@article{MTMT:33644822, title = {HCN channels at the cell soma ensure the rapid electrical reactivity of fast-spiking interneurons in human neocortex}, url = {https://m2.mtmt.hu/api/publication/33644822}, author = {Szegedi, Viktor and Bakos , Emőke and Furdan, Szabina and H. Kovács, Bálint Barna and Varga, Dániel and Erdélyi, Miklós and Barzó, Pál and Szűcs, Attila and Tamás, Gábor and Lamsa, Karri}, doi = {10.1371/journal.pbio.3002001}, journal-iso = {PLOS BIOL}, journal = {PLOS BIOLOGY}, volume = {21}, unique-id = {33644822}, issn = {1544-9173}, abstract = {Accumulating evidence indicates that there are substantial species differences in the properties of mammalian neurons, yet theories on circuit activity and information processing in the human brain are based heavily on results obtained from rodents and other experimental animals. This knowledge gap may be particularly important for understanding the neocortex, the brain area responsible for the most complex neuronal operations and showing the greatest evolutionary divergence. Here, we examined differences in the electrophysiological properties of human and mouse fast-spiking GABAergic basket cells, among the most abundant inhibitory interneurons in cortex. Analyses of membrane potential responses to current input, pharmacologically isolated somatic leak currents, isolated soma outside-out patch recordings, and immunohistochemical staining revealed that human neocortical basket cells abundantly express hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channel isoforms HCN1 and HCN2 at the cell soma membrane, whereas these channels are sparse at the rodent basket cell soma membrane. Antagonist experiments showed that HCN channels in human neurons contribute to the resting membrane potential and cell excitability at the cell soma, accelerate somatic membrane potential kinetics, and shorten the lag between excitatory postsynaptic potentials and action potential generation. These effects are important because the soma of human fast-spiking neurons without HCN channels exhibit low persistent ion leak and slow membrane potential kinetics, compared with mouse fast-spiking neurons. HCN channels speed up human cell membrane potential kinetics and help attain an input–output rate close to that of rodent cells. Computational modeling demonstrated that HCN channel activity at the human fast-spiking cell soma membrane is sufficient to accelerate the input–output function as observed in cell recordings. Thus, human and mouse fast-spiking neurons exhibit functionally significant differences in ion channel composition at the cell soma membrane to set the speed and fidelity of their input–output function. These HCN channels ensure fast electrical reactivity of fast-spiking cells in human neocortex.}, year = {2023}, eissn = {1545-7885}, orcid-numbers = {Szegedi, Viktor/0000-0003-4191-379X; Varga, Dániel/0000-0003-0391-5057; Erdélyi, Miklós/0000-0002-9501-5752; Barzó, Pál/0000-0001-8717-748X; Szűcs, Attila/0000-0001-9733-4135; Tamás, Gábor/0000-0002-7905-6001; Lamsa, Karri/0000-0002-4609-1337} } @article{MTMT:31127691, title = {Robust perisomatic GABAergic self-innervation inhibits basket cells in the human and mouse supragranular neocortex}, url = {https://m2.mtmt.hu/api/publication/31127691}, author = {Szegedi, Viktor and Paizs, Melinda and Baka, Judith and Barzó, Pál and Molnár, Gábor and Tamás, Gábor and Lamsa, Karri}, doi = {10.7554/eLife.51691}, journal-iso = {ELIFE}, journal = {ELIFE}, volume = {9}, unique-id = {31127691}, issn = {2050-084X}, abstract = {Inhibitory autapses are self-innervating synaptic connections in GABAergic interneurons in the brain. Autapses in neocortical layers have not been systematically investigated, and their function in different mammalian species and specific interneuron types is poorly known. We investigated GABAergic parvalbumin-expressing basket cells (pvBCs) in layer 2/3 (L2/3) in human neocortical tissue resected in deep-brain surgery, and in mice as control. Most pvBCs showed robust GABAAR-mediated self-innervation in both species, but autapses were rare in nonfast-spiking GABAergic interneurons. Light- and electron microscopy analyses revealed pvBC axons innervating their own soma and proximal dendrites. GABAergic self-inhibition conductance was similar in human and mouse pvBCs and comparable to that of synapses from pvBCs to other L2/3 neurons. Autaptic conductance prolonged somatic inhibition in pvBCs after a spike and inhibited repetitive firing. Perisomatic autaptic inhibition is common in both human and mouse pvBCs of supragranular neocortex, where they efficiently control discharge of the pvBCs.