Glutamatergic synapses exhibit significant molecular diversity, but circuit-specific mechanisms that underlie synaptic regulation are not well characterized. Prior reports show that Rho-guanine nucleotide exchange factor (RhoGEF) Tiam1 regulates perforant path→dentate gyrus granule neuron synapses. In the present study, we report Tiam1's homolog Tiam2 is implicated in glutamatergic neurotransmission in CA1 pyramidal neurons. We find that Tiam2 regulates evoked excitatory glutamatergic currents via a postsynaptic mechanism mediated by the catalytic Dbl-homology domain. Overall, we present evidence for RhoGEF Tiam2's role in glutamatergic synapse function at Schaffer collateral→CA1 pyramidal neuron synapses.

The zebrafish, a widely used model in neurobiology, relies on hearing in aquatic environments. Unfortunately, its auditory pathways have mainly been studied in larvae. In this study, we examined the involvement of the anterior tuberal nucleus (AT) in auditory processing in adult zebrafish. Our tract-tracing experiments revealed that the dorsal subdivision of AT is strongly bidirectionally connected to the central nucleus of the torus semicircularis (TSc), a major auditory nucleus in fishes. Immunohistochemical visualization of the ribosomal protein S6 (pS6) phosphorylation to map neural activity in response to auditory stimulation substantiated this finding: the dorsal but not the ventral part of AT responded strongly to auditory stimulation. A similar response to auditory stimulation was present in the TSc but not in the nucleus isthmi, a visual region, which we used as a control for testing if the pS6 activation was specific to the auditory stimulation. We also measured the time course of pS6 phosphoryla...

Parvalbumin-expressing (PV) neurons, classified by their expression of the calcium-binding protein parvalbumin, play crucial roles in the function and plasticity of the lateral habenular nucleus (LHb). This study aimed to deepen our understanding of the LHb by collecting information about the heterogeneity of LHb PV neurons in mice. To achieve this, we investigated the proportions of the transmitter machinery in LHb PV neurons, including GABAergic, glutamatergic, serotonergic, cholinergic, and dopaminergic neurotransmitter markers, using transcriptome analysis, mRNA in situ hybridization chain reaction, and immunohistochemistry. LHb PV neurons comprise three subsets: glutamatergic, GABAergic, and double-positive for glutamatergic and GABAergic machinery. By comparing the percentages of the subsets, we found that the LHb was topographically organized anteroposteriorly; the GABAergic and glutamatergic PV neurons were preferentially distributed in the anterior and posterior LHb, respectively, uncovering the a...

Epilepsy is often comorbid with psychiatric illnesses, including anxiety and depression. Despite the high incidence of psychiatric comorbidities in people with epilepsy, few studies address the underlying mechanisms. Stress can trigger epilepsy and depression. Evidence from human and animal studies supports that hypothalamic–pituitary–adrenal (HPA) axis dysfunction may contribute to both disorders and their comorbidity ( [Kanner, 2003][1]). Here, we investigate if HPA axis dysfunction may influence epilepsy outcomes and psychiatric comorbidities. We generated a novel mouse model ( Kcc2 / Crh KO mice) lacking the K+/Cl− cotransporter, KCC2, in corticotropin-releasing hormone (CRH) neurons, which exhibit stress- and seizure-induced HPA axis hyperactivation ( [Melon et al., 2018][2]). We used the Kcc2 / Crh KO mice to examine the impact on epilepsy outcomes, including seizure frequency/burden, comorbid behavioral deficits, and sudden unexpected death in epilepsy (SUDEP) risk. We found sex differences in HPA a...

The magnitude of dopamine signals elicited by rewarding events and their predictors is updated when reward value changes. It is actively debated how readily these dopamine signals adapt and whether adaptation aligns with model-free or model-based reinforcement–learning principles. To investigate this, we trained male rats in a pavlovian-conditioning paradigm and measured dopamine release in the nucleus accumbens core in response to food reward (unconditioned stimulus) and reward-predictive conditioned stimuli (CS), both before and after reward devaluation, induced via either sensory-specific or nonspecific satiety. We demonstrate that (1) such devaluation reduces CS-induced dopamine release rapidly, without additional pairing of CS with devalued reward and irrespective of whether the devaluation was sensory-specific or nonspecific. In contrast, (2) reward devaluation did not decrease food reward-induced dopamine release. Surprisingly, (3) postdevaluation reconditioning, by additional pairing of CS with dev...

