Receptor-mediated Synaptic Input Research Articles

Neurotensin speeds inhibition of dopamine neurons through temporal modulation of GABAA and GABAB receptor-mediated synaptic input

Midbrain dopamine neurons play physiological roles in many processes including reward learning and motivated behavior, and are tonically inhibited by γ-aminobutyric acid (GABA)ergic input from multiple brain regions. Neurotensin (NT) is a neuropeptide which acutely modulates midbrain dopamine neuron excitability through multiple mechanisms, one of which is a decrease of GABA-mediated inhibition. However, the mechanisms through which NT depresses GABA signaling are not known. Here we used whole cell patch-clamp electrophysiology of dopamine neurons in mouse brain slices to show that NT acts both presynaptically to increase GABAA and postsynaptically to decrease GABAB receptor-mediated currents in the substantia nigra. The active peptide fragment NT8-13 enhanced GABAA signaling presynaptically by causing an increase in the size of the readily releasable pool of GABA via activation of the NT type-1 receptor and protein kinase A. Conversely, NT8-13 depressed GABAB signaling postsynaptically via the NT type-2 receptor in a process that was modulated by protein kinase C. Both forms of plasticity could be observed simultaneously in single dopamine neurons. Thus, as the kinetics of GABAA signaling are significantly faster than those of GABAB signaling, NT functionally speeds GABAergic input to midbrain dopamine neurons. This finding contributes to our understanding of how neuropeptide-induced plasticity can simultaneously differentiate and integrate signaling by a single neurotransmitter in a single cell and provides a basis for understanding how neuropeptides use temporal shifts in synaptic strength to encode information.

Novel fast adapting interneurons mediate cholinergic-induced fast GABAA inhibitory postsynaptic currents in striatal spiny neurons.

Previous work suggests that neostriatal cholinergic interneurons control the activity of several classes of GABAergic interneurons through fast nicotinic receptor-mediated synaptic inputs. Although indirect evidence has suggested the existence of several classes of interneurons controlled by this mechanism, only one such cell type, the neuropeptide-Y-expressing neurogliaform neuron, has been identified to date. Here we tested the hypothesis that in addition to the neurogliaform neurons that elicit slow GABAergic inhibitory responses, another interneuron type exists in the striatum that receives strong nicotinic cholinergic input and elicits conventional fast GABAergic synaptic responses in projection neurons. We obtained invitro slice recordings from double transgenic mice in which Channelrhodopsin-2 was natively expressed in cholinergic neurons and a population of serotonin receptor-3a-Cre-expressing GABAergic interneurons were visualized with tdTomato. We show that among the targeted GABAergic interneurons a novel type of interneuron, termed the fast-adapting interneuron, can be identified that is distinct from previously known interneurons based on immunocytochemical and electrophysiological criteria. We show using optogenetic activation of cholinergic inputs that fast-adapting interneurons receive a powerful supra-threshold nicotinic cholinergic input invitro. Moreover, fast adapting neurons are densely connected to projection neurons and elicit fast, GABAA receptor-mediated inhibitory postsynaptic current responses. The nicotinic receptor-mediated activation of fast-adapting interneurons may constitute an important mechanism through which cholinergic interneurons control the activity of projection neurons and perhaps the plasticity of their synaptic inputs when animals encounter reinforcing or otherwise salient stimuli.

GABAergic regulation of cerebellar NG2 cell development is altered in perinatal white matter injury.

Diffuse white matter injury (DWMI), a leading cause of neurodevelopmental disabilities in preterm infants, is characterized by reduced oligodendrocyte formation. Oligodendrocyte precursor cells (NG2-cells) are exposed to various extrinsic regulatory signals, including the neurotransmitter GABA. We investigated GABAergic signaling to cerebellar white matter NG2-cells in a mouse model of DWMI (chronic neonatal hypoxia). We found that hypoxia caused a loss of GABAA receptor-mediated synaptic input to NG2-cells, extensive proliferation of these cells and delayed oligodendrocyte maturation, leading to dysmyelination. Treatment of control mice with a GABAA receptor antagonist or deletion of the chloride-accumulating transporter NKCC1 mimicked the effects of hypoxia. Conversely, blockade of GABA catabolism or GABA uptake reduced NG2-cell numbers and increased the formation of mature oligodendrocytes both in control and hypoxic mice. Our results indicate that GABAergic signaling regulates NG2-cell differentiation and proliferation in vivo, and suggest that its perturbation is a key factor in DWMI.

