaminergic afferents enhance the on-going consolidation of non-spatial object memory. Future studies will entail parsing potential neurotransmitter modulatory afferents via pharmacological antagonists.

The majority of research on drug addiction centers on dopamine (DA)- driven synaptic plasticities and how these changes ultimately lead to compulsive drug seeking. However, growing evidence supports a role of glial factors in various steps that lead to drug abuse and addiction. In this regard, significant evidence implicates glial glutamate (Glu) transporters (GLT-1) and cystine/Glu exchangers (xCT) in determining synaptic and extrasynaptic levels of Glu that support the acute and chronic actions of drugs of abuse. -lactam antibiotics have been found in rodent models to upregulate CNS GLT-1 and xCT and thereby contribute to reinstatement after chronic drug exposure and withdrawal.
Previously, the Blakely lab identified a glial expressing gene, swip-10, in Caenorhabditis elegans, whose deletion results in the hyperdominergic phenotype Swimming-Induced Paralysis (Swip), supported by Glu signalingdependent DA neuron hyperexcitability that ultimately drives oxidative stress and DA neuron degeneration. Both SWIP-10 and its putative mammalian ortholog MBLAC1 possess a highly conserved metallo -lactamase domain, and MBLAC1 has been found to bind the Glu modulating, b-lactam antibiotic ceftriaxone (Cef). Indeed, immunodepletion studies indicate that MBLAC1 may be the major highaffinity Cef-binding protein in the brain, leading to the hypothesis that MBLAC1 has a Glu modulatory role(s). Recently a functional role of MBLAC1 been proposed, involving activity as a 3’ exonuclease that processes polyA- mRNAs, including RNAs encoding cell replication-dependent histones. How this role, or others, may support the actions of MBLAC1 in the brain and the non-microbial actions of Cef to extracellular Glu homeostasis, is unclear. Recently, the Blakely lab generated Mblac1-/- mice as a tool to investigate these issues. The following work investigated the requirements of MBLAC1 in growth and the actions of Cef in mouse embryonic fibroblasts (MEFs) cultured from either Mblac1+/+ and Mblac1-/- mice. The presented data suggested that Mblac1-/- MEFs display attenuated growth and cell proliferation relative to Mblac1+/+ MEFs. For the first time, the in vitro protective actions of Cef against oxidative stress is shown to be dependent on MBLAC1. The following studies presented contribute to a definition of the role of MBLAC1 and as a Cef binding protein in native preparations, with findings that can drive models for the role of MBLAC1 in the CNS.