180 research outputs found

    Inhibition decorrelates visual feature representations in the inner retina

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    The retina extracts visual features for transmission to the brain. Different types of bipolar cell split the photoreceptor input into parallel channels and provide the excitatory drive for downstream visual circuits. Mouse bipolar cell types have been described at great anatomical and genetic detail, but a similarly deep understanding of their functional diversity is lacking. Here, by imaging light-driven glutamate release from more than 13,000 bipolar cell axon terminals in the intact retina, we show that bipolar cell functional diversity is generated by the interplay of dendritic excitatory inputs and axonal inhibitory inputs. The resulting centre and surround components of bipolar cell receptive fields interact to decorrelate bipolar cell output in the spatial and temporal domains. Our findings highlight the importance of inhibitory circuits in generating functionally diverse excitatory pathways and suggest that decorrelation of parallel visual pathways begins as early as the second synapse of the mouse visual system

    Transient receptor potential cation channel, subfamilies V, member 1 (TRPV1) and M, member 1 (TRPM1) contribute to neural signaling in mouse retina.

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    The retina processes light information through parallel pathways in order to extract and encode the visual scene. Light information is transmitted to the brain through approximately 30 ganglion cells (GCs), the retinal output neurons. Trp channels modulate the responses of retinal neurons within specific pathways. The study of the expression and function of the majority of Trp channels in the retina is largely in its infancy. My dissertation first investigated the expression and function of the transient receptor potential vanilloid-1 (TRPV1) receptor/channel in the retina. TRPV1, the first cloned and most highly studied Trp channel in the peripheral nervous system, is a non-selective cation channel with an affinity for Ca2+. The channel can be activated by capsaicin, acid, endovanilloids, noxious heat or pressure (Moreira et al., 2012). Located on the peripheral and central terminals of nociceptive fibers in the PNS and in limited areas of the CNS (Cavanaugh et al, 2011b). TRPV1 plays a role in inflammation, chronic pain, nociceptor sensitization and desensitization, long-term depression and potentiation, and apoptosis. The role of TRPV1 in the retina is not known. Using the electroretinogram (ERG), a mass potential that assesses the function of photoreceptors and bipolar cells, the TRPV1 knockout mouse appears normal. However, TRPV1 is thought to play a role in calcium regulation and glaucoma (Sappington et al., 2009 & Leonelli et al., 2010) so we investigated its role in normal visual transduction in the inner retina. To investigate TRPV1 modulation, I recorded GC spiking responses to light stimuli from mice which either express or lack TRPV1 protein. I found that TRPV1 is critical for: 1. GC responses to dim light. 2. Sustained responses to light 3. Surround suppression of GCs to large spots. Further, I investigate the specific retinal cells that express TRPV1. I used TRPV1cre mice with genetic or viral methods to fluorescently label neurons that express TRPV1. I determined TRPV1 is expressed in four classes of amacrine and three classes of ganglion cells in the inner retina. My results indicate TRPV1 activity in the amacrine cells enhances the sustained spiking responses in GCs. In this way, TRPV1 likely enhances the perception of subtle details in the visual world. TRPV1 also is expressed in subsets of intrinsically photosensitive GCs, which are known to play a role in circadian photoentrainment. TRPV1 therefore has the potential to modulate circadian photoentrainment or other non-image forming visual functions as well. The role of TRPM1 in the retina is well known. It is required for signaling through the ON pathway, which detects light increments. Responses through the vii ON pathway are initiated by synapses between rod and cone photoreceptors with ON bipolar cells (BCs). The human disease, complete congenital stationary night blindness (cCSNB) results from a disruption in signaling within the ON BC mGluR6 G-protein coupled cascade, which culminates in the opening of the TRPM1 channel and signaling through ON BCs. I helped expand our understanding of the role of TRPM1 in the retina by investigating the expression and function of leucine rich repeat immunoglobulin like transmembrane protein 3 (LRIT3), a novel protein component in the mGluR6-TRPM1 signalplex that was found mutated within cCSNB patients and a knockout mouse (Zeitz et al., 2013; Neuillé et al., 2014). The function of LRIT3 within the cascade remains unknown. To better understand the role of LRIT3, we examined retinal structure and function. We compared the structure of the pre and postsynaptic elements in the OPL of WT and Lrit3-/- mice using a variety of antibodies and with confocal microscopy. We assessed overall retinal function with ERG and GC spontaneous and visually evoked activity with single cell and multielectrode array recordings. The overall laminar structure of the Lrit3-/- retina is similar to WT. Consistent with published results and other cCSNB mouse models, Lrit3-/- mouse dark- and lightadapted ERGs have a normal a-wave, but lack a b-wave. The dendritic terminals of Lrit3-/- ON BCs lack expression of nyctalopin and TRPM1. Lrit3-/- mice significantly differ from other cCSNB mutants. Cone ON BCs lack expression of mGluR6, GPR179 and RGS11, whereas rod BCs maintain expression of these proteins. LRIT3 is necessary for expression and localization of nyctalopin and TRPM1 to the ON BC dendrites. As expected there are no ON responses, but surprisingly very few (~22%) Lrit3-/- GCs have even OFF responses. Lrit3-/- OFF BCs express functional kainate glutamate receptors. However, Lrit3-/- OFF BC and OFF GCs have significantly smaller response to light decrements than WT. Like all other mouse models of cCSNB, LRIT3 is critical to signaling in ON BCs, however, unlike all other cCSNB models, LRIT3 also has a trans-synaptic role in enhancing glutamate transmission from cones to BCs