The medial habenula contains a specific nonstellate subtype of astrocyte expressing the ectonucleotidase NTPDase2

ATP-mediated synaptic transmission represents the only transmitter-gated Ca(2+)-entry pathway in neurons of the rodent medial habenula. In addition to direct purinergic receptor-mediated synaptic inputs, the medial habenula contains purinergic systems that modulate synaptic transmission. Purinergic signaling is modulated or terminated by ectonucleotidase, nucleotide-hydrolyzing enzymes of the cell surface. Here we identify the major ectonucleotidase responsible for the hydrolysis of extracellular ATP in the mouse medial habenula as ectonucleoside triphosphate diphosphohydrolase 2 (NTPDase2), using immunostaining and enzyme histochemistry. Double labeling experiments reveal that the enzyme is expressed by astrocytes enwrapping the densely packed neurons and also the myelinated fiber bundles of the stria medullaris. NTPDase2 immunoreactivity is absent from the lateral habenula. The analysis of mice expressing enhanced green fluorescent protein under the promoter of glial fibrillary acidic protein revealed that the medial habenula harbors a highly polar type of astrocytes with very long laminar cellular processes, untypical for grey matter astrocytes. Its morphology strongly differs from that of the stellate astrocytes in the adjacent lateral habenula. Our results suggest that the mouse medial habenula contains a specific perineuronal nonstellate subtype of astrocyte that expresses the ectonucleotidase NTPDase2 and is in a strategic position to modulate purinergic transmission in this subnucleus.

Regulation of fast-spiking basket cell synapses by the chloride channel ClC-2

Parvalbumin-expressing, fast-spiking basket cells play key roles in the generation of synchronous, rhythmic population activities in the hippocampus. Here we show that GABAA receptor-mediated synaptic inputs from murine parvalbumin-expressing basket cells are selectively modulated by the membrane voltage- and intracellular chloride-dependent chloride channel ClC–2. These data demonstrate a novel cell type-specific regulation of intracellular chloride homeostasis in the perisomatic region of hippocampal pyramidal neurons.

Mice Selectively Bred for High- or Low-Alcohol-Induced Locomotion Exhibit Differences in Dopamine Neuron Function

Elevated sensitivity to the euphoric or stimulant effects of ethanol is associated with higher levels of alcohol use in some human populations. Midbrain dopamine neurons are thought to be important mediators of both ethanol reward and locomotor stimulation. Patch-clamp recordings were used to examine the electrical properties of dopamine neurons in a genetic model of heightened (FAST) and reduced (SLOW) sensitivity to the locomotor-activating effects of ethanol. Pacemaker firing of dopamine neurons was faster in FAST than SLOW mice, as was the current density through I(H) channels. Acute administration of ethanol accelerated the firing of dopamine neurons to a greater extent in recordings from FAST than SLOW mice. Dopamine neurons from FAST mice also exhibited reduced GABA(A) receptor-mediated synaptic input, compared with SLOW mice. The results suggest that dopamine neuron I(H) channels, firing rate, and GABAergic input may play a role in sensitivity to the locomotor activation observed at early time points after ethanol administration and could underlie differences in sensitivity to alcohol relevant to risk for alcohol abuse.

