umu.sePublications
Change search
Link to record
Permanent link

Direct link
BETA
Medini, Paolo
Publications (10 of 16) Show all publications
Tran, P., Wanrooij, P. H., Lorenzon, P., Sharma, S., Thelander, L., Nilsson, A. K., . . . Chabes, A. (2019). De novo dNTP production is essential for normal postnatal murine heart development. Journal of Biological Chemistry, Article ID jbc.RA119.009492.
Open this publication in new window or tab >>De novo dNTP production is essential for normal postnatal murine heart development
Show others...
2019 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, article id jbc.RA119.009492Article in journal (Refereed) Epub ahead of print
Abstract [en]

The building blocks of DNA, dNTPs, can be produced de novo or can be salvaged from deoxyribonucleosides. However, to what extent the absence of de novo dNTP production can be compensated for by the salvage pathway is unknown. Here, we eliminated de novo dNTP synthesis in the mouse heart and skeletal muscle by inactivating ribonucleotide reductase (RNR), a key enzyme for the de novo production of dNTPs, at embryonic day 13. All other tissues had normal de novo dNTP synthesis and theoretically could supply heart and skeletal muscle with deoxyribonucleosides needed for dNTP production by salvage. We observed that the dNTP and NTP pools in wild-type postnatal hearts are unexpectedly asymmetric, with unusually high dGTP and GTP levels compared with those in whole mouse embryos or murine cell cultures. We found that RNR inactivation in heart led to strongly decreased dGTP and increased dCTP, dTTP, and dATP pools; aberrant DNA replication; defective expression of muscle-specific proteins; progressive heart abnormalities; disturbance of the cardiac conduction system; and lethality between the second and fourth weeks after birth. We conclude that dNTP salvage cannot substitute for de novo dNTP synthesis in the heart and that cardiomyocytes and myocytes initiate DNA replication despite an inadequate dNTP supply. We discuss the possible reasons for the observed asymmetry in dNTP and NTP pools in wildtype hearts.

Keywords
cardiac function, cardiac muscle, dNTP metabolism, dNTP salvage, deoxyribonucleoside kinases, desmin, heart development, nucleoside/nucleotide biosynthesis, nucleoside/nucleotide metabolism, ribonucleotide reductase
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-161767 (URN)10.1074/jbc.RA119.009492 (DOI)31300555 (PubMedID)
Funder
Swedish Research CouncilSwedish Cancer Society
Available from: 2019-07-30 Created: 2019-07-30 Last updated: 2019-08-06
Kokinovic, B. & Medini, P. (2018). Loss of GABAB-mediated interhemispheric synaptic inhibition in stroke periphery. Journal of Physiology, 596(10), 1949-1964
Open this publication in new window or tab >>Loss of GABAB-mediated interhemispheric synaptic inhibition in stroke periphery
2018 (English)In: Journal of Physiology, ISSN 0022-3751, E-ISSN 1469-7793, Vol. 596, no 10, p. 1949-1964Article in journal (Refereed) Published
Abstract [en]

Recovery after stroke is mediated by plastic changes largely occurring in the lesion periphery. However, little is known about the microcircuit changes underlying recovery, the extent to which perilesional plasticity occurs at synaptic input vs. spike output level, and the connectivity behind such synaptic plasticity. We combined intrinsic imaging with extracellular and intracellular recordings and pharmacological inactivation in a focal stroke in mouse somatosensory cortex (S1). In vivo whole-cell recordings in hindlimb S1 (hS1) showed synaptic responses also to forelimb stimulation in controls, and such responses were abolished by stroke in the neighbouring forelimb area (fS1), suggesting that, under normal conditions, they originate via horizontal connections from the neighbouring fS1. Synaptic and spike responses to forelimb stimulation in hS1 recovered to quasi-normal levels 2weeks after stroke, without changes in intrinsic excitability and hindlimb-evoked spike responses. Recovered synaptic responses had longer latencies, suggesting a long-range origin of the recovery, prompting us to investigate the role of callosal inputs in the recovery process. Contralesional S1 silencing unmasked significantly larger responses to both limbs in controls, a phenomenon that was not observed when GABAB receptors were antagonized in the recorded area. Conversely, such GABAB-mediated interhemispheric inhibition was not detectable after stroke: callosal input silencing failed to change hindlimb responses, whereas it robustly reduced recovered forelimb responses. Thus, recovery of subthreshold responsiveness in the stroke periphery is accompanied by a loss of interhemispheric inhibition and this is a result of pathway-specific facilitatory action on the affected sensory response from the contralateral cortex.