}, year = {2020}, eissn = {2050-084X}, orcid-numbers = {Szegedi, Viktor/0000-0003-4191-379X; Baka, Judith/0000-0002-8803-0217; Barzó, Pál/0000-0001-8717-748X; Tamás, Gábor/0000-0002-7905-6001; Lamsa, Karri/0000-0002-4609-1337} } @article{MTMT:3415159, title = {Long-term plasticity of hippocampal interneurons during in vivo memory processes.}, url = {https://m2.mtmt.hu/api/publication/3415159}, author = {Lamsa, Karri and Lau, P}, doi = {10.1016/j.conb.2018.08.006}, journal-iso = {CURR OPIN NEUROBIOL}, journal = {CURRENT OPINION IN NEUROBIOLOGY}, volume = {54}, unique-id = {3415159}, issn = {0959-4388}, abstract = {Formation of a cell assembly, a group of cortical neurons that function co-operatively to sustain an active memory trace, arises from changes in the connections between neurons. Establishment of memory traces is thought to rely on long-term plasticity in excitatory glutamatergic synapses interconnecting principal cells. In addition, recent studies in the hippocampus in vivo indicate that reconfiguration of GABAergic inhibitory interneuron activity also occurs during long-term memory encoding. Recent experiments in anesthetized, as well as in freely moving animals, demonstrate that learning-related hippocampal activities are associated with persistent changes in GABAergic interneuron firing rates and alterations in protein expression levels regulating GABA release.}, year = {2019}, eissn = {1873-6882}, pages = {20-27}, orcid-numbers = {Lamsa, Karri/0000-0002-4609-1337} } @article{MTMT:3415168, title = {Neuregulin 1 Type I Overexpression Is Associated with Reduced NMDA Receptor-Mediated Synaptic Signaling in Hippocampal Interneurons Expressing PV or CCK.}, url = {https://m2.mtmt.hu/api/publication/3415168}, author = {Kotzadimitriou, D and Nissen, W and Paizs, Melinda and Newton, K and Harrison, PJ and Paulsen, O and Lamsa, Karri}, doi = {10.1523/ENEURO.0418-17.2018}, journal-iso = {ENEURO}, journal = {ENEURO}, volume = {5}, unique-id = {3415168}, abstract = {Hypofunction of N-methyl-d-aspartate receptors (NMDARs) in inhibitory GABAergic interneurons is implicated in the pathophysiology of schizophrenia (SZ), a heritable disorder with many susceptibility genes. However, it is still unclear how SZ risk genes interfere with NMDAR-mediated synaptic transmission in diverse inhibitory interneuron populations. One putative risk gene is neuregulin 1 (NRG1), which signals via the receptor tyrosine kinase ErbB4, itself a schizophrenia risk gene. The type I isoform of NRG1 shows increased expression in the brain of SZ patients, and ErbB4 is enriched in GABAergic interneurons expressing parvalbumin (PV) or cholecystokinin (CCK). Here, we investigated ErbB4 expression and synaptic transmission in interneuronal populations of the hippocampus of transgenic mice overexpressing NRG1 type I (NRG1(tg-type-I) mice). Immunohistochemical analyses confirmed that ErbB4 was coexpressed with either PV or CCK in hippocampal interneurons, but we observed a reduced number of ErbB4-immunopositive interneurons in the NRG1(tg-type-I) mice. NMDAR-mediated currents in interneurons expressing PV (including PV(+) basket cells) or CCK were reduced in NRG1(tg-type-I) mice compared to their littermate controls. We found no difference in AMPA receptor-mediated currents. Optogenetic activation (5 pulses at 20 Hz) of local glutamatergic fibers revealed a decreased NMDAR-mediated contribution to disynaptic GABAergic inhibition of pyramidal cells in the NRG1(tg-type-I) mice. GABAergic synaptic transmission from either PV(+) or CCK(+) interneurons, and glutamatergic transmission onto pyramidal cells, did not significantly differ between genotypes. The results indicate that synaptic NMDAR-mediated signaling in hippocampal interneurons is sensitive to chronically elevated NGR1 type I levels. This may contribute to the pathophysiological consequences of increased NRG1 expression in SZ.