Pathway-specificity in N-methyl-d-aspartate receptor-mediated synaptic inputs onto subplate neurons

The subplate plays an important role in forming neuronal connections during early cortical development. We characterized by the use of whole-cell and cell-attached patch-clamp recordings in coronal brain slices from newborn mice (postnatal day [P] 0–3) the functional properties of two major pathways onto subplate neurons (SPn), the thalamocortical and the intra-subplate synaptic input. The two afferent pathways were stimulated extracellularly with bipolar electrodes placed in the thalamus and the subplate, respectively. Synaptically evoked and pharmacologically isolated N-methyl-d-aspartate receptor (NMDAR) –mediated responses with an onset latency of ∼6 ms could be reliably recorded in P0-3 SPn. Whereas the intra-subplate input revealed a pronounced facilitation using paired pulse stimulation at 60–120 ms or repetitive activation at 10–40 Hz, the thalamocortical input was either stable or markedly suppressed under these conditions. Single cell reverse transcription PCR revealed the expression of the NR2A, B and D subunit in all investigated SPn. The intra-subplate and the thalamocortical synaptic input did not differ in their sensitivity to NVP-AAM077 or ifenprodil, indicating that both synaptic inputs have a similar NR2A/2B subunit composition. At P0, NMDAR-mediated synaptic inputs arising from the thalamus were significantly larger as compared with the intra-subplate input. This difference could no longer be detected in P2-3 SPn, indicating an input-specific developmental regulation during the first Ps. Our data indicate that the thalamocortical and intra-subplate synaptic input onto P0-3 SPn differs in functional, molecular and developmental properties. The intra-subplate synaptic input shows more mature functional properties and sustains high stimulation frequencies, thereby promoting the immature thalamocortical input to the developing neocortical circuit.

Properties of Persistent Postnatal Cortical Subplate Neurons

Subplate (SP) neurons are important for the proper development of thalamocortical innervation. They are necessary for formation of ocular dominance and orientation columns in visual cortex. During the perinatal period, many SP neurons die. The surviving cohort forms interstitial cells in the white matter (WM) and a band of horizontally oriented cells below layer VI (layer VIb, layer VII, or subplate cells). Although the function of embryonic SP neurons has been well established, the functional roles of WM and postnatal SP cells are not known. We used a combination of anatomical, immunohistochemical, and electrophysiological techniques to explore the dendritic morphology, neurotransmitter phenotype, intrinsic electrophysiological, and synaptic input properties of these surviving cells in the rat visual cortex. The density of SP and WM cells significantly decreases during the first month of life. Both populations express neuronal markers and have extensive dendritic arborizations within the SP, WM, and to the overlying visual cortex. Some intrinsic electrophysiological properties of SP and WM cells are similar: each generates high-frequency slowly adapting trains of action potentials in response to a sustained depolarization. However, SP cells exhibit greater frequency-dependent action potential broadening than WM neurons. Both cell types receive predominantly AMPA/kainate receptor-mediated excitatory synaptic input that undergoes paired-pulse facilitation as well as NMDA receptor and GABAergic input. Synaptic inputs to these cells can also undergo long-term synaptic plasticity. Thus, surviving SP and WM cells are functional electrogenic neurons integrated within the postnatal visual cortical circuit.

AMPA/Kainate Receptors Drive Rapid Output and Precise Synchrony in Olfactory Bulb Granule Cells

Gamma frequency (30-70 Hz) synchronized oscillatory activity in the olfactory bulb is widely believed to be important for odor detection and discrimination. As in other circuits with "gamma activity," the activity in the bulb is driven by GABAergic interneurons, specifically a class of axonless cells called granule cells. However, bulb granule cells appear to lack some key mechanistic features that promote rapid synchrony in other circuits, including direct electrical interconnections and dominant actions for fast neurotransmitter receptors. At least under "static" stimulus conditions, granule cells are driven by kinetically slow NMDA receptors. Here, I used patch-clamp recordings in rat olfactory bulb slices to better understand mechanisms that shape granule cell activity under "dynamic" stimulus conditions that mimic a natural odor stimulus. During a 4 Hz patterned stimulation of olfactory nerve afferents, activation of single granule cells was primarily controlled by two classes of AMPA/kainate receptor-mediated synaptic inputs derived from output mitral cells. The rapid kinetics of these receptors, together with inactivation of A-type potassium channels, ensured that granule cells had short spike-response times. Studies in cell pairs, moreover, indicated that excitatory inputs could synchronize granule cells on a rapid time scale (2-5 ms), in turn resulting in phase-locked GABA release onto mitral cells. The precision of granule cell synchrony was controlled by the same biophysical mechanisms that promoted rapid single-cell spiking. These studies demonstrate the mechanistic underpinnings that transform a circuit with slow, uncoupled activity under static conditions into a fast, dynamic circuit operating with high precision under physiological conditions.