National Category
Physiology Neurosciences
Identifiers
urn:nbn:se:umu:diva-149023 (URN)10.1113/JP275690 (DOI)000433597200019 ()29508394 (PubMedID)2-s2.0-85045387876 (Scopus ID)
Available from: 2018-06-15 Created: 2018-06-15 Last updated: 2018-06-15Bibliographically approved
Mazzaro, N., Barini, E., Spillantini, M. G., Goedert, M., Medini, P. & Gasparini, L. (2016). Tau-Driven Neuronal and Neurotrophic Dysfunction in a Mouse Model of Early Tauopathy. Journal of Neuroscience, 36(7), 2086-2100
Open this publication in new window or tab >>Tau-Driven Neuronal and Neurotrophic Dysfunction in a Mouse Model of Early Tauopathy
Show others...
2016 (English)In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 36, no 7, p. 2086-2100Article in journal (Refereed) Published
Abstract [en]

Tauopathies are neurodegenerative diseases characterized by intraneuronal inclusions of hyperphosphorylated tau protein and abnormal expression of brain-derived neurotrophic factor (BDNF), a key modulator of neuronal survival and function. The severity of both these pathological hallmarks correlate with the degree of cognitive impairment in patients. However, how tau pathology specifically modifies BDNF signaling and affects neuronal function during early prodromal stages of tauopathy remains unclear. Here, we report that the mild tauopathy developing in retinal ganglion cells (RGCs) of the P301S tau transgenic (P301S) mouse induces functional retinal changes by disrupting BDNF signaling via the TrkB receptor. In adult P301S mice, the physiological visual response of RGCs to pattern light stimuli and retinal acuity decline significantly. As a consequence, the activity-dependent secretion of BDNF in the vitreous is impaired in P301S mice. Further, in P301S retinas, TrkB receptors are selectively upregulated, but uncoupled from downstream extracellular signal-regulated kinase (ERK) 1/2 signaling. We also show that the impairment of TrkB signaling is triggered by tau pathology and mediates the tau-induced dysfunction of visual response. Overall our results identify a neurotrophin-mediated mechanism by which tau induces neuronal dysfunction during prodromal stages of tauopathy and define tau-driven pathophysiological changes of potential value to support early diagnosis and informed therapeutic decisions.

Keywords
BDNF, electroretinography, neuronal dysfunction, retinal ganglion cells, tau protein, TrkB receptor
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-129999 (URN)10.1523/JNEUROSCI.0774-15.2016 (DOI)000370818700003 ()26888921 (PubMedID)
Available from: 2017-01-13 Created: 2017-01-11 Last updated: 2018-06-09Bibliographically approved
Medini, P. (2014). Experience-dependent plasticity of visual cortical microcircuits. Neuroscience, 278, 367-384
Open this publication in new window or tab >>Experience-dependent plasticity of visual cortical microcircuits
2014 (English)In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 278, p. 367-384Article, review/survey (Refereed) Published
Abstract [en]

The recent decade testified a tremendous increase in our knowledge on how cell-type-specific microcircuits process sensory information in the neocortex and on how such circuitry reacts to manipulations of the sensory environment. Experience-dependent plasticity has now been investigated with techniques endowed with cell resolution during both postnatal development and in adult animals. This review recapitulates the main recent findings in the field using mainly the primary visual cortex as a model system to highlight the more important questions and physiological principles (such as the role of non-competitive mechanisms, the role of inhibition in excitatory cell plasticity, the functional importance of spine and axonal plasticity on a microscale level). I will also discuss on which scientific problems the debate and controversies are more pronounced. New technologies that allow to perturbate cell-type-specific subcircuits will certainly shine new light in the years to come at least on some of the still open questions. (C) 2014 The Author. Published by Elsevier Ltd. on behalf of IBRO.

