Spatial and temporal features of synaptic inputs engage integration mechanisms on multiple scales, including presynaptic release sites, postsynaptic dendrites, and networks of inhibitory interneurons. Here we investigate how these mechanisms cooperate to filter synaptic input in hippocampal area CA1. Dendritic recordings from CA1 pyramidal neurons reveal that proximal inputs from CA3 as well as distal inputs from entorhinal cortex layer III (ECIII) sum sublinearly or linearly at low firing rates due to feedforward inhibition, but sum supralinearly at high firing rates due to synaptic facilitation, producing a high-pass filter. However, during ECIII and CA3 input comparison, supralinear dendritic integration is dynamically balanced by feedforward and feedback inhibition, resulting in suppression of dendritic complex spiking. We find that a particular subpopulation of CA1 interneurons expressing neuropeptide Y (NPY) contributes prominently to this dynamic filter by integrating both ECIII and CA3 input pathways and potently inhibiting CA1 pyramidal neuron dendrites.

SUMMARY Dissecting the functional roles of excitatory and inhibitory neurons in cortical circuits is a fundamental goal in neuroscience. Of particular interest are their roles in emergent cortical computations such as binocular integration in primary visual cortex (V1). We measured the binocular response selectivity of genetically-defined subpopulations of excitatory and inhibitory neurons. Parvalbumin (PV+) interneurons received strong inputs from both eyes, but lacked selectivity for binocular disparity. Because broad selectivity could result from heterogeneous synaptic input from neighboring neurons, we examined how individual PV+ interneuron selectivity compared to that of the local neuronal network, which is primarily composed of excitatory neurons. PV+ neurons showed functional similarity to neighboring neuronal populations over spatial distances resembling measurements of synaptic connectivity. On the other hand, excitatory neurons expressing CaMKIIα displayed no such functional similarity with the neighboring population. Our findings suggest that broad selectivity of PV+ interneurons results from nonspecific integration within local networks.

Many biological processes involve the mechanistic/mammalian target of rapamycin complex 1 (mTORC1). Thus, the challenge of deciphering mTORC1-mediated functions during normal and pathological states in the central nervous system is challenging. Because mTORC1 is at the core of translation, we have investigated mTORC1 function in global and regional protein expression. Activation of mTORC1 has been generally regarded to promote translation. Few but recent works have shown that suppression of mTORC1 can also promote local protein synthesis. Moreover, excessive mTORC1 activation during diseased states represses basal and activity-induced protein synthesis. To determine the role of mTORC1 activation in protein expression, we have used an unbiased, large-scale proteomic approach. We provide evidence that a brief repression of mTORC1 activity in vivo by rapamycin has little effect globally, yet leads to a significant remodeling of synaptic proteins, in particular those proteins that reside in the postsynaptic density. We have also found that curtailing the activity of mTORC1 bidirectionally alters the expression of proteins associated with epilepsy, Alzheimer's disease, and autism spectrum disorder-neurological disorders that exhibit elevated mTORC1 activity. Through a protein-protein interaction network analysis, we have identified common proteins shared among these mTORC1-related diseases. One such protein is Parkinson protein 7, which has been implicated in Parkinson's disease, yet not associated with epilepsy, Alzheimers disease, or autism spectrum disorder. To verify our finding, we provide evidence that the protein expression of Parkinson protein 7, including new protein synthesis, is sensitive to mTORC1 inhibition. Using a mouse model of tuberous sclerosis complex, a disease that displays both epilepsy and autism spectrum disorder phenotypes and has overactive mTORC1 signaling, we show that Parkinson protein 7 protein is elevated in the dendrites and colocalizes with the postsynaptic marker postsynaptic density-95. Our work offers a comprehensive view of mTORC1 and its role in regulating regional protein expression in normal and diseased states. The mechanistic/mammalian target of rapamycin complex 1 (mTORC1) 1 is a serine/threonine protein kinase that is highly Author contributions: FN and KRG designed research. FN and SN conducted experiments and analyzed data. SN performed bioinformatics analyses. ES and YM conducted mass spectrometry analyses. GS facilitated mass spectrometry experiments and provided technical advice. GAD and BVZ provided the virus and performed stereotaxic injections. FN, SN, and KRG wrote the manuscript. 1 The abbreviations used are: mTORC1, mechanistic/mammalian target of rapamycin complex 1; AD, Alzheimer's disease; AHA, azidohomoalanine; APP, amyloid precursor protein; ASD, autism spectrum disorder; BONCAT, bioorthogonal noncanonical amino acid

