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Serotonin, Via 5-HT Receptors, Increases Epscs in Layer V

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Serotonin, Via 5-HT Receptors, Increases Epscs in Layer V Brain Research 825Ž. 1999 161±171 Research report Serotonin, via 5-HT2A receptors, increases EPSCs in layer V pyramidal cells of prefrontal cortex by an asynchronous mode of glutamate release George K. Aghajanian ), Gerard J. Marek Departments of Psychiatry and Pharmacology, Yale School of Medicine, Yale UniÕersity, New HaÕen, CT 06508, USA Connecticut Mental Health Center, 34 Park St., New HaÕen, CT 06508, USA Accepted 9 February 1999 Abstract Previously, serotoninŽ. 5-HT was found to induce a marked increase in glutamatergic spontaneous excitatory postsynaptic currents Ž.EPSCs in apical dendrites of layer V pyramidal cells of prefrontal cortex; this effect was mediated by 5-HT2A receptors, a proposed site of action of hallucinogenic and atypical antipsychotic drugs. Unexpectedly, although the effect of 5-HT was Ca2q-dependent and tetrodotoxin-sensitive, it did not appear to involve the activation of excitatory afferent impulse flow. This paradox prompted us to investigateŽ. in rat brain slices whether 5-HT was acting through an atypical mode of excitatory transmitter release. We found that the frequency of 5-HT-induced spontaneous EPSCs was fully supported by Sr 2q in the absence of added Ca2q, implicating the mechanism of asynchronous transmitter release which has been linked to the high-affinity Ca2q-sensor synaptotagmin III. Although the early, synchronous component of electrically eÕoked EPSCs was reduced while 5-HT was being applied, late, nonsynchronous components were enhanced during 5-HT washout and also by the 5-HT2 partial agonist 1-ŽŽ. 2,5-dimethoxy-4-iodophenyl-2-aminopropane DOI ; the effect of DOI was blocked by a selective 5-HT2A antagonistŽ. MDL 100,907 . This late, nonsynchronous component was distinct from conventional polysynaptic EPSCs evoked in the presence of the GABAA antagonist bicuculline, but resembled asynchronous glutamater- gic excitatory postsynaptic potentialsŽ. EPSPs evoked in the presence of Sr2q . An enhancement of asynchronous EPSCs by a specific neurotransmitter receptor has not been reported previously. The possible role of excessive asynchronous transmission in the cerebral cortex in mediating the hallucinogenic effects of 5-HT2A agonists such as DOI is discussed. q 1999 Elsevier Science B.V. All rights reserved. Keywords: Apical dendrite; Brain slice; Hallucinogen; Sr 2q; Synaptotagmin III; Whole-cell recording wx 1. Introduction 1 where 5-HT2A receptors are enriched in pyramidal cell apical dendriteswx 10,12,33 . The increase in EPSCs in Previously, by whole-cell recording in rat brain slices, neocortex was surprising because previous studies in pale- we found that serotoninŽ. 5-HT induces a rapid and dra- ocortical regionsŽ e.g., piriform cortex, dentate gyrus, and matic increase in the frequency and amplitude of sponta- hippocampus. had shown predominantly an activation of neousŽ. nonelectrically evoked , glutamatergic excitatory inhibitory postsynaptic potentialsŽ. IPSPs by 5-HT2A re- postsynaptic potentialsrcurrentsŽ. EPSPsrEPSCs in layer wx wx ceptor stimulation 15,21,25,26 . The induction of EPSCs V pyramidal cells of transitional and neocortex 1 . The by 5-HT appears to occur through a novel, tetrodotoxin 5-HT-induced increase in spontaneous EPSCs was blocked Ž.TTX -sensitive, Ca2q -dependent mechanism which, para- by selective antagonists of 5-HT2A Ž. e.g., MDL 100907 but wx doxically, does not involve the activation of afferent im- not 5-HT2C receptors 1,19 and was seen most promi- pulse flowwx 1 . Instead, as shown by 5-HT-responsive `hot nently in medial prefrontal cortex and other frontal areas spots' on the apical but not basilar dendrites of layer V pyramidal cells, there was a focal mechanism for the wx ) Corresponding author. Connecticut Mental Health Center, 34 Park increase in spontaneous EPSCs 1 . St., New Haven, CT 06508, USA. Fax: q1-203-974-7897; e-mail: The present study investigated possible mechanisms by q [email protected] which 5-HT could induce a focal, TTXrCa2 -sensitive 0006-8993r99r$ - see front matter q 1999 Elsevier Science B.V. All rights reserved. PII: S0006-8993Ž. 99 01224-X 162 G.K. Aghajanian, G.J. MarekrBrain Research 825() 1999 161±171 release of glutamate in the absence of an increase in trodes containing 1 M K-acetateŽ. 30±60 MV ; voltage- afferent impulse flow. Studies in cortical synaptosomal clamping was carried out in the discontinuous single-elec- preparations have shown that mildly depolarizing agents trode voltage-clamp mode of the Axoclamp 2AŽ Axon such as the Kq channel blocker 4-aminopyridineŽ. 4-AP Inst.. at switching frequencies of 4±6 kHz and a loop gain can induce a TTX-sensitive release of glutamate from of 10 nArmVŽ. 