Place, publisher, year, edition, pages
Elsevier, 2014
Keywords
experience-dependent plasticity, microcircuits, layer specificity, cell-type specificity, visual system, barrel cortex
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-94938 (URN)10.1016/j.neuroscience.2014.08.022 (DOI)000342058700033 ()
Available from: 2014-11-12 Created: 2014-10-20 Last updated: 2018-06-07Bibliographically approved
Olcese, U., Iurilli, G. & Medini, P. (2013). Cellular and synaptic architecture of multisensory integration in the mouse neocortex. Neuron, 79(3), 579-593
Open this publication in new window or tab >>Cellular and synaptic architecture of multisensory integration in the mouse neocortex
2013 (English)In: Neuron, ISSN 0896-6273, E-ISSN 1097-4199, Vol. 79, no 3, p. 579-593Article in journal (Refereed) Published
Abstract [en]

Multisensory integration (MI) is crucial for sensory processing, but it is unclear how MI is organized in cortical microcircuits. Whole-cell recordings in a mouse visuotactile area located between primary visual and somatosensory cortices revealed that spike responses were less bimodal than synaptic responses but displayed larger multisensory enhancement. MI was layer and cell type specific, with multisensory enhancement being rare in the major class of inhibitory interneurons and in the output infragranular layers. Optogenetic manipulation of parvalbumin-positive interneuron activity revealed that the scarce MI of interneurons enables MI in neighboring pyramids. Finally, single-cell resolution calcium imaging revealed a gradual merging of modalities: unisensory neurons had higher densities toward the borders of the primary cortices, but were located in unimodal clusters in the middle of the cortical area. These findings reveal the role of different neuronal subcircuits in the synaptic process of MI in the rodent parietal cortex.

National Category
Basic Medicine
Identifiers
urn:nbn:se:umu:diva-79153 (URN)10.1016/j.neuron.2013.06.010 (DOI)23850594 (PubMedID)
Available from: 2013-08-17 Created: 2013-08-09 Last updated: 2018-06-08Bibliographically approved
Iurilli, G., Olcese, U. & Medini, P. (2013). Preserved Excitatory-Inhibitory Balance of Cortical Synaptic Inputs following Deprived Eye Stimulation after a Saturating Period of Monocular Deprivation in Rats. PloS one, 8(12), e82044
Open this publication in new window or tab >>Preserved Excitatory-Inhibitory Balance of Cortical Synaptic Inputs following Deprived Eye Stimulation after a Saturating Period of Monocular Deprivation in Rats
2013 (English)In: PloS one, ISSN 1932-6203, Vol. 8, no 12, p. e82044-Article in journal (Refereed) Published
Abstract [en]

Monocular deprivation (MD) during development leads to a dramatic loss of responsiveness through the deprived eye in primary visual cortical neurons, and to degraded spatial vision (amblyopia) in all species tested so far, including rodents. Such loss of responsiveness is accompanied since the beginning by a decreased excitatory drive from the thalamo-cortical inputs. However, in the thalamorecipient layer 4, inhibitory interneurons are initially unaffected by MD and their synapses onto pyramidal cells potentiate. It remains controversial whether ocular dominance plasticity similarly or differentially affects the excitatory and inhibitory synaptic conductances driven by visual stimulation of the deprived eye and impinging onto visual cortical pyramids, after a saturating period of MD. To address this issue, we isolated visually-driven excitatory and inhibitory conductances by in vivo whole-cell recordings from layer 4 regular-spiking neurons in the primary visual cortex (V1) of juvenile rats. We found that a saturating period of MD comparably reduced visually-driven excitatory and inhibitory conductances driven by visual stimulation of the deprived eye. Also, the excitatory and inhibitory conductances underlying the synaptic responses driven by the ipsilateral, left open eye were similarly potentiated compared to controls. Multiunit recordings in layer 4 followed by spike sorting indicated that the suprathreshold loss of responsiveness and the MD-driven ocular preference shifts were similar for narrow spiking, putative inhibitory neurons and broad spiking, putative excitatory neurons. Thus, by the time the plastic response has reached a plateau, inhibitory circuits adjust to preserve the normal balance between excitation and inhibition in the cortical network of the main thalamorecipient layer.

