Pyramidal Cell Activity Research Articles

Bidirectional Hebbian Plasticity at Hippocampal Mossy Fiber Synapses on CA3 Interneurons

Hippocampal area CA3 is critically involved in the formation of nonoverlapping neuronal subpopulations ("pattern separation") to store memory representations as distinct events. Efficient pattern separation relies on the strong and sparse excitatory input from the mossy fibers (MFs) to pyramidal cells and feedforward inhibitory interneurons. However, MF synapses on CA3 pyramidal cells undergo long-term potentiation (LTP), which, if unopposed, will degrade pattern separation because MF activation will now recruit additional CA3 pyramidal cells. Here, we demonstrate MF LTP in stratum lacunosum-moleculare (L-M) interneurons induced by the same stimulation protocol that induces MF LTP in pyramidal cells. This LTP was NMDA receptor (NMDAR) independent and occurred at MF Ca(2+)-impermeable AMPA receptor synapses. LTP was prevented by with voltage clamping the postsynaptic cell soma during high-frequency stimulation (HFS), intracellular injections of the Ca(2+) chelator BAPTA (20 mm), or bath applications of the L-type Ca(2+) channel blocker nimodipine (10 microm). We propose that MF LTP in L-M interneurons preserves the sparsity of pyramidal cell activation, thus allowing CA3 to maintain its role in pattern separation. In the presence of the mGluR1alpha antagonist LY367385 [(S)-(+)-a-amino-4-carboxy-2-methylbenzeneacetic acid] (100 microm), the same HFS that induces MF LTP in naive slices triggered NMDAR-independent MF LTD. This LTD, like LTP, required activation of the L-type Ca(2+) channel and also was induced after blockade of IP(3) receptors with heparin (4 mg/ml) or the selective depletion of receptor-gated Ca(2+) stores with ryanodine (10 or 100 microm). We conclude that L-M interneurons are endowed with Ca(2+) signaling cascades suitable for controlling the polarity of MF long-term plasticity induced by joint presynaptic and postsynaptic activities.

Potential Network Mechanisms Mediating Electroencephalographic Beta Rhythm Changes during Propofol-Induced Paradoxical Excitation

Propofol, like most general anesthetic drugs, can induce both behavioral and electroencephalographic (EEG) manifestations of excitation, rather than sedation, at low doses. Neuronal excitation is unexpected in the presence of this GABA(A)-potentiating drug. We construct a series of network models to understand this paradox. Individual neurons have ion channel conductances with Hodgkin-Huxley-type formulations. Propofol increases the maximal conductance and time constant of decay of the synaptic GABA(A) current. Networks range in size from 2 to 230 neurons. Population output is measured as a function of pyramidal cell activity, with the electroencephalogram approximated by the sum of population AMPA activity between pyramidal cells. These model networks suggest propofol-induced paradoxical excitation may result from a membrane level interaction between the GABA(A) current and an intrinsic membrane slow potassium current (M-current). This membrane level interaction has consequences at the level of multicellular networks enabling a switch from baseline interneuron synchrony to propofol-induced interneuron antisynchrony. Large network models reproduce the clinical EEG changes characteristic of propofol-induced paradoxical excitation. The EEG changes coincide with the emergence of antisynchronous interneuron clusters in the model networks. Our findings suggest interneuron antisynchrony as a potential network mechanism underlying the generation of propofol-induced paradoxical excitation. As correlates of behavioral phenomenology, these networks may refine our understanding of the specific behavioral states associated with general anesthesia.

Orbitofrontal cortex neurons as a common target for classic and glutamatergic antipsychotic drugs