}, year = {2018}, eissn = {2373-2822}, orcid-numbers = {Lamsa, Karri/0000-0002-4609-1337} } @article{MTMT:3293390, title = {Deficiency of Cks1 Leads to Learning and Long-Term Memory Defects and p27 Dependent Formation of Neuronal Cofilin Aggregates}, url = {https://m2.mtmt.hu/api/publication/3293390}, author = {Kukalev, A and Ng, YM and Ju, LM and Saidi, A and Lane, S and Mondragon, A and Dormann, D and Walker, SE and Grey, W and Ho, PWL and Stephens, DN and Carr, AM and Lamsa, Karri and Tse, E and Yu, VPCC}, doi = {10.1093/cercor/bhw354}, journal-iso = {CEREB CORTEX}, journal = {CEREBRAL CORTEX}, volume = {27}, unique-id = {3293390}, issn = {1047-3211}, abstract = {In mitotic cells, the cyclin-dependent kinase (CDK) subunit protein CKS1 regulates S phase entry by mediating degradation of the CDK inhibitor p27. Although mature neurons lack mitotic CDKs, we found that CKS1 was actively expressed in post-mitotic neurons of the adult hippocampus. Interestingly, Cks1 knockout (Cks1(-/-)) mice exhibited poor long-term memory, and diminished maintenance of long-term potentiation in the hippocampal circuits. Furthermore, there was neuronal accumulation of cofilin-actin rods or cofilin aggregates, which are associated with defective dendritic spine maturation and synaptic loss. We further demonstrated that it was the increased p27 level that activated cofilin by suppressing the RhoA kinase-mediated inhibitory phosphorylation of cofilin, resulting in the formation of cofilin aggregates in the Cks1(-/-) neuronal cells. Consistent with reports that the peptidyl-prolyl-isomerase PIN1 competes with CKS1 for p27 binding, we found that inhibition of PIN1 diminished the formation of cofilin aggregates through decreasing p27 levels, thereby activating RhoA and increasing cofilin phosphorylation. Our results revealed that CKS1 is involved in normal glutamatergic synapse development and dendritic spine maturation in adult hippocampus through modulating p27 stability.}, keywords = {IN-VIVO; hippocampus; MICROTUBULE-ASSOCIATED PROTEIN; MIGRATION; ACTIN DYNAMICS; DENDRITIC SPINES; SYNAPTIC PLASTICITY; LONG-TERM POTENTIATION; RHO; Cyclin-dependent kinase; myosin IIB; P27(KIP1); RhoA; CDK5}, year = {2017}, eissn = {1460-2199}, pages = {11-23}, orcid-numbers = {Lamsa, Karri/0000-0002-4609-1337} } @article{MTMT:3284277, title = {High-Precision Fast-Spiking Basket Cell Discharges during Complex Events in the Human Neocortex}, url = {https://m2.mtmt.hu/api/publication/3284277}, author = {Szegedi, Viktor and Molnár, Gábor and Paizs, Melinda and Csákvári, Eszter and Barzó, Pál and Tamás, Gábor and Lamsa, Karri}, doi = {10.1523/ENEURO.0260-17.2017}, journal-iso = {ENEURO}, journal = {ENEURO}, volume = {4}, unique-id = {3284277}, abstract = {In the human neocortex, solitary action potentials in some layer 2-3 pyramidal cells (PCs) trigger brief episodes of network activity known as complex events through strong excitatory synapses that specifically innervate GABAergic interneurons. Yet, how these "master PCs" configure the local network activity is not well understood. We report that single spikes in the PCs, studied here in synaptically connected cell pairs in frontal or temporal neocortical areas of both males and females, elicit firing of fast-spiking basket cells (FSBCs) with a short delay (on average 2.7 ms). The FSBC discharge is triggered by 13 mV (on average) monosynaptic EPSPs, and the action potential is time locked to the master PC spike with high temporal precision, showing little jitter in delay. In the complex events, the FSBC discharge occurs in the beginning of the activity episode, forming the first wave of the complex event activity. Firing of FSBCs generates GABAergic IPSCs with fast kinetics in layer 2-3 PCs, and similar IPSCs regularly occur time locked to master PC spikes in the beginning of the complex events with high probability and short (median 4.1 ms) delay with little jitter. In comparison, discharge of nonfast spiking interneurons (non-FSINs) investigated here appears inconsistently in the complex events and shows low probability. Thus, firing of layer 2-3 FSBCs with high temporal fidelity characterizes early phase of the complex events in the human neocortex.