G protein–coupled receptors (GPCRs) that couple to Gi/o proteins modulate neurotransmission presynaptically by inhibiting exocytosis. Release of Gβγ subunits from activated G proteins decreases the activity of voltage-gated Ca2+ channels (VGCCs), decreasing excitability. A less understood Gβγ-mediated mechanism downstream of Ca2+ entry is the binding of Gβγ to SNARE complexes, which facilitate the fusion of vesicles with the cell plasma membrane in exocytosis. Here, we generated mice expressing a form of the SNARE protein SNAP25 with premature truncation of the C terminus and that were therefore partially deficient in this interaction. SNAP25Δ3 homozygote mice exhibited normal presynaptic inhibition by GABAB receptors, which inhibit VGCCs, but defective presynaptic inhibition by receptors that work directly on the SNARE complex, such as 5-hydroxytryptamine (serotonin) 5-HT1b receptors and adrenergic α2a receptors. Simultaneously stimulating receptors that act through both mechanisms showed synergistic inhibitory effects. SNAP25Δ3 homozygote mice had various behavioral phenotypes, including increased stress-induced hyperthermia, defective spatial learning, impaired gait, and supraspinal nociception. These data suggest that the inhibition of exocytosis by Gi/o-coupled GPCRs through the Gβγ-SNARE interaction is a crucial component of numerous physiological and behavioral processes.
We identify problematic areas throughout the Science, Technology, Engineering and Mathematics (STEM) pipeline that perpetuate racial disparities in academia. Distinct ways to curtail these disparities include early exposure and access to resources, supportive mentoring networks and comprehensive training programs specifically for racially minoritized students and trainees at each career stage. These actions will revitalize the STEM pipeline. ll
The mesolimbic dopamine system-which originates in the ventral tegmental area and projects to the striatum-has been shown to be involved in the expression of sex-specific behavior and is thought to be a critical mediator of many psychiatric diseases. While substantial work has focused on sex differences in the anatomy of dopamine neurons and relative dopamine levels between males and females, an important characteristic of dopamine release from axon terminals in the striatum is that it is rapidly modulated by local regulatory mechanisms independent of somatic activity. These processes can occur via homosynaptic mechanisms-such as presynaptic dopamine autoreceptors and dopamine transporters-as well as heterosynaptic mechanisms, such as retrograde signaling from postsynaptic cholinergic and GABAergic systems, among others. These regulators serve as potential targets for the expression of sex differences in dopamine regulation in both ovarian hormone-dependent and independent fashions. This review describes how sex differences in microcircuit regulatory mechanisms can alter dopamine dynamics between males and females. We then describe what is known about the hormonal mechanisms controlling/regulating these processes. Finally, we highlight the missing gaps in our knowledge of these systems in females. Together, a more comprehensive and mechanistic understanding of how sex differences in dopamine function manifest will be particularly important in developing evidence-based therapeutics that target this system and show efficacy in both sexes.
Regulation of axonal dopamine release by local microcircuitry is at the hub of several biological processes that govern the timing and magnitude of signaling events in reward-related brain regions. An important characteristic of dopamine release from axon terminals in the striatum is that it is rapidly modulated by local regulatory mechanisms. These processes can occur via homosynaptic mechanisms-such How to cite this article: NolanSO, Zachry JF, Johnson AR,
Circuit dysfunction in complex brain disorders such as schizophrenia and autism is caused by imbalances between inhibitory and excitatory synaptic transmission (I/E). Short-term plasticity differentially alters responses from excitatory and inhibitory synapses, causing the I/E ratio to change as a function of frequency. However, little is known about I/E ratio dynamics in complex brain disorders. Transcriptional dysregulation in interneurons, particularly parvalbumin interneurons, is a consistent pathophysiological feature of schizophrenia. Peroxisome proliferator activated receptor ␥ coactivator 1␣ (PGC-1␣) is a transcriptional coactivator that in hippocampus is highly concentrated in inhibitory interneurons and regulates parvalbumin transcription. Here, we used PGC-1␣ Ϫ/Ϫ mice to investigate effects of interneuron transcriptional dysregulation on the dynamics of the I/E ratio at the synaptic and circuit level in hippocampus. We find that loss of PGC-1␣ increases the I/E ratio onto CA1 pyramidal cells in response to Schaffer collateral stimulation in slices from young adult mice. The underlying mechanism is enhanced basal inhibition, including increased inhibition from parvalbumin interneurons. This decreases the spread of activation in CA1 and dramatically limits pyramidal cell spiking, reducing hippocampal output. The I/E ratio and CA1 output are partially restored by paired-pulse stimulation at short intervals, indicating frequency-dependent effects. However, circuit dysfunction persists, indicated by alterations in kainate-induced gamma oscillations and impaired nest building. Together, these results show that transcriptional dysregulation in hippocampal interneurons causes frequency-dependent alterations in I/E ratio and circuit function, suggesting that PGC-1␣ deficiency in psychiatric and neurological disorders contributes to disease by causing functionally relevant alterations in I/E balance.
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