Treatment of Alzheimer's disease by targeting the antiamyloid beta (Aβ) peptide with immunotherapy has led to Food and Drug Administration approval of several new Aβ monoclonal antibodies. These approvals have come with restrictions, but the uptake of these new therapies in the clinic is expected to increase rapidly, at least in the USA. Hailed as a “breakthrough” by some, there has been stiff countercommentary questioning both safety and efficacy. The authors of this piece have been among those most concerned about the wisdom of releasing these drugs for clinical use. We note that the debate has been thus far largely confined to the clinical literature. With this Social Issues commentary, the authors hope to bring the basic science research community into the discussion. In 2021, despite investing tens of billions of research dollars, the field of Alzheimer's disease (AD) research was struggling. Since the approval of memantine in 2003 and the extension of donepezil for the treatment of severe AD in 2006...

Decision-making is a fundamental process that guides actions by selecting between various options based on their known or presumed outcomes, often using sensory inputs (Carandini and Churchland, 2013). The neural mechanisms by which the brain integrates complex information to make decisions are typically studied by measuring neural recordings, response times, and choice accuracy using well-trained animals (Carandini and Churchland, 2013). These experiments often employ two-alternative forced-choice (2AFC) designs, where animals are trained to choose between two stimuli presented simultaneously, assuming that the animal learns the value of each stimulus and decides based on an internal comparative evaluation. However, the traditional 2AFC design may be limited, as it does not consider that stimuli are not encountered simultaneously in nature and that decision-making strategies evolve during learning (White et al., 2024). Kacelnik et al. (2011) highlight these concerns, arguing that animals’ choices on a 2A...

Synapsins are highly abundant presynaptic proteins that play a crucial role in neurotransmission and plasticity via the clustering of synaptic vesicles. The synapsin III isoform is usually downregulated after development, but in hippocampal mossy fiber boutons, it persists in adulthood. Mossy fiber boutons express presynaptic forms of short- and long-term plasticity, which are thought to underlie different forms of learning. Previous research on synapsins at this synapse focused on synapsin isoforms I and II. Thus, a complete picture regarding the role of synapsins in mossy fiber plasticity is still missing. Here, we investigated presynaptic plasticity at hippocampal mossy fiber boutons by combining electrophysiological field recordings and transmission electron microscopy in a mouse model lacking all synapsin isoforms. We found decreased short-term plasticity, i.e., decreased facilitation and post-tetanic potentiation, but increased long-term potentiation in male synapsin triple knock-out (KO) mice. At th...

Previous studies have shown that ligands that bind to sigma-2 receptor/TMEM97 (s2R/TMEM97), a transmembrane protein, have anxiolytic/antidepressant-like properties and relieve neuropathic pain-like effects in rodents. Despite medical interest in s2R/TMEM97, little affective and pain behavioral characterization has been done using transgenic mice, which limits the development of s2R/TMEM97 as a viable therapeutic target. Using wild-type (WT) and global Tmem97 knock-out (KO) mice, we sought to identify the contribution of Tmem97 in modulating affective and pain-like behaviors using a battery of affective and pain assays, including open field, light/dark preference, elevated plus maze, forced swim test, tail suspension test, and the mechanical sensitivity tests. Our results demonstrate that female Tmem97 KO mice show less anxiety-like and depressive-like behaviors in light/dark preference and tail suspension tests but not in an open field, elevated plus maze, and forced swim tests at baseline. We next perform...

Individuals exhibit significant variability in their ability to adapt locomotor skills, with some adapting quickly and others more slowly. Differences in brain activity likely contribute to this variability, but direct neural evidence is lacking. We investigated individual differences in electrocortical activity that led to faster locomotor adaptation rates. We recorded high-density electroencephalography while young, neurotypical adults adapted their walking on a split-belt treadmill and grouped them based on how quickly they restored their gait symmetry. Results revealed unique spectral signatures within the posterior parietal, bilateral sensorimotor, and right visual cortices that differ between fast and slow adapters. Specifically, fast adapters exhibited lower alpha power in the posterior parietal and right visual cortices during early adaptation, associated with quicker attainment of steady-state step length symmetry. Decreased posterior parietal alpha may reflect enhanced spatial attention, sensory ...