}, year = {2017}, eissn = {2373-2822}, orcid-numbers = {Szegedi, Viktor/0000-0003-4191-379X; Barzó, Pál/0000-0001-8717-748X; Tamás, Gábor/0000-0002-7905-6001; Lamsa, Karri/0000-0002-4609-1337} } @article{MTMT:3189214, title = {Long-term plasticity in identified hippocampal GABAergic interneurons in the CA1 area in vivo}, url = {https://m2.mtmt.hu/api/publication/3189214}, author = {Lau, PY and Katona, L and Saghy, P and Newton, K and Somogyi, P and Lamsa, Karri}, doi = {10.1007/s00429-016-1309-7}, journal-iso = {BRAIN STRUCT FUNC}, journal = {BRAIN STRUCTURE & FUNCTION}, volume = {222}, unique-id = {3189214}, issn = {1863-2653}, abstract = {Long-term plasticity is well documented in synapses between glutamatergic principal cells in the cortex both in vitro and in vivo. Long-term potentiation (LTP) and -depression (LTD) have also been reported in glutamatergic connections to hippocampal GABAergic interneurons expressing parvalbumin (PV+) or nitric oxide synthase (NOS+) in brain slices, but plasticity in these cells has not been tested in vivo. We investigated synaptically-evoked suprathreshold excitation of identified hippocampal neurons in the CA1 area of urethane-anaesthetized rats. Neurons were recorded extracellularly with glass microelectrodes, and labelled with neurobiotin for anatomical analyses. Single-shock electrical stimulation of afferents from the contralateral CA1 elicited postsynaptic action potentials with monosynaptic features showing short delay (9.95 +/- 0.41 ms) and small jitter in 13 neurons through the commissural pathway. Theta-burst stimulation (TBS) generated LTP of the synaptically-evoked spike probability in pyramidal cells, and in a bistratified cell and two unidentified fast-spiking interneurons. On the contrary, PV+ basket cells and NOS+ ivy cells exhibited either LTD or LTP. An identified axo-axonic cell failed to show long-term change in its response to stimulation. Discharge of the cells did not explain whether LTP or LTD was generated. For the fast-spiking interneurons, as a group, no correlation was found between plasticity and local field potential oscillations (1-3 or 3-6 Hz components) recorded immediately prior to TBS. The results demonstrate activity-induced long-term plasticity in synaptic excitation of hippocampal PV+ and NOS+ interneurons in vivo. Physiological and pathological activity patterns in vivo may generate similar plasticity in these interneurons.}, year = {2017}, eissn = {1863-2661}, pages = {1809-1827}, orcid-numbers = {Lamsa, Karri/0000-0002-4609-1337} } @article{MTMT:3189215, title = {Adenosine A1 Receptor Suppresses Tonic GABAA Receptor Currents in Hippocampal Pyramidal Cells and in a Defined Subpopulation of Interneurons}, url = {https://m2.mtmt.hu/api/publication/3189215}, author = {Rombo, DM and Dias, RB and Duarte, ST and Ribeiro, JA and Lamsa, Karri and Sebastiao, AM}, doi = {10.1093/cercor/bhu288}, journal-iso = {CEREB CORTEX}, journal = {CEREBRAL CORTEX}, volume = {26}, unique-id = {3189215}, issn = {1047-3211}, abstract = {Adenosine is an endogenous neuromodulator that decreases excitability of hippocampal circuits activating membrane-bound metabotropic A1 receptor (A1R). The presynaptic inhibitory action of adenosine A1R in glutamatergic synapses is well documented, but its influence on inhibitory GABAergic transmission is poorly known. We report that GABAA receptor (GABAAR)-mediated tonic, but not phasic, transmission is suppressed by A1R in hippocampal neurons. Adenosine A1R activation strongly inhibits GABAAR agonist (muscimol)-evoked currents in Cornu Ammonis 1 (CA1) pyramidal neurons and in a specific subpopulation of interneurons expressing axonal cannabinoid receptor type 1. In addition, A1R suppresses tonic GABAAR currents measured in the presence of elevated ambient GABA as well as in naive slices. The inhibition of GABAergic currents involves both protein kinase A (PKA) and protein kinase C (PKC) signaling pathways and decreases GABAAR delta-subunit expression. On the contrary, no A1R-mediated modulation was detected in phasic inhibitory postsynaptic currents evoked either by afferent electrical stimulation or by spontaneous quantal release. The results show that A1R modulates extrasynaptic rather than synaptic GABAAR-mediated signaling, and that this modulation selectively occurs in hippocampal pyramidal neurons and in a specific subpopulation of inhibitory interneurons. We conclude that modulation of tonic GABAAR signaling by adenosine A1R in specific neuron types may regulate neuronal gain and excitability in the hippocampus.