A single injection of N-methyl-D-aspartate receptor (NMDAR) antagonists produces a rapid antidepressant response. Lasting changes in the synapse structure and composition underlie the effectiveness of these drugs. We recently discovered that rapid antidepressants cause a shift in the γ-aminobutyric acid receptor (GABABR) signaling pathway, such that GABABR activation shifts from opening inwardly rectifiying potassium channels (Kir/GIRK) to increasing resting dendritic calcium signal and mammalian Target of Rapamycin activity. However, little is known about the molecular and biochemical mechanisms that initiate this shift. Herein, we show that GABABR signaling to Kir3 (GIRK) channels decreases with NMDAR blockade. Blocking NMDAR signaling stabilizes the adaptor protein 14-3-3η, which decouples GABABR signaling from Kir3 and is required for the rapid antidepressant efficacy. Consistent with these results, we find that key proteins involved in GABABR signaling bidirectionally change in a depression model and with rapid antidepressants. In socially defeated rodents, a model for depression, GABABR and 14-3-3η levels decrease in the hippocampus. The NMDAR antagonists AP5 and Ro-25-6981, acting as rapid antidepressants, increase GABABR and 14-3-3η expression and decrease Kir3.2. Taken together, these data suggest that the shift in GABABR function requires a loss of GABABR-Kir3 channel activity mediated by 14-3-3η. Our findings support a central role for 14-3-3η in the efficacy of rapid antidepressants and define a critical molecular mechanism for activity-dependent alterations in GABABR signaling.

Background Ethanol affects prefrontal cortex functional roles such as decision making, working memory, and behavioral control. Yet, the pharmacological effect of ethanol on dopamine, a neuromodulator in the medial prefrontal cortex, is unclear. Past studies exploring this topic produced conflicting outcomes; however, a handful of factors (temporal resolution, method of drug administration, estrous cycle) possibly contributed to these discrepancies. We sought to mitigate these factors in order to elucidate ethanol’s pharmacological effects on medial prefrontal cortical dopamine in Long-Evans rats. Methods We administered experimental solutions via an intravenous, handling-free route, monitored dopamine in the medial prefrontal cortex via microdialysis (10-minute samples), and used male rats to avoid estrous cycle/ethanol interactions. First, we rapidly (~2.7 ml/min) or slowly (~0.6 ml/min) administered 1.0 g/kg ethanol and saline infusions, showing that the experimental methods did not contribute to dopamine changes. Then a cumulative dosing protocol was used to administer 0.25, 0.75, 1.50, and 2.25 g/kg intravenous ethanol doses to evaluate dose-response. Finally, we monitored dialysate ethanol levels during an oral ethanol self-administration session to compare the dialysate ethanol levels achieved during the pharmacological experiments to those seen during self-administration. Results Intravenous administration of a rapid or slow 1.0 g/kg ethanol infusion resulted in similar significant 55 ± 9% and 63 ± 15% peak dialysate dopamine increases, respectively. The 0.25, 0.75, 1.50, and 2.25 g/kg ethanol doses produced a non-significant 17 ± 5% and significant 36 ± 15%, 68 ± 19%, and 86 ± 20 % peak dialysate dopamine increases, respectively. Self-administration dialysate ethanol concentrations fell within the range of concentrations noted during the ethanol dose-response curve. Conclusions These experiments show that, using experimental methods which minimize possibly confounding factors, acute intravenous ethanol increases extracellular dopamine in the medial prefrontal cortex in a dose-dependent manner, thereby clarifying ethanol’s pharmacological effects on the mesocortical-dopamine system.