    MAGUK SCAFFOLDS ORGANIZE A KEY SYNAPTIC COMPLEX IN HORIZONTAL CELL PROCESSES CONTACTING PHOTORECEPTORS

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    Synaptic processes and plasticity of synapses are mediated by large suites of proteins. In most cases, many of these proteins are tethered together by synaptic scaffold proteins. Scaffold proteins have a large number and typically a variety of protein interaction domains that allow many different proteins to be assembled into functional complexes. As each scaffold protein has a different set of protein interaction domains and a unique set of interacting partners, the presence of synaptic scaffolds can provide insight into the molecular mechanisms that regulate synaptic processes. In studies of rabbit retina, we found SAP102 and Chapsyn110 selectively localized in the tips of B-type horizontal cell processes where they contact cone and rod photoreceptors. We further identified some known SAP102 binding partners, kainate receptor GluR6/7 and inward rectifier potassium channel Kir2.1, closely associated with SAP102 in the processes of invaginating HCs. In contrast, in the mouse retina we identified Chapsyn110 as the major scaffold in the tips of horizontal cells contacting photoreceptors. Kir2.1 was found to be assembled with SAP102 into a complex with GluR6/7 in photoreceptor invaginations in Rabbit. GluR6/7 and Kir2.1 presumably are involved in synaptic processes that govern cell-to-cell communication, and could both contribute in different ways to synaptic currents that mediate feedback signaling. Notably, we failed to find evidence for the presence of Cx57 or Cx59, but Pannexin1 immunolabeling was positive in the OPL of mouse retina suggesting that it could play a role in ephaptic and pH mediated signaling. Polyamines regulate many ion channels including Kir2.1. During the day polyamine immunolabeling was unexpectedly high in photoreceptor terminals compared to other areas of the retina. If polyamines are released, they may regulate the activity of Kir2.1 channels located in the tips of HCs. Alternatively, the presence of polyamines may potentiate GluR6/7 by reducing the transition to desensitized state causing an increase in channel conductance. The presence of SAP102 and Chapsyn110 and their binding partners in both cone and rod invaginating synapses suggests that whatever mechanism is supported by this protein complex is present in both types of photoreceptors

    Dynamic changes in the localization of synapse associated proteins during development and differentiation of the mammalian retina

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    We have examined the developmental distribution and differential localization of presynaptic terminal associated proteins in the mammalian retina. We have used antibodies specific for synaptic vesicle associated proteins Synaptotagmin, Rab 3A, Synaptophysin and Synaptobrevin, and presynaptic terminal membrane associated proteins SNAP-25 and Syntaxin, to characterize their spatio-temporal distribution during retinal differentiation and in the mature retina;The vertebrate retina has a laminar organization consisting of three cellular layers separated by two synaptic layers, the inner piexiform layer and the outer plexiform layer. In general, immunoreactivity for presynaptic terminal associated proteins was first observed in cellular layers, and as differentiation progressed, immunoreactivity was localized to the synaptic or plexiform layers. However, there were distinct differences in the relative intensities and localization of patterns of immunoreactivity for these proteins;This analysis revealed a temporal difference in the onset of detectable immunoreactivity for Synaptotagmin and Rab 3A compared with Synaptophysin and Synaptobrevin, suggesting they may have additional roles in vesicle trafficking during neural development. Immunoreactivity for presynaptic terminal membrane associated protein SNAP-25 is at relatively high levels in cholinergic amacrine cells during their differentiation, but not at maturity. This transient expression of high levels of SNAP-25 may contribute to the functional role these cells play in propagation of spontaneous retinal activity. Spatial and temporal differences in localization of SNARE complex proteins (Synaptophysin, SNAP-25 and Syntaxin), were also observed during development and at maturity. Detectable SNAP-25- and Syntaxin-immunoreactivity preceded Synaptobrevin-immunoreactivity during differentiation of synaptic layers. In addition, immunoreactivity for each protein had a distinct pattern of differential intensities within the inner plexiform or synaptic layer during development and in the mature retina, and differential localization in the OPL;This analysis was the first to systematically characterize the distribution of multiple presynaptic terminal associated proteins, including proteins of the SNARE complex, during development of an organized tissue like the retina. The dynamic, differential patterns of immunoreactivity for these proteins suggests several of them may have additional roles in the development of the nervous system