Functional Properties of ES Cell–Derived Neurons Engrafted into the Hippocampus of Adult Normal and Chronically Epileptic Rats

Embryonic stem (ES) cell-based therapy strategies are thought to bear considerable promise in chronic neurologic disorders. Nonetheless, studies addressing the functional properties of ES cell-derived progeny after transplantation into the adult, pathologically modified CNS are scarce. We therefore transplanted ES cell-derived neural precursors expressing enhanced green fluorescent protein only in neuronal progeny bilaterally into the hippocampi of pilocarpine-treated chronically epileptic and sham-control rats. Whole-cell patch-clamp recordings of identified ES cell-derived neurons (ESNs) in hippocampal slices were performed 13 to 34 days after transplantation. Most ESNs were found in clusters at the transplant site and did not migrate into host tissue. However, they gave rise to a dense network of processes extending over large distances into the host tissue. All ESNs possessed the ability to generate action potentials and expressed voltage-gated Na+ and K+ currents, as well as hyperpolarization-activated currents. Likewise, most ESNs received non-N-methyl-D-aspartate (NMDA) and gamma-aminobutyric acid (GABA)A receptor-mediated synaptic input. Both types of synapses displayed intact short-term plasticity. An unusual feature of the majority of ESNs was the occurrence of spontaneous pacemaking activity at frequencies approximately 3 Hertz. No obvious differences were found between the functional properties of ESNs in sham-control and in pilocarpine-treated rats. After transplantation into adult control and epileptic rats, ESNs displayed intrinsic and synaptic properties characteristic of neurons. Even though ESNs remained close to the transplant site, the formation of extensive networks of graft-derived processes may be useful for ES cell-based substance delivery.

Changes in mIPSCs and sIPSCs After Kainate Treatment: Evidence for Loss of Inhibitory Input to Dentate Granule Cells and Possible Compensatory Responses

How inhibition is altered after status epilepticus and the role of inhibition during epileptogenesis remain unsettled issues. The present study examined acute (4-7 days) and chronic (>3 mo) changes of GABA(A) receptor-mediated inhibitory synaptic input to dentate granule cells after kainate-induced status epilepticus. Whole cell patch-clamp techniques were used to record spontaneous and miniature inhibitory postsynaptic currents (sIPSCs and mIPSCs) in the presence of 6,7-dinitroquinoxaline-2,3-dione and dl-2-amino-5-phosphonopentanoic acid to block glutamatergic excitatory synaptic transmission. In both groups, mean sIPSC frequency of dentate granule cells from the saline- and kainate-treated rats was not significantly different. However, mIPSC frequency from the kainate-treated rats of both groups was approximately 30% lower than that of the respective saline controls. The mean amplitude of sIPSCs and mIPSCs from kainate-treated rats was not reduced in either the acute or chronic groups. The mean 10-90% rise time of IPSCs was not altered in kainate-treated rats, but the decay time constant was slightly longer than in controls, and the charge transfer 4-7 days after kainate treatment was significantly larger. The similar reduction of mIPSC frequency (i.e., approximately 30%) in the two groups of kainate-treated rats suggests a decreased inhibitory input to dentate granule cells (presumably due to a partial loss of inhibitory interneurons that innervate them) without recovery during epileptogenesis. The lack of effect on sIPSC frequency and the decreased mIPSC frequency in both groups suggests a possible compensatory increase in firing rate of interneurons, which may involve a hypothetical reduction of inhibitory input to the remaining interneurons.

Cell type-specific synaptic dynamics of synchronized bursting in the juvenile CA3 rat hippocampus.

