Target cell-specific plasticity rules of NMDA receptor-mediated synaptic transmission in the hippocampus

Long-term potentiation and depression of NMDA receptor-mediated synaptic transmission (NMDAR LTP/LTD) can significantly impact synapse function and information transfer in several brain areas. However, the mechanisms that determine the direction of NMDAR plasticity are poorly understood. Here, using physiologically relevant patterns of presynaptic and postsynaptic burst activities, whole-cell patch clamp recordings, 2-photon laser calcium imaging in acute rat hippocampal slices and immunoelectron microscopy, we tested whether distinct calcium dynamics and group I metabotropic glutamate receptor (I-mGluR) subtypes control the sign of NMDAR plasticity. We found that postsynaptic calcium transients (CaTs) in response to hippocampal MF stimulation were significantly larger during the induction of NMDAR-LTP compared to NMDAR-LTD at the MF-to-CA3 pyramidal cell (MF-CA3) synapse. This difference was abolished by pharmacological blockade of mGluR5 and was significantly reduced by depletion of intracellular calcium stores, whereas blocking mGluR1 had no effect on these CaTs. In addition, we discovered that MF to hilar mossy cell (MF-MC) synapses, which share several structural and functional commonalities with MF-CA3 synapses, also undergoes NMDAR plasticity. To our surprise, however, we found that the postsynaptic distribution of I-mGluR subtypes at these two synapses differ, and the same induction protocol that induces NMDAR-LTD at MF-CA3 synapses, only triggered NMDAR-LTP at MF-MC synapses, despite a comparable calcium dynamics. Thus, postsynaptic calcium dynamics alone cannot predict the sign of NMDAR plasticity, indicating that both postsynaptic calcium rise and the relative contribution of I-mGluR subtypes likely determine the learning rules of NMDAR plasticity.This research was supported by the National Institutes of Health (NIH), R01-NS113600, R01-MH125772, R01-MH116673, and R01-MH081935 to PC, and by The Basque Government (IT1620-22), Red de Investigación en Atención Primaria de Adicciones (RIAPAd), Instituto de Salud Carlos III (RD21/0009/0006), and Ministry of Science and Innovation (PID2019-107548RB-I00) to PG

Cognitive-Affective Functions of the Cerebellum

The cerebellum, traditionally associated with motor coordination and balance, also plays a crucial role in various aspects of higher-order function and dysfunction. Emerging research has shed light on the cerebellum’s broader contributions to cognitive, emotional, and reward processes. The cerebellum’s influence on autonomic function further highlights its significance in regulating motivational and emotional states. Perturbations in cerebellar development and function have been implicated in various neurodevelopmental disorders, including autism spectrum disorder and attention deficit hyperactivity disorder. An increasing appreciation for neuropsychiatric symptoms that arise from cerebellar dysfunction underscores the importance of elucidating the circuit mechanisms that underlie complex interactions between the cerebellum and other brain regions for a comprehensive understanding of complex behavior. By briefly discussing new advances in mapping cerebellar function in affective, cognitive, autonomic, and social processing and reviewing the role of the cerebellum in neuropathology beyond the motor domain, this Mini-Symposium review aims to provide a broad perspective of cerebellar intersections with the limbic brain in health and disease.</p

Cognitive-Affective Functions of the Cerebellum.

The cerebellum, traditionally associated with motor coordination and balance, also plays a crucial role in various aspects of higher-order function and dysfunction. Emerging research has shed light on the cerebellum's broader contributions to cognitive, emotional, and reward processes. The cerebellum's influence on autonomic function further highlights its significance in regulating motivational and emotional states. Perturbations in cerebellar development and function have been implicated in various neurodevelopmental disorders, including autism spectrum disorder and attention deficit hyperactivity disorder. An increasing appreciation for neuropsychiatric symptoms that arise from cerebellar dysfunction underscores the importance of elucidating the circuit mechanisms that underlie complex interactions between the cerebellum and other brain regions for a comprehensive understanding of complex behavior. By briefly discussing new advances in mapping cerebellar function in affective, cognitive, autonomic, and social processing and reviewing the role of the cerebellum in neuropathology beyond the motor domain, this Mini-Symposium review aims to provide a broad perspective of cerebellar intersections with the limbic brain in health and disease