    Assembly of the outer retina in the absence of GABA synthesis in horizontal cells

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    <p>Abstract</p> <p>Background</p> <p>The inhibitory neurotransmitter gamma-amino-butyric acid (GABA) not only modulates excitability in the mature nervous system but also regulates neuronal differentiation and circuit development. Horizontal cells, a subset of interneurons in the outer retina, are transiently GABAergic during the period of cone photoreceptor synaptogenesis. In rodents, both horizontal cells and cone axonal terminals express GABA<sub>A </sub>receptors. To explore the possibility that transient GABA expression in mouse neonatal horizontal cells influences the structural development of synaptic connectivity in the outer retina, we examined a mutant in which expression of GAD67, the major synthesizing enzyme for GABA, is selectively knocked out in the retina.</p> <p>Results</p> <p>Immunocytochemistry and electron microscopy revealed that the assembly of triad synapses involving cone axonal pedicles and the dendrites of horizontal and bipolar cells is unaffected in the mutant retina. Moreover, loss of GABA synthesis in the outer retina did not perturb the spatial distributions and cell densities of cones and horizontal cells. However, there were some structural alterations at the cellular level: the average size of horizontal cell dendritic clusters was larger in the mutant, and there was also a small but significant increase in cone photoreceptor pedicle area. Moreover, metabotropic glutamate receptor 6 (mGluR6) receptors on the dendrites of ON bipolar cells occupied a slightly larger proportion of the cone pedicle in the mutant.</p> <p>Conclusions</p> <p>Together, our analysis shows that transient GABA synthesis in horizontal cells is not critical for synapse assembly and axonal and dendritic lamination in the outer retina. However, pre- and postsynaptic structures are somewhat enlarged in the absence of GABA in the developing outer retina, providing for a modest increase in potential contact area between cone photoreceptors and their targets. These findings differ from previous results in which pharmacological blockade of GABA<sub>A </sub>receptors in the neonatal rabbit retina caused a reduction in cone numbers and led to a grossly disorganized outer retina.</p

