Chair: Jerzy Mozrzymas (Medical University, Wroclaw, Poland)

Symposium 13: Plasticity and encoding at synapses and neuronal networks and beyond

Symposium focuses on two major problems: synaptic plasticity with particular emphasis on GABAergic plasticity and information encoding in the neuronal networks interacting with astrocytes (Curreli et al.) and extracellular matrix (Wiera et al.). The first two presentations (Curreli et al., Barberis et al.) from IIT (Italy) are presenting data on information encoding using methodology based on cutting edge optical techniques. Curreli et al. will show new data on encoding spatial information in the hippocampus emphasizing the role of astrocytes whose activity is monitored as calcium signaling. Andrea Barberis will talk about signaling between basolateral amygdala and ventral hippocampus in the context of transmitting by the BLA neurons both positive and negative predicting cues. They suggest that valence-activated BLA neurons contact vCA1 dendrites in a precise spatial organization that together with inhibitory synapses can generate unique valence-related spiking patterns in the postsynaptic neuron. To validate this hypothesis, they built a map of the spatial location of functional synaptic inputs from BLA, vCA3 and bistratified interneurons onto vCA1 pyramidal neurons. They have developed an automated procedure to perform single-spine calcium imaging in the whole vCA1 dendritic arbor exploiting custom made neural network algorithms combined with electrophysiology and optogenetics. This integrated approach allowed them to reveal the unique distribution of BLA and vCA3 and inhibitory inputs onto the whole dendritic arbor of vCA1 pyramidal neurons. The third speech will be given by prof. Dariusz Rakus and the leitmotif of this presentation are novel findings that Inhibition of glycogen phosphorylase (PYG), an enzyme responsible for glycogen breakdown, disrupts LTP induction and memory formation in young animals. However, intriguingly, in aged brains, PYG inhibition enhances LTP and improves cognitive performance. Prof. Rakus will present recent data that this paradoxical effect may relate to elevated lactate concentrations observed in aged brains and in neurodegenerative conditions such as Alzheimer’s disease (AD). In particular, their preliminary data demonstrate a significant increase in expression of the lactate receptor GPR81 (HCAR1) in the CA1 and CA3 hippocampal regions of aged mice, suggesting that excessive lactate signaling could contribute to impaired synaptic plasticity. Altered cross-talk between neurons and astrocytes in aged animals will be emphasized. The last speech will be given by Dr. Grzegorz Wiera (cooperation with Jerzy Mozrzymas) will be dedicated to the phenomenon of co-plasticity which is manifested as distinct plasticity phenomena at inhibitory and excitatory synapses, depending on where the inhibitory input is located on pyramidal neurons (soma, proximal dendrites in the CA1 stratum radiatum, and the distal dendrites in the stratum lacunosum-moleculare). These phenomena was found to be markedly regulated by the extracellular matrix that acts as a gatekeeper, restricting certain forms of inhibitory plasticity – when it is removed, hidden GABAergic plasticity emerges. Furthermore, they showed that maintaining inhibitory long-term potentiation (iLTP) relies on a key transsynaptic interaction between neuroligin-2 and neurexin.


Sebastiano Curreli, PhD, Optical Approaches to Brain Function, Istituto Italiano di Tecnologia, Genova, Italy

Spatial information encoding in the brain: beyond neural cells

Animals encode information about their position in neuronal circuits of the hippocampus as patterns of spikes. This cellular representation of space is thought to be the basis for essential higher brain functions, including spatial navigation. However, whether this cellular representation of spatial information extends beyond neuronal circuits has long been unknown. In this talk, I will present experimental evidence obtained in head-fixed mice during virtual spatial navigation demonstrating that hippocampal astrocytes, a main type of non-neuronal cells, encode information about the animal’s position in their intracellular calcium dynamics. Information encoded in astrocytes is complementary to that encoded in the spike output of nearby neurons. Moreover, perturbation of astrocytic calcium signals alters the coding properties of neuronal cells shaping their tuning functions and modulating their information content. Finally, I will discuss recent experimental findings showing spatial information encoding in astrocytic calcium signals recorded with miniaturized head-mounted two-photon microscopes (Mini2P) during freely moving spatial navigation. These findings challenge current models of brain information processing and advocate for the inclusion of an additional non-neural reservoir of information in the conceptualization of the network mechanisms that support how brains encode and process spatial information.


