Biology subjects

Caliskan, G.

Publications and source records attributed to Caliskan, G..

7 recordsLinked to original sources

bioRxiv2023

Increasing NPYergic transmission in the hippocampus rescues aging-related deficits of long-term potentiation in the mouse dentate gyrus

Loss of neuropeptide Y (NPY)-expressing interneurons in the hippocampus and decaying cholinergic neuromodulation are thought to contribute to impaired cognitive function during aging. However, the interaction of these two neuromodulatory systems in maintaining hippocampal synaptic plasticity during healthy aging has not been explored so far. Here we report profound sex differences in the Neuropeptide-Y (NPY) levels in the dorsal dentate gyrus (DG) with higher NPY concentrations in the male mice compared to their female counterparts and a reduction of NPY levels during aging specifically in males. This change in aged males is accompanied by a deficit in theta burst-induced long-term potentiation (LTP) in the medial perforant path-to-dorsal DG (MPP-DG) synapse, which can be rescued by enhancing cholinergic activation with the acetylcholine esterase blocker, physostigmine. Importantly, NPYergic transmission is required for this rescue of LTP. Moreover, exogenous NPY application alone is sufficient to recover LTP induction in aged male mice, even in the absence of the cholinergic stimulator. Together, our results suggest that in male mice NPYergic neurotransmission is a critical factor for maintaining dorsal DG LTP during aging.

neuroscience↗

bioRxiv2023

Neural Extracellular Matrix Remodeling Signatures in Genetic and Acquired Mouse Models of Epilepsy

Epilepsies are multifaceted neurological disorders characterized by abnormal brain activity, e.g., caused by imbalanced synaptic excitation and inhibition. The neural extracellular matrix (ECM) is dynamically modulated by physiological and pathophysiological activity and critically involved in controlling the brains excitability. We used different epilepsy models, i.e. mice lacking the presynaptic scaffolding protein Bassoon at excitatory, inhibitory or all synapse types as genetic models for rapidly generalizing early-onset epilepsy, and intra-hippocampal kainate injection, a model for acquired temporal lobe epilepsy, to study the relationship between epileptic seizures and ECM composition. Electroencephalogram recordings revealed Bassoon deletion at excitatory or inhibitory synapses having diverse effects on epilepsy-related phenotypes. While constitutive Bsn mutants and GABAergic neuron-specific knockouts (BsnDlx5/6cKO) displayed severe epilepsy with more and stronger seizures than kainate-injected animals, mutants lacking Bassoon solely in excitatory forebrain neurons (BsnEmx1cKO) showed only mild impairments. By semiquantitative immunoblotting and immunohistochemistry we show model-specific patterns of neural ECM remodeling, and we also demonstrate significant upregulation of the ECM receptor CD44 in null and BsnDlx5/6cKO mutants. ECM-associated WFA-binding chondroitin sulfates were strongly augmented in seizure models. Strikingly, Brevican, Neurocan, Aggrecan and link protein Hapln1 levels reliably predicted seizure properties across models, suggesting a link between ECM state and epileptic phenotype.