Spontaneous synchronous bursting of the CA3 hippocampus in vitro is a widely studied model of physiological and pathological network synchronization. The role of inhibitory conductances during network bursting is not understood in detail, despite the fact that several antiepileptic drugs target GABA(A) receptors. Here, we show that the first manifestation of a burst event is a cell type-specific flurry of GABA(A) receptor-mediated inhibitory input to pyramidal cells, but not to stratum oriens horizontal interneurons. Moreover, GABA(A) receptor-mediated synaptic input is proportionally smaller in these interneurons compared with pyramidal cells. Computational models and dynamic-clamp studies using experimentally derived conductance waveforms indicate that both these factors modulate spike timing during synchronized activity. In particular, the different kinetics and the larger strength of GABAergic input to pyramidal cells defer action potential initiation and contribute to the observed delay of firing, so that the interneuronal activity leads the burst cycle. In contrast, excitatory inputs to both neuronal populations during a burst are kinetically similar, as required to maintain synchronicity. We also show that the natural pattern of activation of inhibitory and excitatory conductances during a synchronized burst cycle is different within the same neuronal population. In particular, GABA(A) receptor-mediated currents activate earlier and outlast the excitatory components driving the bursts. Thus, cell type-specific balance and timing of GABA(A) receptor-mediated input are critical to set the appropriate spike timing in pyramidal cells and interneurons and coordinate additional neurotransmitter release modulating burst strength and network frequency.

Neonatal NMDA receptor blockade disturbs neuronal migration in rat somatosensory cortex in vivo.

Glutamate plays an important role in the control of neuronal migration in the developing cerebral cortex. The present study describes changes in the structure and function of the cerebral cortex after transient blockade of N-methyl-D-aspartate (NMDA) receptors during the late period of neuronal migration. Elvax slices containing the NMDA antagonist MK801 were placed over the somatosensory cortex of newborn rats and the drug was released over a period of 2-3 days. After survival times of 1 or 2 weeks, neuroanatomical and in vitro electrophysiological analyses revealed prominent structural and functional alterations in the cortical region underlying the implant. Cortical lamination was disturbed and heterotopic cell clusters were found in layer I of MK801-treated animals. Morphologically identified pyramidal neurons recorded in MK801-treated cortex revealed late NMDA receptor-mediated synaptic inputs and fragile monosynaptic responses at stimulation frequencies >0.2 Hz. Our data indicate that impairment of NMDA receptors during early corticogenesis induces neuronal migration disorders and delays the functional maturation of the developing cortical network.

Complex interactions between mGluR1 and mGluR5 shape neuronal network activity in the rat hippocampus

Group I metabotropic glutamate receptors (mGluRs) cause increased neuronal excitability that can lead to epileptogenesis and neurodegeneration. Here we have examined how individual members of this subgroup of mGluRs affect synchronised hippocampal synaptic activity under normal and disinhibited conditions similar to those that occur during certain epileptic states. We demonstrate that activation of both mGluR1 and mGluR5 are important in increasing neuronal synaptic excitability by increasing synchrony between cells and driving correlated network activity in circuits that contain, or are devoid of, GABA A receptor-mediated synaptic inputs. The precise patterning of activity that occurs is complex and depends upon: (1) the existing pattern of ongoing network activity prior to mGluR activation; and (2) the relative extent of activation of each mGluR subtype. However, mGluR5 appears to be the principal mGluR subtype that initiates bursting activity irrespective of the inhibitory synaptic tone within the neuronal network.

Analysis of the function of GABA(B) receptors on inhibitory afferent neurons of Purkinje cells in the cerebellar cortex of the rat.