Npas4 Is a Critical Regulator of Learning-Induced Plasticity at Mossy Fiber-CA3 Synapses during Contextual Memory Formation

Synaptic connections between hippocampal mossy fibers (MFs) and CA3 pyramidal neurons are essential for contextual memory encoding, but the molecular mechanisms regulating MF-CA3 synapses during memory formation and the exact nature of this regulation are poorly understood. Here we report that the activity-dependent transcription factor Npas4 selectively regulates the structure and strength of MF-CA3 synapses by restricting the number of their functional synaptic contacts without affecting the other synaptic inputs onto CA3 pyramidal neurons. Using an activity-dependent reporter, we identified CA3 pyramidal cells that were activated by contextual learning and found that MF inputs on these cells were selectively strengthened. Deletion of Npas4 prevented both contextual memory formation and this learning-induced synaptic modification. We further show that Npas4 regulates MF-CA3 synapses by controlling the expression of the polo-like kinase Plk2. Thus, Npas4 is a critical regulator of experience-dependent, structural, and functional plasticity at MF-CA3 synapses during contextual memory formation. Weng et al. report that the transcription factor Npas4 selectively regulates the number of functional synaptic contacts between CA3 pyramidal neurons and mossy fibers, allowing for learning-induced modification of MF-CA3 synapses during contextual memory formation.NIH (Grants DA017392, NS090473, MH081935, MH091220, NS088421, and DC014701

Changes in suppression of sIPSC frequency induced by WIN 55212-2, baclofen, or quinpirole in mPFC neurons of FR rats during anticipatory and consummatory phase.

<p>(<b>A</b>) Effect of 5 µM WIN 55212-2 and subsequent co-application of 1 µM SR141716 on sIPSC frequency in mPFC neurons from animals fed ad libitum (n = 6 neurons). (<b>B</b>) Effect of 5 µM WIN 55212-2 on sIPSC frequency in mPFC neurons from control and FR rats (sacrificed at 5 min before food presentation) (n = 16 to 22 neurons). (<b>C</b>) Summary of the percentage change in sIPSC frequency from baseline induced by WIN 55212-2 in mPFC neurons from control and FR rats (tested at different times relative to food presentation). (<b>D, E</b>) Effects of 10 µM baclofen and 1 µM quinpirole, respectively, on sIPSC frequency in mPFC neurons from control and FR rats (sacrificed at 5 min before food presentation) (n = 4 to 7 neurons). (<b>F</b>) Summary of the percentage change in sIPSC frequency from baseline induced by WIN 55212-2, baclofen, or quinpirole in control rats and FR rats (5 min before food presentation). Data are means ± SEM. Two-way ANOVA and Bonferroni post-hoc test, ^a<i>P</i><0.05 versus baseline, ^a’<i>P</i><0.01 versus control, ^b<i>P</i><0.05 versus corresponding control.</p

Effect of food restriction on the amount of CB1 receptors in mPFC.

<p>(<b>A</b>) Confocal images of CB1 receptor (green, nuclei blue); (<b>B</b>) Semiquantitative determination of the abundance of CB1 receptor, evaluated by image analysis of the immunohistochemistry, in mPFC of rat exposed to food restriction during anticipatory and consummatory phase with respect to fed ad libitum animals. (<b>C</b>) Confocal images of CB1 receptor (green) localization in CCK positive neurons (red, nuclei blue); (<b>D</b>) Semiquantitative determination of the abundance of the colocalization CCK/CB1 receptor, determined by image analysis of the immunohistochemistry data, in FR and fed ad libitum animals. (<b>E</b>) colocalization of GAD65/CB1 cluster (CB1 receptors green; GAD65 fuchsia, nuclei blue). (<b>F</b>) Semiquantitative determination of the abundance of the cluster GAD65/CB1 receptor as determined by image analysis of the immunohistochemistry data. Results are expressed as percentage of change in cluster numbers relative to fed ad libitum rats and are mean ± SEM of values of 5 rats for each experimental group. ^a<i>P</i><0.005; ^a’<i>P</i><0.001 versus fed ad libitum rats, one way ANOVA; image scale bar 10 µm.</p