Andrea Barberis, Dario Cupolillo, Vincenzo Regio,  Istituto Italiano di Tecnologia, Genova, Italy

Mapping spatial organization of functional inputs in valence-related amygdalo-hippocampal circuits

The formation of memories in response to aversive or rewarding stimuli is crucial in guiding avoidance or approach behaviors. Scattered, projection-defined neuronal populations within the basolateral amygdala (BLA) selectively activate during encoding and retrieval of memories associated with either positive or negative valence. Interestingly, BLA neurons projecting to the CA1 area of ventral hippocampus (vCA1) respond to both positive or negative predicting cues with no marked bias, suggesting that, within the whole responding population, two distinct subnetworks relay opposite information to vCA1.

However, the mechanism by which vCA1 pyramidal neurons discern between positive and negative-related information remains unclear. The valence information might stay segregated within two distinct neuronal populations in vCA1, or it might also converge onto the same vCA1 neurons, which have the capability to specifically encode negative or positive valence. We suggest that valence-activated BLA neurons contact vCA1 dendrites in a precise spatial organization that together with inhibitory synapses can generate unique valence-related spiking patterns in the postsynaptic neuron. To validate this hypothesis, we aimed at building a map of the spatial location of functional synaptic inputs from BLA, vCA3 and bistratified interneurons onto vCA1 pyramidal neurons. To this end, we have developed an automated procedure to perform single-spine calcium imaging in the whole vCA1 dendritic arbor exploiting custom made neural network algorithms combined with electrophysiology and optogenetics. This integrated approach allowed to reveal the unique distribution of BLA and vCA3 and inhibitory inputs onto the whole dendritic arbor of vCA1 pyramidal neurons.


Dariusz Rakus1, Dominika Drulis-Fajdasz1, Agnieszka Gizak1, Daria Hajka1, Olga Wójcicka1, Przemysław Duda1, Jakub Janczara1, Bartosz Budziak1, Tomasz Szczęsny1, Janusz Wiśniewski1, Adam Krzystyniak2, Agata Pytyś2, Marcin Wawrzyniak2, Tomasz Wójtowicz2, Jakub Włodarczyk2, Alicja Puścian3, Kinga Gostomska-Pampuch4, Kamila Duś-Szachniewicz5, Jerzy W. Mozrzymas6, Natalia Pudełko-Malik7, Jerzy Ł. Wiśniewski7, Piotr Młynarz7, Arkadiusz Miążek8, Jacek R. Wiśniewski9, Miłosz Ruszkowski10, Jakub Barciszewski10, Mariusz Jaskólski10,11, Aleksander Czogalla12, Piotr Hinc12, Daniel Krowarsch13, Aleksandra Czyrek13

1Department of Molecular Physiology and Neurobiology, University of Wrocław, Wroclaw, Poland
2Laboratory of Cell Biophysics, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland
3Nencki-EMBL Partnership for Neural Plasticity and Brain Disorders – BRAINCITY, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland
4Department of Biochemistry and Immunochemistry, Wroclaw Medical University, Wrocław, Poland
5Department of Clinical and Experimental Pathology, Institute of General and Experimental Pathology, Wroclaw Medical University, Wrocław, Poland
6Faculty of Medicine, Department of Biophysics and Neuroscience, Wroclaw Medical University, Wrocław, Poland
7Department of Biochemistry, Molecular Biology and Biotechnology, Faculty of Chemistry, Wrocław University of Science and Technology, Wrocław, Poland
8Laboratory of Tumor Immunology, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wrocław, Poland
9Biochemical Proteomics Group, Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany
10Institute of Bioorganic Chemistry, Polish Academy of Sciences, Poznań, Poland
11Department of Crystallography, Faculty of Chemistry, Adam Mickiewicz University, Poznań, Poland
12Department of Cytobiochemistry, Faculty of Biotechnology, University of Wrocław, Wrocław, Poland
13Department of Protein Biotechnology, University of Wrocław, Wrocław, Poland