30% duty cycle . The headstage voltage isolated cortical synaptosomesŽ in contrast to the TTX-in- was monitored continually to ensure that voltage transients sensitive release produced by strongly depolarizing, high decayed fully before voltage was sampled; false clamping concentrations of KCl. wx 29 . Interestingly, 4-AP preferen- was avoided by using optimal capacitance compensation tially enhances the `slow' rather then `fast' component of and by selecting switching frequencies that allowed the glutamate release and is supported by Sr 2q in the absence input voltage to settle to a horizontal baseline. of Ca2q, suggesting the involvement of the `asynchronous' Whole-cell recordingsŽ used for analysis of spontaneous mode of releasewx 11 . Sr2q substitutes for Ca2q at the EPSCs. were performed with an Axoclamp 2A amplifier high-affinity Ca2q sensor synaptotagmin III, which is be- using low-resistance patch pipettesŽ. 2.5±3 MV contain- lieved to be responsible for slow, asynchronous transmitter ingŽ. in mM : K-gluconate 120, Hepes 10, BAPTA K4 5, 2q 2q release, while Sr is ineffective at the low-affinity Ca sucrose 20, CaCl222 2.38, MgCl 1, K ATP 1, and GTP 0.1 sensor synaptotagmin I which is thought to be responsible Ž.pH;7.35 . Cells were located by passing hyperpolariz- for fast, synchronous transmitter releasewx 7,9,14 . In vari- ing pulsesŽ. 0.2 nAr200 ms in current clamp mode using ous regions of brain including cerebral cortexwx 2,25,28 , the the blind methodwx 4 . Following giga-seal formationŽ 1±5 effects of 5-HT2A -receptor activation resemble those of GV. induced by gentle suction, an additional pulse of 4-AP in producing a slow depolarization through a reduc- suction was applied to attain whole cell mode. Series tion in Kq channel conductance. Therefore, by analogy resistance, monitored continually throughout the experi- with 4-AP, it is possible that 5-HT induces a focal, mentŽ. except during periods of data collection , was usu- TTXrCa2q-sensitive, impulse-flow independent increase ally between 4 to 8 MV. To minimize series resistance in spontaneous EPSCs through the asynchronous mode of errors, cells were discarded if access resistance rose above glutamate release. To test this possibility, we have exam- 10 MV. As noted previouslywx 1 , when series resistance ined the ability of Sr 2q to substitute for Ca2q in support- was maintained in this low rangeŽ. i.e., close to full access , ing 5-HT-induced spontaneous EPSCs. In addition, we the input resistance of cells recorded by whole cell record- have examined the effects of 5-HT and 1-Ž 2,5-dimethoxy- ing were not different from values obtained with intra- 4-iodophenyl-2-aminopropaneŽ. DOI , a selective 5-HT2 cellular recording provided that in the latter case adequate agonistwx 30 , on a late, nonsynchronous component of time is allowed for a stable seal to form after impalement. electrically-evoked EPSCs. Postsynaptic currents were studied in the continuous sin- gle-electrode voltage-clamp modeŽ 3 kHz low-pass filter cutoff frequency. ; to minimize holding currents, cells were 2. Materials and methods clamped near their resting potentialŽ typically y70 to y 80 mV. At these holding potentials, GABAA and NMDA currents were minimized. 2.1. Preparation of brain slices Layer V pyramidal cells were recorded in the medial r wx prefrontal anterior cingulate cortex in a zone approxi- Brain slices were prepared as previously described 1 . mately 1r2to2r3 the distance between the pial surface Ž In brief, young adult male albino rats 120±170 g; Camm, and the subcortical white matter. Pyramidal cells in this . Charles River, or Harlan were anesthetized with chloral study had the following electrophysiological characteristics Ž.r hydrate 400 mg kg prior to decapitation. Brains were Ž.intracellular and whole cell groups combined : resting then removed and trimmed in ice-cold artificial cere- potential, y72"1 mV; action potential amplitude, 96"2 Ž. brospinal fluid ACSF ; coronal prefrontal cortical slices mV; action potential durationŽ. at half amplitude , 0.77" Ž.m 500 m were cut with an oscillating-knife microtome 0.1 ms; input resistance Ž.y0.2 nA test pulse , 33"3MV and placed in an interface-type chamber through which Ž.ns38 . Electrically evoked EPSPs were induced with a ; r ACSF flowed at 1±1.5 ml min. The ACSF and cham- bipolar tungsten electrode placed on the subcortical white r ber were equilibrated with 95% O225% CO and main- matterŽ. forceps minor on a line approximately perpendicu- 8 8 Ž. tained at 33 ±34 C. ACSF was composed of in mM : lar to the recorded layer V pyramidal cellŽ see Fig. 2, NaCl 128, KCl 3, NaH24 PO 1.25, D-glucose 10, NaHCO 3 inset.Ž. The monophasic constant-current stimulus 0.2 ms Ž.; 25, CaCl24 2, MgSO 2 pH 7.35 . was set at an intensityŽ. range: 0.06 to 0.2 mA sufficient to induce a monosynaptic EPSC of ;0.5 to 1 nA. If an- 2.2. Recording and electrical stimulation tidromic spikes were observed from a given stimulation site, the position of the stimulating electrode was shifted Intracellular recordingsŽ used for the electrically evoked along the forceps minor until a site was found that did not response experiments.
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