neuroscience↗

bioRxiv2023

Sex differences in anxiety and threat avoidance in GAD65 knock-out mice

Anxiety disorders have been linked to a disbalance of excitation and inhibition in a network of brain structures comprising frontal cortical regions, the amygdala and the hippocampus, among others. Recent imaging studies suggest sex differences in the activation of this anxiety network during the processing of emotional information. Rodent models with genetically altered {Upsilon}-amino butyric acid (GABA) neurotransmission allow studying the neuronal basis of such activation shifts and their relation to anxiety endophenotypes, but to date sex effects have rarely been addressed. Using mice with a null mutation of the GABA synthetizing enzyme glutamate decarboxylase 65 (GAD65-/-), we started to compare anxiety-like behavior and avoidance in male vs. female GAD65-/- mice and their wildtype littermates. In an open field, female GAD65-/- mice displayed increased activity, while male GAD65-/- mice showed an increased adaptation of anxiety-like behavior over time. GAD65-/- mice of both sexes had a higher preference for social interaction partners, which was further heightened in male mice. In male mice higher escape responses were observed during an active avoidance task. Together, female mice showed more stable emotional responses despite GAD65 deficiency. To gain insights into interneuron function in network structures controlling anxiety and threat perception, fast oscillations (10-45 Hz) were measured in ex vivo slice preparations of the anterior cingulate cortex (ACC). GAD65-/- mice of both sexes displayed increased gamma power in the ACC and a higher density of PV-positive interneurons, which are crucial for generating such rhythmic activity. In addition, GAD65-/- mice had lower numbers of somatostatin-positive interneurons in the basolateral amygdala and in the dorsal dentate gyrus especially in male mice, two key regions important for anxiety and active avoidance responses. Our data suggest sex differences in the configuration of GABAergic interneurons in a cortico-amygdala-hippocampal network controlling network activity patterns, anxiety and threat avoidance behavior. HighlightsO_LIRole of GABA in sex-specific anxiety endophenotypes demonstrated in GAD65-/- mice C_LIO_LISex- and GAD65-dependent alterations in anxiety, social preference and avoidance C_LIO_LIEnhanced in vitro gamma-beta oscillations in ACC slices of GAD65-/- mice C_LIO_LIIncreased parvalbumin(+) interneuron counts in ACC slices of GAD65-/- mice C_LIO_LIReduced somatostatin(+) interneuron counts in dorsal DG and BLA of male GAD65-/- mice C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=88 SRC="FIGDIR/small/532980v2_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@85ac09org.highwire.dtl.DTLVardef@1e1a70aorg.highwire.dtl.DTLVardef@19dbbeforg.highwire.dtl.DTLVardef@9d52ff_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2022

Choosing memory retrieval strategies: a critical role for inhibition in the dentate gyrus

Remembering the location of food is essential for survival. Rodents and humans employ mainly hippocampus-dependent spatial strategies, but when being stressed they shift to striatum-mediated stimulus-based strategies. To investigate underlying brain circuits, we tested mice with a heightened stress susceptibility due to a lack of the GABA-synthetizing enzyme GAD65 (GAD65-/- mice) in a dual solution task. Here, GAD65-/- mice preferred to locate a food reward in an open field via a proximal cue, while their wildtype littermates preferred a spatial strategy. The analysis of cFos co-activation across brain regions and of stress-induced mRNA expression changes of GAD65 pointed towards the hippocampal dorsal dentate gyrus (dDG) as a central structure for mediating stress effects on strategy choices via GAD65. Reducing the GAD65 expression locally in the dDG by a shRNA mediated knock down was sufficient to replicate the phenotype of the global GAD65 knock out and to increase dDG excitability. Using DREADD vectors to specifically interfere with dDG circuit activity during dual solution retrieval but not learning confirmed that the dDG modulates strategy choices and that a balanced excitability of this structure is necessary to establish spatial strategy preference. These data highlight the dDG as a critical hub for choosing between spatial and non-spatial foraging strategies.

neuroscience↗

bioRxiv2022

Fear engrams and NPYergic circuit in the dorsal dentate gyrus determine remote fear memory generalization.

Generalization is a critical feature of aversive memories and significantly contributes to post-traumatic stress disorder (PTSD) pathogenesis. While fear memories over time tend to generalize across differences in the contextual background and even to novel contextual settings, this effect can be counteracted by exposure to controlled reminder sessions even at remote time points. Using Pavlovian fear conditioning in mice, we show that generalization to a novel context of remote memory is associated with a loss of cellular engram activation in the dorsal dentate gyrus (dDG) and can be effectively counteracted by a preceding contextual reminder session. In addition to engram cells activation in response to a novel context, the reminder session also leads to a recovery of neuropeptide Y (NPY) function in the dDG and dDG-CA3 neurotransmission. In line with a proposed role of NPY as a resilience factor, we found that chronic viral knockdown of NPY in the dDG and blockage of its activity-dependent expression in NPYergic dDG interneurons with dominant-negative CREBS133A both increase remote memory generalization. With chemogenetic silencing of these interneurons, we could localize their critical involvement to a time window during and immediately following the fear memory acquisition. Together, these findings suggest that NPYergic interneurons of the dDG, shaping the memory engram during fear learning and early consolidation, determine fear generalization.