Place, publisher, year, edition, pages
PLOS ONE, 2013
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:umu:diva-85067 (URN)10.1371/journal.pone.0082044 (DOI)24349181 (PubMedID)
Available from: 2014-01-27 Created: 2014-01-27 Last updated: 2018-06-08Bibliographically approved
Iurilli, G., Benfenati, F. & Medini, P. (2012). Loss of Visually Driven Synaptic Responses in Layer 4 Regular-Spiking Neurons of Rat Visual Cortex in Absence of Competing Inputs. Cerebral Cortex, 22(9), 2171-2181
Open this publication in new window or tab >>Loss of Visually Driven Synaptic Responses in Layer 4 Regular-Spiking Neurons of Rat Visual Cortex in Absence of Competing Inputs
2012 (English)In: Cerebral Cortex, ISSN 1047-3211, E-ISSN 1460-2199, Vol. 22, no 9, p. 2171-2181Article in journal (Refereed) Published
Abstract [en]

Monocular deprivation (MD) during development shifts the ocular preference of primary visual cortex (V1) neurons by depressing closed-eye responses and potentiating open-eye responses. As these 2 processes are temporally and mechanistically distinct, we tested whether loss of responsiveness occurs also in absence of competing inputs. We thus compared the effects of long-term MD in layer 4 regular-spiking pyramidal neurons (L4Ns) of binocular and monocular V1 (bV1 and mV1) with whole-cell recordings. In bV1, input depression was larger than potentiation, and the ocular dominance shift was larger for spike outputs. MD-but not retinal inactivation with tetrodotoxin-caused a comparable loss of synaptic and spike responsiveness in mV1, which is innervated only by the deprived eye. Conversely, brief MD depressed synaptic responses only in bV1. MD-driven depression in mV1 was accompanied by a proportional reduction of visual thalamic inputs, as assessed upon pharmacological silencing of intracortical transmission. Finally, sub- and suprathreshold responsiveness was similarly degraded in L4Ns of bV1 upon complete deprivation of patterned vision through a binocular deprivation period of comparable length. Thus, loss of synaptic inputs from the deprived eye occurs also in absence of competition in the main thalamorecipient lamina, albeit at a slower pace.

Keywords
in vivo whole cell, layer specificity; ocular dominance plasticityin vivo whole cell, layer specificity, ocular dominance plasticity, primary visual cortex primary visual cortex
National Category
Basic Medicine
Identifiers
urn:nbn:se:umu:diva-79150 (URN)10.1093/cercor/bhr304 (DOI)000307505900019 ()22047965 (PubMedID)
Available from: 2013-08-17 Created: 2013-08-09 Last updated: 2018-06-08Bibliographically approved
Iurilli, G., Ghezzi, D., Olcese, U., Lassi, G., Nazzaro, C., Tonini, R., . . . Medini, P. (2012). Sound-Driven Synaptic Inhibition in Primary Visual Cortex. Neuron, 73(4), 814-28
Open this publication in new window or tab >>Sound-Driven Synaptic Inhibition in Primary Visual Cortex
Show others...
2012 (English)In: Neuron, ISSN 0896-6273, E-ISSN 1097-4199, Vol. 73, no 4, p. 814-28Article in journal (Refereed) Published
Abstract [en]

Multimodal objects and events activate many sensory cortical areas simultaneously. This is possibly reflected in reciprocal modulations of neuronal activity, even at the level of primary cortical areas. However, the synaptic character of these interareal interactions, and their impact on synaptic and behavioral sensory responses are unclear. Here, we found that activation of auditory cortex by a noise burst drove local GABAergic inhibition on supragranular pyramids of the mouse primary visual cortex, via cortico-cortical connections. This inhibition was generated by sound-driven excitation of a limited number of cells in infragranular visual cortical neurons. Consequently, visually driven synaptic and spike responses were reduced upon bimodal stimulation. Also, acoustic stimulation suppressed conditioned behavioral responses to a dim flash, an effect that was prevented by acute blockade of GABAergic transmission in visual cortex. Thus, auditory cortex activation by salient stimuli degrades potentially distracting sensory processing in visual cortex by recruiting local, translaminar, inhibitory circuits.

National Category
Basic Medicine
Identifiers
urn:nbn:se:umu:diva-79152 (URN)10.1016/j.neuron.2011.12.026 (DOI)000300815400018 ()22365553 (PubMedID)
Available from: 2013-08-17 Created: 2013-08-09 Last updated: 2018-06-08Bibliographically approved
Medini, P. (2011). Cell-type-specific sub- and suprathreshold receptive fields of layer 4 and layer 2/3 pyramids in rat primary visual cortex.. Neuroscience, 190, 112-26
Open this publication in new window or tab >>Cell-type-specific sub- and suprathreshold receptive fields of layer 4 and layer 2/3 pyramids in rat primary visual cortex.
2011 (English)In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 190, p. 112-26Article in journal (Refereed) Published
Abstract [en]