Purkinje cells, the output neurons of the cerebellar cortex, receive inhibitory input from basket, stellate and neighbouring Purkinje cells. The aim of the present study was to clarify the role of GABAB receptors on neurons giving inhibitory input to Purkinje cells. In sagittal slices prepared from the cerebellar vermis of the rat, the GABAB receptor agonist baclofen lowered the frequency and amplitude of spontaneous inhibitory postsynaptic currents (IPSCs) recorded in Purkinje cells. These effects were prevented by the GABAB receptor antagonist CGP 55845. Two mechanisms were involved in the depression of the inhibitory input to Purkinje cells. The first mechanism was suppression of the firing of basket, stellate and Purkinje cells. The second mechanism was presynaptic inhibition of GABA release from terminals of the afferent axons. This was indicated by the finding that baclofen decreased the amplitude of IPSCs occurring in Purkinje cells synchronously with action potentials recorded in basket cells. A further support for the presynaptic inhibition is the observation that baclofen decreased the amplitude of autoreceptor currents which are due to activation of GABAA autoreceptors at axon terminals of basket cells by synaptically released GABA. The presynaptic inhibition was partly due to direct inhibition of the vesicular release mechanism, because baclofen lowered the frequency of miniature IPSCs recorded in Purkinje cells in the presence of cadmium and in the presence of tetrodotoxin plus ionomycin. The results show that activation of GABAB receptors decreased GABAA receptor-mediated synaptic input to cerebellar Purkinje cells both by lowering the firing rate of the inhibitory input neurons and by inhibiting GABA release from their axon terminals with a presynaptic mechanism.

An Update on Estrogen: Higher Cognitive Function, Receptor Mapping, Neurotrophic Effects

An Update on Estrogen: Higher Cognitive Function, Receptor Mapping, Neurotrophic Effects

Spontaneous GABAergic postsynaptic currents in Cajal–Retzius cells in neonatal rat cerebral cortex

Cajal-Retzius cells are among the first neurons appearing during corticogenesis, and play an important role in the establishment of cortical lamination. The variety of neurotransmitter receptors recently found on these cells imply that they are integrated in the neonatal cortical network. To investigate the presence and properties of spontaneous synaptic activity we performed whole-cell patch-clamp recordings from visually identified and biocytin-labelled Cajal-Retzius cells in a tangential slice preparation of neonatal rat cerebral cortex (postnatal days P0-P5). Spontaneous postsynaptic currents (sPSCs) could be observed in about 23% of the cells using a pipette solution containing 136 m M Cl-. The sPSCs occurred at a low frequency (0.07 +/- 0.07 Hz, n = 42 cells), had an average amplitude of 24.3 +/- 12.4 pA (n = 415 events) and could not be divided in subpopulations according to their amplitude distribution or kinetic properties. The sPSCs were blocked by the GABAA antagonist bicuculline (100 microM), while the glutamatergic antagonists (+/-)-2-amino-5-phosphonopentatonic acid (APV, 30 microM) and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 10 microM), as well as tetrodotoxin (1-2 microM), a blocker of voltage-gated sodium-currents, had no significant effect on sPSCs. The incidence rate of sPSCs declined within the age of the rats and no sPSCs could be observed after P4. These results suggest that Cajal-Retzius cells transiently receive action potential-independent and GABA(A) receptor-mediated spontaneous synaptic input, which may contribute to the refinement of cortical circuits.

Effects of oestradiol on hippocampal circuitry.

Oestradiol produces structural and functional changes in hippocampal circuitry of adult female rats. The density of both dendritic spines and axospinous synapses on hippocampal CA1 pyramidal cells is regulated by oestradiol. Additionally, oestradiol-induced differences in synaptic connectivity are paralleled by changes in NMDA receptor binding, immunoreactivity for NMDA receptors and sensitivity to NMDA receptor-mediated synaptic input. Curiously, while oestradiol effects are observed in CA1 pyramidal cells, most evidence indicates that these cells lack genomic oestradiol receptors. In contrast, at least some inhibitory neurons in CA1 do express oestradiol receptors. Others' in vitro studies suggest that oestradiol-induced increases in spine density require an initial decrease in inhibitory (GABAergic) drive onto pyramidal cells. We have used single and double label immunohistochemistry for c-Fos (as a measure of neuronal activation) and glutamic acid decarboxylase 65 (as a marker for inhibitory circuitry) to determine: (1) which hippocampal neuronal populations are activated by oestradiol and the time-course of this activation, as well as (2) whether oestradiol affects inhibitory circuitry in vivo as it does in vitro. Our findings are consistent with the suggestion that oestradiol increases dendritic spine density through a mechanism involving disinhibition of pyramidal cells.