neuroscience↗

bioRxiv2021

Antibiotic treatment induces activation of microglia and impairment of cholinergic gamma oscillations in the hippocampus

Antibiotics are widely applied for the treatment of bacterial infections, but their long-term use may lead to gut flora dysbiosis and detrimental effects on brain physiology, behavior as well as cognitive performance. Still, a striking lack of knowledge exists concerning electrophysiological correlates of antibiotic-induced changes in gut microbiota and behavior. Here, we investigated changes in the synaptic transmission and plasticity together with behaviorally-relevant network activities from the hippocampus of antibiotic-treated mice. The prolonged antibiotic treatment led to a strong reduction of myeloid cell pools in bone marrow, circulation and those surveilling the brain. Upon antibiotic treatment, circulating Ly6Chi inflammatory monocytes adopted a proinflammatory phenotype with increased expression of CD40 and MHC II. In the central nervous system, microglia displayed typical signs of activation with elevated CD40 and MHC II expression, as well as increased IL-6 and TNF production. Concomitantly, we detected a substantial reduction in the synaptic transmission in the hippocampal CA1 after antibiotic treatment. In line, carbachol-induced cholinergic gamma oscillation were reduced upon antibiotic treatment while the incidence of hippocampal sharp waves was elevated. These changes were associated with the global changes in the expression of neurotrophin nerve growth factor and inducible nitric oxide synthase, both of which have been shown to influence cholinergic functions. Overall, our study demonstrates that antibiotic-induced changes in the gut microbiome and immune cell function are associated with a drastic reduction in the synaptic transmission and gamma oscillations in the hippocampus, a brain region that is critically involved in mediation of innate and cognitive behavior.

neuroscience↗

bioRxiv2021

Hippocampal gamma-band oscillopathy in a mouse model of Fragile X Syndrome

Fragile X syndrome (FXS) is the most common inherited form of intellectual disability arising from the loss of fragile X mental retardation protein (FMRP), a protein that plays a central role in neuronal function and plasticity. FXS patients show sensory hypersensitivity, hyperarousal and hippocampus-dependent learning deficits that can be recapitulated in the FMR1 KO mice. Enhanced metabotropic glutamate receptor (mGluR) signaling and muscarinic acetylcholine receptor (mAChR) signaling in the FMR1 KO mouse are implicated as the primary causes of the disease pathogenesis. Furthermore, glutamatergic kainate receptor (KAR) function is reduced in the cortex of the FMR1 KO mice. Of note, activation of these signaling pathways leads to slow gamma-range oscillations in the hippocampus in vitro and abnormal gamma oscillations have been reported in FMR1 KO mice and patients with FXS. Thus, we hypothesized that aberrant activation of these receptors leads to the observed gamma oscillopathy. We recorded gamma oscillations induced by either cholinergic agonist carbachol (CCh), mGluR1/5 agonist Dihydroxyphenylglycine (DHPG) or ionotropic glutamatergic agonist KA from the hippocampal CA3 in WT and FMR1 KO mice in vitro. We show a specific increase in the power of DHPG and CCh-induced gamma oscillations and reduction in the synchronicity of gamma oscillations induced by KA. We further elucidate an aberrant spiking activity during CCh-induced and kainate-induced gamma oscillations which may underlie the altered gamma oscillation synchronization in the FMR1 KO mice. Last, we also noted a reduced incidence of spontaneously-occurring hippocampal sharp wave-ripple events. Our study provides further evidence for aberrant hippocampal rhythms in the FMR1 KO mice and identifies potential signaling pathways underlying gamma band oscillopathy in FXS.

neuroscience↗