From astrocytic glycogen to memory formation and brain rejuvenation

Even so-called „healthy aging” is associated with a significant decline in memory and cognitive abilities. However, the molecular basis underlying age-related cognitive impairment remains poorly understood. Long-Term Potentiation (LTP), defined as the long-lasting strengthening of synaptic connections between excitatory neurons, is the best-characterized form of synaptic plasticity, and its attenuation is linked to cognitive decline observed during aging and neurodegenerative diseases.
LTP induction critically depends on astrocytic activity, as astrocytes form tripartite synapses with neurons. In young animals, glycogen-derived lactate released from astrocytes is essential for the establishment of LTP. Lactate role in LTP involves an increase in the NADH/NAD ratio, enhancing NMDA receptor signaling and/or promoting CAMK2 autoactivation through interactions with the dimeric form of fructose 1,6-bisphosphatase 2 (FBP2).

Inhibition of glycogen phosphorylase (PYG), an enzyme responsible for glycogen breakdown, disrupts LTP induction and memory formation in young animals. Intriguingly, in aged brains, PYG inhibition conversely enhances LTP and improves cognitive performance. The precise molecular mechanism behind this paradoxical effect remains unclear but may relate to elevated lactate concentrations observed in aged brains and in neurodegenerative conditions such as Alzheimer’s disease (AD). Our preliminary data demonstrate a significant increase in expression of the lactate receptor GPR81 (HCAR1) in the CA1 and CA3 hippocampal regions of aged mice, suggesting that excessive lactate signaling could contribute to impaired synaptic plasticity.

Unlike LTP, much less is known about age-related changes in Long-Term Depression (LTD) and about the effects of lactate on the molecular mechanisms underlying this form of synaptic plasticity. Here, we present the first data demonstrating the impact of FBP2 conformational manipulation on molecular signatures associated with LTD.


Grzegorz Wiera1, Jadwiga Jabłońska1, Anna Lech1, Jerzy Mozrzymas1

1Medical University, Wroclaw, Poland

The molecular mechanisms of intersynaptic co-plasticity: How excitatory and different inhibitory synapses shape each other.

Far from being static, GABAergic synapses exhibit a remarkable capacity for plasticity, reshaping neural circuits to fine-tune brain function. Yet, the rules that govern inhibitory plasticity and its interaction with excitatory synapses remain unclear. Given the diversity of hippocampal interneurons, it is likely that inhibitory plasticity follows unique, synapse-specific mechanisms that have yet to be fully uncovered.
 
In our experiments, we discovered a form of communication between excitatory and inhibitory plasticity, which we call co-plasticity. The way these synapses change together depends on where the inhibitory input is located on pyramidal neurons. Co-plasticity follows different patterns at the soma, the proximal dendrites in the CA1 stratum radiatum, and the distal dendrites in the stratum lacunosum-moleculare. We also found that the extracellular matrix acts as a gatekeeper, restricting certain forms of inhibitory plasticity—when it is removed, hidden GABAergic plasticity emerges. Furthermore, we showed that maintaining inhibitory long-term potentiation (iLTP) relies on a key transsynaptic interaction between neuroligin-2 and neurexin. Interfering with this adhesion abolished already induced GABAergic plasticity, demonstrating that plastic changes at inhibitory synapses also exhibit a late phase. Finally, we found that naturally occurring neurosteroids, such as allopregnanolone and pregnanolone sulfate, act as metaplastic regulators, shaping the balance between excitatory and inhibitory plasticity.

Together, these findings provide new insights into the molecular and structural mechanisms regulating inhibitory plasticity and its coordination with excitatory synaptic changes, highlighting its relevance for experience-dependent circuit remodeling.

Fundings: This work was supported by National Science Centre, Poland NCN grant 2021/43/B/NZ4/01675

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