    MORPHOLOGY AND ELECTROPHYSIOLOGY OF RETINAL PHOTORECEPTOR TERMINATIONS IN THE OCTOPUS (ELEDONE CIRROSA) OPTIC LOBE

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    Cephalopods possess a well-developed visual system encompassing a pair of camera-type eyes attached to specific visual processing regions of the central nervous system known as the optic lobes. The retina contains a single type of photoreceptive cell, which send axons via a dorso-ventral chiasma to the optic lobes. Although electrophysiological recordings have been routinely obtained from the retina there are few recordings from the optic lobe. This study investigated the morphology and electrophysiology of the first synapse in the Octopus (Eledone cirrosa) visual system. The morphology and innervation patterns of individual optic nerves onto the optic lobe were revealed using the carbocyanine dye, Oil. Optic nerves had characteristic mapping patterns depending upon where they entered the optic lobe. Nerves innervating central regions of the optic lobe spread laterally in both directions for equal distances. Optic nerves that entered the lobe on the dorsal and ventral surfaces of the lobes spread for greater distances in only one direction. The morphology of the photoreceptor terminations in the cortex were comparable to the morphologies revealed in previous studies. A brain slice preparation of the octopus optic lobe was developed in order to make the first in vitro electrophysiological recordings from the first synapse in the visual pathway. Extracellular pre- and postsynaptic responses were recorded from the optic lobe and these were characterised. Using a variety of techniques (paired-pulse tests, frequency inhibition, ionic substitution) the different evoked field potentials recorded from different layers of the optic lobe slice were separated into pre- and postsynaptic components. Postsynaptic responses obtained in the outer regions of the plexiform zone were polysynaptic and negative in inflection whilst those obtained from the inner granular cell layer and medulla were positive. The effects of altering the extracellular concentrations of Ca2+, Mg2+ and K+ were all investigated. The resultant electrical activity after orthodromic stimulation of a single optic nerve was mapped in the optic lobe slice and plots of lines of isopotential produced. Pharmacological studies using the in vitro slice preparation in conjunction with specific antagonists to vertebrate receptors were employed to reveal the identity of the neurotransmitter released from the retinal photoreceptor terminations. The abolishment of postsynaptic responses with alpha-bungarotoxin and the increase with the acetylcholinesterase inhibitor (eserine) indicated that the transmitter released is acetylcholine. Histochemical and immunohistochemical localisations of putative neurotransmitters (or their synthetic enzymes) in the cephalopod optic lobe were attempted. No neurotransmitter-like immunoreactivity was seen in the optic lobe, this was probably due to the primary antibodies used not recognising antigens in the tissue. In the decapod squid, Alloteuthis subulata and Loligo forbesii, AChE histochemistry revealed precise anatomical localisation of this enzyme which concurred with previous studies on other decapod species. This study has enhanced the understanding of the cephalopod visual system by providing a preparation of the optic lobe from which electrophysiological recordings can repeatabley be obtained. This preparation has been used to provide information about how visual information is passed from the retina to the central nervous system.Marine Biological Association of the United Kingdo

    Local signal processing in mouse horizontal cell dendrites

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    Most neurons in the central nervous system have elaborate dendritic arbours which come in a large variety of sizes and morphologies (Lefebvre et al., 2015). For many decades, dendrites have been thought to simply relay presynaptic signals to the soma and to the axon terminal system by acting as “passive cables”. However, it has become clear that dendrites are capable of much more than passively integrating synaptic input, they can also act independently and modulate presynaptic signals (reviewed by Branco and Häusser, 2010). Dendritic signal processing has been reported to support sophisticated functions in the cortex, hippocampus, and cerebellum as well as in the retina. In the latter case, multiple processing within one dendrite is essential to process considerable amounts of information from the outside world but, at the same time to use space efficiently: The retina needs to be thin and transparent to reduce light scattering within the tissue. Dendritic processing has already been described in inner retinal neurons (Euler et al., 2002; Grimes et al., 2010; Oesch et al., 2005; Sivyer and Williams, 2013). In the outer retina, the horizontal cell (HC) dendrites, which are directly postsynaptic to the cone photoreceptors (cones) have recently been suggested to be plausible candidates for local signal processing (Grassmeyer and Thoreson, 2017; Jackman et al., 2011; Vroman et al., 2014) despite their involvement in global tasks such as contrast enhancement. To test this hypothesis physiologically, I used two-photon imaging to record calcium (Ca2+) signals in cones and HCs, as well as, cone glutamate release in mouse retinal slices. I used green (578 nm) and ultra violet (UV, 360 nm) light stimuli and recorded from different retinal regions to specifically activate different combinations of medium (M-) and short (S-) wavelength-sensitive opsin expressed in cones. This approach allowed to assess if signals from individual cones remain “isolated” within a local dendritic region of a HC, or if they spread across the entire dendritic tree or, in the electrically coupled HC network. In contrast to what one would expect in a purely globally acting HC (network), responses measured in neighbouring HC compartments varied markedly in their chromatic preference suggesting that HC dendrites are able to process cone input in a highly local manner. Moreover, I found local HC feedback to play a role in shaping the temporal properties of cone output

    Genetic Control of Circuit Function: Vsx1 and Irx5 Transcription Factors Regulate Contrast Adaptation in the Mouse Retina

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    Transcriptional programs guide the specification of neural cell types in the developing nervous system. However, it is unclear whether such programs also control specific aspects of neural circuit function at maturity. In the mammalian retina, Vsx1 and Irx5 transcription factors are present in a subset of bipolar interneurons that convey signals from photoreceptors to ganglion cells. The biased expression of Vsx1 and Irx5 in hyperpolarizing OFF compared with depolarizing ON bipolar cells suggests that these transcription factors may selectively regulate signal processing in OFF circuits. To test this hypothesis, we generated mice lacking both Vsx1 and Irx5. Bipolar cells in these mice were morphologically normal, but the expression of cell-specific markers in some OFF but not ON bipolar cells was reduced or absent. To assess visual function in Vsx1/Irx5/ retinas, we recorded light responses from ensembles of retinal ganglion cells (RGCs). We first identified functional RGC types in control mice and describe their response properties and adaptation to temporal contrast using a simple linearnonlinear model. We found that spacetime receptive fields of RGCs are unchanged in Vsx1/Irx5/ mice compared with control retinas. In contrast, response threshold, gain, and range were lowered in a cell-type-specific manner in OFF but not ON RGCs in Vsx1/Irx5/ retinas. Finally, we discovered that the ability to adapt to temporal contrast is greatly reduced in OFF RGCs in the double mutant, suggesting that Vsx1 and Irx5 control specific aspects of visual function in circuits of the mammalian retina

