Dual regulation of spine-specific and synapse-to-nucleus signaling by PKCδ during plasticity

The activity-dependent plasticity of synapses is believed to be the cellular basis of learning. These synaptic changes are mediated through the coordination of local biochemical reactions in synapses and changes in gene transcription in the nucleus to modulate neuronal circuits and behavior. The protein kinase C (PKC) family of isozymes has long been established as critical for synaptic plasticity. However, due to a lack of suitable isozyme-specific tools, the role of the novel subfamily of PKC isozymes is largely unknown. Here, through the development of FLIM-FRET activity sensors, we investigate novel PKC isozymes in synaptic plasticity in mouse CA1 pyramidal neurons. We find that PKCδ is activated downstream of TrkB and that the spatiotemporal nature of its activation depends on the plasticity stimulation. In response to single spine plasticity, PKCδ is activated primarily in the stimulated spine and is required for local expression of plasticity. However, in response to multi-spine stimulation, a long-lasting and spreading activation of PKCδ scales with the number of spines stimulated and, by regulating CREB activity, couples spine plasticity to transcription in the nucleus. Thus, PKCδ plays a dual functional role in facilitating synaptic plasticity.

RGS14 Regulation of Post-Synaptic Signaling and Spine Plasticity in Brain

The regulator of G-protein signaling 14 (RGS14) is a multifunctional signaling protein that regulates post synaptic plasticity in neurons. RGS14 is expressed in the brain regions essential for learning, memory, emotion, and stimulus-induced behaviors, including the basal ganglia, limbic system, and cortex. Behaviorally, RGS14 regulates spatial and object memory, female-specific responses to cued fear conditioning, and environmental- and psychostimulant-induced locomotion. At the cellular level, RGS14 acts as a scaffolding protein that integrates G protein, Ras/ERK, and calcium/calmodulin signaling pathways essential for spine plasticity and cell signaling, allowing RGS14 to naturally suppress long-term potentiation (LTP) and structural plasticity in hippocampal area CA2 pyramidal cells. Recent proteomics findings indicate that RGS14 also engages the actomyosin system in the brain, perhaps to impact spine morphogenesis. Of note, RGS14 is also a nucleocytoplasmic shuttling protein, where its role in the nucleus remains uncertain. Balanced nuclear import/export and dendritic spine localization are likely essential for RGS14 neuronal functions as a regulator of synaptic plasticity. Supporting this idea, human genetic variants disrupting RGS14 localization also disrupt RGS14’s effects on plasticity. This review will focus on the known and unexplored roles of RGS14 in cell signaling, physiology, disease and behavior.

Induction of Bdnf from promoter I following electroconvulsive seizures contributes to structural plasticity in neurons of the piriform cortex

The efficacy of electroconvulsive therapy (ECT) as a treatment for psychiatric disorders, including major depressive disorder (MDD) is hypothesized to depend on induction of molecular and cellular events that trigger structural plasticity in neurons. Electroconvulsive seizures (ECS) in animal models can help to inform our understanding of how electroconvulsive therapy (ECT) impacts the brain. ECS induces structural plasticity in neuronal dendrites in many brain regions, including the piriform cortex, a highly epileptogenic region that has also been implicated in depression. ECS-induced structural plasticity is associated with differential expression of unique isoforms encoding the neurotrophin, brain-derived neurotrophic factor (BDNF), but the functional significance of these transcripts in dendritic plasticity is not clear. Here, we demonstrate that different Bdnf isoforms are expressed non-stochastically across neurons of the piriform cortex following ECS. Specifically, cells expressing Bdnf exon 1-containing transcripts show a unique spatial recruitment pattern in response to ECS. We further demonstrate that Bdnf Ex1 expression in these cells is necessary for ECS-induced dendritic spine plasticity.

Controlled activation of cortical astrocytes can reverse neuropathic chronic pain

Chronic pain is a major public health problem that currently lacks effective treatment options. Here, we report a novel combination therapy that can effectively reverse chronic pain induced by nerve injury in mice. By combing transient nerve block to inhibit noxious afferent input from injured peripheral nerves, with transient concurrent activation of astrocytes in the somatosensory cortex (S1) by either transcranial direct current stimulation (tDCS) or via the chemogenetic DREADD system, we could reverse allodynia previously established by partial sciatic nerve ligation (PSL). Activation of astrocytes initiated spine plasticity to reduce synapses formed shortly after PSL. The cure from allodynia persisted long after ceasing active treatment. Thus, our study represents the first report of a robust, readily translatable approach for treating chronic pain that capitalizes on the causative interplay between noxious afferents, sensitized central neuronal circuits and astrocytic-activation induced plasticity.

Interneuron activity-structural plasticity association is driven by context-dependent sensory experience

Neuronal dendritic spine dynamics provide a plasticity mechanism for altering brain circuit connectivity to integrate new information for learning and memory. Previous in vivo studies in the olfactory bulb (OB) showed that regional increases in activity caused localized spine stability, at a population level, yet how activity affects spine dynamics at an individual neuron level remains unknown. In this study, we tracked in vivo the correlation between an individual neuron’s activity and its dendritic spine dynamics of OB granule cell (GC) interneurons. Odor experience caused a consistent correlation between individual GC activity and spine stability. Dissecting the components of the OB circuit showed that increased principal cell (MC) activity was sufficient to drive this correlation, whereas cell-autonomously driven GC activity had no effect. A mathematical model was able to replicate the GC activity-spine stability correlation and showed MC output having improved odor discriminability while retaining odor memory. These results reveal that GC spine plasticity provides a sufficient network mechanism to decorrelate odors and maintain a memory trace.

Distribution of cortactin in cerebellar Purkinje cell spines

Dendritic spines are the primary sites of excitatory transmission in the mammalian brain. Spines of cerebellar Purkinje Cells (PCs) are plastic, but they differ from forebrain spines in a number of important respects, and the mechanisms of spine plasticity differ between forebrain and cerebellum. Our previous studies indicate that in hippocampal spines cortactin—a protein that stabilizes actin branch points—resides in the spine core, avoiding the spine shell. To see whether the distribution of cortactin differs in PC spines, we examined its subcellular organization using quantitative preembedding immunoelectron microscopy. We found that cortactin was enriched in the spine shell, associated with the non-synaptic membrane, and was also situated within the postsynaptic density (PSD). This previously unrecognized distribution of cortactin within PC spines may underlie structural and functional differences in excitatory spine synapses between forebrain, and cerebellum.