}, keywords = {Animals; Male; immunohistochemistry; immunoblotting; Rats, Wistar; Receptors, GABA-A/*metabolism; Neural Inhibition/drug effects/physiology; Patch-Clamp Techniques; Tissue Culture Techniques; CA1 Region, Hippocampal/cytology/drug effects/*physiology; Cyclic AMP-Dependent Protein Kinases/metabolism; Protein Kinase C/metabolism; Receptor, Adenosine A1/*metabolism; Inhibitory Postsynaptic Potentials/drug effects/physiology; Pyramidal Cells/cytology/drug effects/*physiology; Miniature Postsynaptic Potentials/drug effects/physiology; Interneurons/cytology/drug effects/*physiology}, year = {2016}, eissn = {1460-2199}, pages = {1081-1095}, orcid-numbers = {Lamsa, Karri/0000-0002-4609-1337} } @article{MTMT:3137400, title = {Plasticity in Single Axon Glutamatergic Connection to GABAergic Interneurons Regulates Complex Events in the Human Neocortex}, url = {https://m2.mtmt.hu/api/publication/3137400}, author = {Szegedi, Viktor and Paizs, Melinda and Csákvári, Eszter and Molnár, Gábor and Barzó, Pál and Tamás, Gábor and Lamsa, Karri}, doi = {10.1371/journal.pbio.2000237}, journal-iso = {PLOS BIOL}, journal = {PLOS BIOLOGY}, volume = {14}, unique-id = {3137400}, issn = {1544-9173}, abstract = {In the human neocortex, single excitatory pyramidal cells can elicit very large glutamatergic EPSPs (VLEs) in inhibitory GABAergic interneurons capable of triggering their firing with short (3-5 ms) delay. Similar strong excitatory connections between two individual neurons have not been found in nonhuman cortices, suggesting that these synapses are specific to human interneurons. The VLEs are crucial for generating neocortical complex events, observed as single pyramidal cell spike-evoked discharge of cell assemblies in the frontal and temporal cortices. However, long-term plasticity of the VLE connections and how the plasticity modulates neocortical complex events has not been studied. Using triple and dual whole-cell recordings from synaptically connected human neocortical layers 2-3 neurons, we show that VLEs in fast-spiking GABAergic interneurons exhibit robust activity-induced long-term depression (LTD). The LTD by single pyramidal cell 40 Hz spike bursts is specific to connections with VLEs, requires group I metabotropic glutamate receptors, and has a presynaptic mechanism. The LTD of VLE connections alters suprathreshold activation of interneurons in the complex events suppressing the discharge of fast-spiking GABAergic cells. The VLEs triggering the complex events may contribute to cognitive processes in the human neocortex, and their long-term plasticity can alter the discharging cortical cell assemblies by learning.}, year = {2016}, eissn = {1545-7885}, orcid-numbers = {Szegedi, Viktor/0000-0003-4191-379X; Barzó, Pál/0000-0001-8717-748X; Tamás, Gábor/0000-0002-7905-6001; Lamsa, Karri/0000-0002-4609-1337} } @article{MTMT:2966592, title = {Synaptic mechanisms of adenosine A2A receptor-mediated hyperexcitability in the hippocampus.}, url = {https://m2.mtmt.hu/api/publication/2966592}, author = {Rombo, DM and Newton, K and Nissen, W and Badurek, S and Horn, JM and Minichiello, L and Jefferys, JG and Sebastiao, AM and Lamsa, Karri}, doi = {10.1002/hipo.22392}, journal-iso = {HIPPOCAMPUS}, journal = {HIPPOCAMPUS}, volume = {25}, unique-id = {2966592}, issn = {1050-9631}, abstract = {Adenosine inhibits excitatory neurons widely in the brain through adenosine A1 receptor, but activation of adenosine A2A receptor (A2A R) has an opposite effect promoting discharge in neuronal networks. In the hippocampus A2A R expression level is low, and the receptor's effect on identified neuronal circuits is unknown. Using optogenetic afferent stimulation and whole-cell recording from identified postsynaptic neurons we show that A2A R facilitates excitatory glutamatergic Schaffer collateral synapses to CA1 pyramidal cells, but not to GABAergic inhibitory interneurons. In addition, A2A R enhances GABAergic inhibitory transmission between CA1 area interneurons leading to disinhibition of pyramidal cells. Adenosine A2A R has no direct modulatory effect on GABAergic synapses to pyramidal cells. As a result adenosine A2A R activation alters the synaptic excitation - inhibition balance in the CA1 area resulting in increased pyramidal cell discharge to glutamatergic Schaffer collateral stimulation. In line with this, we show that A2A R promotes synchronous pyramidal cell firing in hyperexcitable conditions where extracellular potassium is elevated or following high-frequency electrical stimulation. Our results revealed selective synapse- and cell type specific adenosine A2A R effects in hippocampal CA1 area. The uncovered mechanisms help our understanding of A2A R's facilitatory effect on cortical network activity.}, year = {2015}, eissn = {1098-1063}, pages = {566-580}, orcid-numbers = {Lamsa, Karri/0000-0002-4609-1337} }