Estradiol induces a phasic Fos response in the hippocampal CA1 and CA3 regions of adult female rats.

Previous studies have shown that estradiol induces structural and functional changes in hippocampal CA1 pyramidal cells of the adult female rat. Estradiol increases the density of dendritic spines and axospinous synapses on CA1 pyramidal cells, and increases these cells' sensitivity to NMDA receptor-mediated synaptic input. Curiously, while estradiol effects are observed in CA1 pyramidal cells, the majority of the evidence indicates that these cells lack genomic estradiol receptors. In contrast, genomic estradiol receptors are expressed in at least some hippocampal interneurons in CA1. The goal of the present study was to determine which hippocampal neuronal populations are activated by estradiol, as determined by induction of c-Fos immunoreactivity, as well as the time-course of this activation. We quantified c-Fos expression in each of the major subdivisions of the hippocampus in adult female rats at various time points during the same estradiol treatment regimen known to regulate dendritic spines and synapses on CA1 pyramidal cells. Our results show a phasic estradiol-induced c-Fos response in the pyramidal cell layers of both CA1 and CA3. c-Fos was induced within 2 h of treatment, decreased at 6 and 12 h, and subsequently increased again at 24 h after treatment with estradiol. Double labeling for c-Fos and GAD 65 or GAD 67 suggests that c-Fos is induced primarily in principal cells, though a small proportion of GABAergic cells is also labeled. These estradiol-induced changes in c-Fos expression may reflect phasic neuronal activation and coupling to gene expression, which could be involved in estradiol's effects on excitatory synaptic connectivity in the hippocampus.

Metabotropic glutamate receptor enhancement of spontaneous IPSCs in neocortical interneurons.

Metabotropic glutamate receptor enhancement of spontaneous IPSCs in neocortical interneurons. J. Neurophysiol. 78: 2287-2295, 1997. Using neocortical layer I neurons as a model for GABAergic interneurons, we have studied gamma-aminobutyric acid-A (GABAA) receptor-mediated spontaneous inhibitory postsynaptic currents (IPSCs) and modulation by metabotropic glutamate receptors (mGluRs). In the presence of 0.5 mu M tetrodotoxin (TTX) and ionotropic glutamate receptor antagonists and under symmetrical Cl- conditions, the mean amplitude of miniature IPSCs (mIPSCs) was approximately 50 pA at a holding potential of -70 mV with individual events ranging from 10 to 400 pA. Averaged mIPSCs had a 10-90% rise time of approximately 0.6 ms. The decay was double exponential. The fast component had a time constant of approximately 4 ms and comprised approximately 40% of the total amplitude. The slow component had a time constant of approximately 22 ms. The frequency of spontaneous IPSCs (sIPSCs), recorded in the absence of TTX, was increased by bath application of the mGluR agonist 1S,3R-1-aminocyclopentane-1, 3-dicarboxylic acid (ACPD; 10-100 mu M) or the group I mGluR selective agonist quisqualic acid (Quis; 0.5-1 mu M). Under identical conditions, mIPSCs were not affected. The kinetics of sIPSCs and mIPSCs were not altered by ACPD or Quis. Quis (1 mu M) induced an inward current of approximately 70 pA at a holding potential of -70 mV, whereas ACPD (40-200 mu M) induced a smaller inward current. This current was linear over the voltage range -70 to +30 mV and reversed polarity near 0 mV. In current-clamp recordings, both Quis and ACPD induced a depolarization and action potential firing in layer I and deeper layer interneurons. We conclude that neocortical layer I neurons receive GABAA receptor-mediated inhibitory synaptic inputs. Activation of mGluRs, possibly mGluR1 and/or mGluR5, causes an enhancement of inhibitory synaptic transmission by directly depolarizing corticalGABAergic interneurons through the opening of nonselective cation channels.