Connectivity of cortical pyramidal neurons is layer-specific in the primary visual cortex (V1) and this is thought to be reflected in different receptive field (RF) properties of layer 4 and layer 2/3 pyramidal neurons (L4Ps and L2/3Ps, respectively). However, it remains unclear how the two cell populations convert incoming visually driven synaptic inputs into action potential (AP) outputs. Here I compared postsynaptic potentials (PSPs) and AP responses of L4Ps and L2/3Ps in the binocular portion of rat V1 by intrinsic optical imaging (IOI)-targeted whole-cell recordings followed by anatomical identification and dendritic reconstructions. L2/3Ps had about 2-fold longer dendritic branches and a higher number of branch points and endings in their apical portions. Functionally, L2/3Ps had more hyperpolarized resting potentials and lower rates of spontaneous APs (medians: 0.07 vs. 0.60 AP/s). PSP responses to optimally oriented moving bars were comparable in terms of amplitude (16.0±0.9 vs. 17.3±1.1 mV for L2/3Ps and L4Ps, respectively), reliability and size of the RF. The modulated component of subthreshold responses of L4Ps to optimal sinusoidal drifting gratings was larger and their PSP onset latency in response to bars flashed in the cell's RF center were shorter (60 vs. 86 ms). In contrast to the similarities of PSP responses to moving bars, AP responses of L2/3Ps were more sparse (medians: 0.7 vs. 2.9 APs/stimulus passage), less reliable, but sharper in terms of angular size. Based on the differences of subthreshold inputs, I conclude that L4Ps may receive mostly thalamic inputs, whereas L2/3Ps may receive both thalamic and cortical inputs from layer 4. The comparable subthreshold responses to moving bars are converted by L2/3Ps into sparser but sharper AP outputs possibly by cell-type-specific AP-generating mechanisms or differences in visually driven inhibitory inputs.

Keywords
in vivo whole cell, layer specificity, cell-type specificity, primary visual cortex
National Category
Basic Medicine
Identifiers
urn:nbn:se:umu:diva-79149 (URN)10.1016/j.neuroscience.2011.05.026 (DOI)21704132 (PubMedID)
Available from: 2013-08-17 Created: 2013-08-09 Last updated: 2018-06-08Bibliographically approved
Blau, A., Murr, A., Wolff, S., Sernagor, E., Medini, P., Iurilli, G., . . . Benfenati, F. (2011). Flexible, all-polymer microelectrode arrays for the capture of cardiac and neuronal signals. Biomaterials, 32(7), 1778-1786
Open this publication in new window or tab >>Flexible, all-polymer microelectrode arrays for the capture of cardiac and neuronal signals
Show others...
2011 (English)In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 32, no 7, p. 1778-1786Article in journal (Refereed) Published
Abstract [en]

Microelectrode electrophysiology has become a widespread technique for the extracellular recording of bioelectrical signals. To date, electrodes are made of metals or inorganic semiconductors, or hybrids thereof. We demonstrate that these traditional conductors can be completely substituted by highly flexible electroconductive polymers. Pursuing a two-level replica-forming strategy, conductive areas for electrodes, leads and contact pads are defined as microchannels in poly(dimethylsiloxane) (PDMS) as a plastic carrier and track insulation material. These channels are coated by films of organic conductors such as polystyrenesulfonate-doped poly(3,4-ethylenedioxy-thiophene) (PEDOT:PSS) or filled with a graphite-PDMS (gPDMS) composite, either alone or in combination. The bendable, somewhat stretchable, non-cytotoxic and biostable all-polymer microelectrode arrays (polyMEAs) with a thickness below 500 μm and up to 60 electrodes reliably capture action potentials (APs) and local field potentials (LFPs) from acute preparations of heart muscle cells and retinal whole mounts, in vivo epicortical and epidural recordings as well as during long-term in vitro recordings from cortico-hippocampal co-cultures.

Place, publisher, year, edition, pages
Elsevier, 2011
Keywords
Polymer electronics, PEDOT:PSS, PDMS, Replica molding, Neuroprosthetics, Electrophysiology, Neurotechnology
National Category
Biomaterials Science
Identifiers
urn:nbn:se:umu:diva-79148 (URN)10.1016/j.biomaterials.2010.11.014 (DOI)000287069400002 ()21145588 (PubMedID)
Available from: 2013-08-17 Created: 2013-08-09 Last updated: 2018-06-08Bibliographically approved
Organisations

Search in DiVA

Show all publications