    Expression of functional GABAc receptors in the brain

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    γ-aminobutyric acid (GABA) is the main inhibitory transmitter in the nervous system and acts via three distinct receptor classes: A, B, and C. GABAC receptors are ionotropic receptors comprising ρ subunits. In this work, we aimed to elucidate the expression of ρ subunits in the postnatal brain, the characteristics of ρ2 homo-oligomeric receptors, and the function of GABAC receptors in the hippocampus. In situ hybridization on rat brain slices showed ρ2 mRNA expression from the newborn in the superficial grey layer of the superior colliculus, from the first postnatal week in the hippocampal CA1 region and the pretectal nucleus of the optic tract, and in the adult dorsal lateral geniculate nucleus. Quantitative RT-PCR revealed expression of all three ρ subunits in the hippocampus and superior colliculus from the first postnatal day. In the hippocampus, ρ2 mRNA expression clearly dominated over ρ1 and ρ3. GABAC receptor protein expression was confirmed in the adult hippocampus, superior colliculus, and dorsal lateral geniculate nucleus by immunohistochemistry. From the selective distribution of ρ subunits, GABAC receptors may be hypothesized to be specifically involved in aspects of visual image motion processing in the rat brain. Although previous data had indicated a much higher expression level for ρ2 subunit transcripts than for ρ1 or ρ3 in the brain, previous work done on Xenopus oocytes had suggested that rat ρ2 subunits do not form functional homo-oligomeric GABAC receptors but need ρ1 or ρ3 subunits to form hetero-oligomers. Our results demonstrated, for the first time, that HEK 293 cells transfected with ρ2 cDNA displayed currents in whole-cell patch-clamp recordings. Homomeric rat ρ2 receptors had a decreased sensitivity to, but a high affinity for picrotoxin and a marked sensitivity to the GABAC receptor agonist CACA. Our results suggest that ρ2 subunits may contribute to brain function, also in areas not expressing other ρ subunits. Using extracellular electrophysiological recordings, we aimed to study the effects of the GABAC receptor agonists and antagonists on responses of the hippocampal neurons to electrical stimulation. Activation of GABAC receptors with CACA suppressed postsynaptic excitability and the GABAC receptor antagonist TPMPA inhibited the effects of CACA. Next, we aimed to display the activation of the GABAC receptors by synaptically released GABA using intracellular recordings. GABA-mediated long-lasting depolarizing responses evoked by high-frequency stimulation were prolonged by TPMPA. For weaker stimulation, the effect of TPMPA was enhanced after GABA uptake was inhibited. Our data demonstrate that GABAC receptors can be activated by endogenous synaptic transmitter release following strong stimulation or under conditions of reduced GABA uptake. The lack of GABAC receptor activation by less intensive stimulation under control conditions suggests that these receptors are extrasynaptic and activated via spillover of synaptically released GABA. Taken together with the restricted expression pattern of GABAC receptors in the brain and their distinctive pharmacological and biophysical properties, our findings supporting extrasynaptic localization of these receptors raise interesting possibilities for novel pharmacological therapies in the treatment of, for example, epilepsy and sleep disorders.Gamma-aminovoihappo (GABA) on keskushermoston tärkein ehkäisevä välittäjäaine. GABA-reseptorit jaetaan rakenteen ja farmakologisten ominaisuuksien perusteella kolmeen ryhmään. GABAA- ja GABAC-reseptorit ovat ionotrooppisia kloridikanavareseptoreita, kun taas GABAB-reseptorit ovat metabotrooppisia. Ionotrooppiset GABA-reseptorit koostuvat viidestä alayksiköstä, joita tunnetaan GABAC-reseptoreille kolme erilaista: ρ1, ρ2 ja ρ3. Väitöskirjatyön tarkoituksena oli selvittää GABAC-reseptoreiden ilmentymistä ja toimintaa keskushermostossa, erityisesti hippokampuksessa. Ensimmäisessä osatyössä GABAC-reseptoreiden ρ-alayksikköjä löytyi varhaisemmassa yksilönkehityksen vaiheessa ja useammalta keskushermoston alueelta kuin aiemmin oli havaittu. In situ -hybridisaatiomenetelmällä havaittiin ρ2-alayksikön lähetti-RNA:ta verkkokalvon, hippokampuksen, ylemmän nelikukkulalevyn ja muiden näköjärjestelmän tumakkeiden lisäksi myös näköaivokuorelta kolmesta eri kerroksesta. Kvantitatiivisella RT-PCR-menetelmällä todettiin kaikkien kolmen alayksikön lähetti-RNA:ta hippokampuksesta jo vastasyntyneeltä. Immunosytokemiallisilla vasta-ainevärjäyksillä voitiin vahvistaa, että ρ-proteiinia löytyi kaikilta niiltä aivoalueilta, joilla oli todettu ρ2-alayksikön mRNA:ta. Toisessa osatyössä pystyttiin ensimmäistä kertaa ekspressoimaan toimivia rotan ρ2-alayksikön muodostamia homomeerisiä reseptoreita HEK-293-soluissa. Ne olivat herkempiä sekä GABAlle että pelkästään GABAC-reseptoreihin vaikuttavalle CACAlle kuin ρ1ρ2-heteromeerit, mutta huomattavan epäherkkiä pikrotoksiinille, joka pystyi suurillakin pitoisuuksilla aiheuttamaan vain osittaisen antagonismin. Toisaalta kuitenkin tällä homomeerillä oli hyvin korkea-affiininen pikrotoksiinin sitoutumiskohta. Kolmannessa osatyössä voitiin osoittaa, että hippokampuksen CA1-alueen pyramidaalisoluissa on toimivia GABAC-reseptoreita. Niiden aktivaatio hyvin pienellä, toisen osatyön perusteella ρ2-alayksikköspesifisellä CACA-pitoisuudella pienensi hermosoluryhmän vasteita. Hyvin voimakas stimulaatiosarja aktivoi sekä GABAA- että GABAC-reseptorit CA1-alueella ja saadaan kaksiosainen vaste, joka koostuu tavanomaisesta hyperpolarisaatiosta ja pitkäkestoisesta depolarisaatiosta. GABAC-reseptoriantagonisti TPMPA sai aikaan oleellisia muutoksia erityisesti depolarisaatiovaiheen kestossa. Samantyyppinen vaste TPMPA:lle saatiin myös ilman erittäin voimakasta stimulaatiota silloin, kun välittäjäaineen poisto synapsiraosta oli estetty ja GABAa diffundoitui enemmän synapsiraon ulkopuolelle. Tulokset tukevat hypoteesia, että hippokampuksen GABAC-reseptorit saattavat olla ekstrasynaptisia eli sijaita välittömästi synapsin ulkopuolella ja aktivoitua silloin, kun välittäjäainetta läikkyy yli synapsiraosta. Ekstrasynaptisia GABAA-reseptoreja on aiemmin löydetty useilta alueilta, myös hippokampuksesta. GABAC-reseptorit ja nämä δ-alayksikön sisältävät ekstrasynaptiset GABAA-reseptorit muistuttavat toisiaan erityisesti herkkyydessään GABAlle ja desensitisoitumattomuudessaan. Väitöskirjatyön perusteella voidaan yhteenvetona olettaa, että GABAC-reseptorit osallistuvat liikkuvan kuvan prosessointiin aivoissa ja että hippokampuksen GABAC-reseptorit ovat ekstrasynaptisia ja optimoivat hippokampuksen tietojenkäsittelykapasiteettia läikkymisinhibition avulla. Hippokampuksessa GABAC-reseptoreiden aktivaatio pystyi hillitsemään epileptistyyppisiä, patologisen voimakkaita neuronipopulaation vasteita, jotka GABAA-reseptorien estäminen bikukulliinilla oli saanut aikaan. Kun lisäksi huomioidaan GABAC-reseptoreiden sijainti vain osassa keskushermostoa ja niiden erityinen farmakologia ja kinetiikka, väitöskirjatyön löydökset voivat tulevaisuudessa olla tärkeitä kehitettäessä uusia lääkkeitä toisaalta epilepsiaan, toisaalta unihäiriöihin, erityisesti narkolepsiaan ja unettomuuteen
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