Until recently, all known antipsychotic drugs were thought to block the dopamine D2 receptor. New evidence that agonists of the metabotropic glutamate 2/3 (mGlu2/3) receptors ameliorate psychotic and affective symptoms of schizophrenia suggests that compounds with different molecular targets may act on a common cellular target to treat schizophrenia. We hypothesized that normalizing the activity of neurons in the orbitofrontal cortex (OFC), a region that is increasingly implicated in the pathophysiology of schizophrenia, presents such a target. We disrupted OFC activity in behaving rats with a use-dependent NMDA antagonist to model the NMDA hypofunction state that may occur in schizophrenia. This systemic treatment increased the activity of most pyramidal cells while inhibiting the activity of putative inhibitory GABA interneurons and increasing behavioral stereotypy. A similar pattern of OFC firing disruption was observed after amphetamine, which models a dopamine hyperactivity state in schizophrenia and which produces a pattern of firing disruption different from those of NMDA antagonists in other prefrontal cortex regions. Antipsychotic drugs haloperidol and clozapine, which target monoamine receptors, as well as an mGlu2/3 agonist and an mGlu5 receptor modulator proposed to have antipsychotic efficacy, reversed the impact of NMDA hypofunction on OFC cells and on behavior. A similar pattern of normalization of OFC activity was observed when treatments were given after amphetamine. Thus, proven or putative antipsychotic drugs with different mechanisms of action similarly reduced the impact of NMDA hypofunction and dopamine hyperfunction on OFC neurons, suggesting that these neurons are a candidate target for the therapeutic effects of antipsychotic medications.

Subunit-Selective Modulation of GABA Type A Receptor Neurotransmission and Cognition in Schizophrenia

Deficits in working memory and cognitive control in schizophrenia are associated with impairments in prefrontal cortical function, including altered gamma band oscillations. These abnormalities are thought to reflect a deficiency in the synchronization of pyramidal cell activity that is dependent, in part, on gamma-aminobutyric acid (GABA) neurotransmission through GABA type A (GABA(A)) receptors containing alpha(2) subunits. The authors conducted a proof-of-concept clinical trial designed to test the hypothesis that a novel compound with relatively selective agonist activity at GABA(A) receptors containing alpha(2) subunits would improve cognitive function and gamma band oscillations in individuals with schizophrenia. Participants were male subjects (N=15) with chronic schizophrenia who were randomly assigned to receive 4 weeks of treatment with the study drug MK-0777, a benzodiazepine-like agent with selective activity at GABA(A) receptors containing alpha(2) or alpha(3) subunits, or a matched placebo in a double-blind fashion. Outcome measures were the Brief Psychiatric Rating Scale (BPRS), Repeatable Battery for the Assessment of Neuropsychological Status, three tests of working memory and/or cognitive control (N-back, AX Continuous Performance Test, and Preparing to Overcome Prepotency), and EEG measures of gamma band oscillations induced during the Preparing to Overcome Prepotency task. Compared with placebo, the MK-0777 compound was associated with improved performance on the N-back, AX Continuous Performance Test, and Preparing to Overcome Prepotency tasks. The compound was also associated with increased frontal gamma band power during the Preparing to Overcome Prepotency task. No effects of the MK-0777 compound were detected in BPRS or Repeatable Battery for the Assessment of Neuropsychological Status scores, with the exception of improvement on the Repeatable Battery for the Assessment of Neuropsychological Status delayed memory index. The MK-0777 agent was well-tolerated. These findings provide preliminary support for the hypothesis that enhanced GABA activity at alpha(2) subunit containing GABA(A) receptors improves behavioral and electrophysiological measures of prefrontal function in individuals with schizophrenia.

Dopaminergic innervation of interneurons in the rat basolateral amygdala

The basolateral nuclear complex of the amygdala (BLC) receives a dense dopaminergic innervation that plays a critical role in the formation of emotional memory. Dopamine has been shown to influence the activity of BLC GABAergic interneurons, which differentially control the activity of pyramidal cells. However, little is known about how dopaminergic inputs interface with different interneuronal subpopulations in this region. To address this question, dual-labeling immunohistochemical techniques were used at the light and electron microscopic levels to examine inputs from tyrosine hydroxylase–immunoreactive (TH+) dopaminergic terminals to two different interneuronal populations in the rat basolateral nucleus labeled using antibodies to parvalbumin (PV) or calretinin (CR). The basolateral nucleus exhibited a dense innervation by TH+ axons. Partial serial section reconstruction of TH+ terminals found that at least 43–50% of these terminals formed synaptic junctions in the basolateral nucleus. All of the synapses examined were symmetrical. In both TH/PV and TH/CR preparations the main targets of TH+ terminals were spines and distal dendrites of unlabeled cells. In sections dual-labeled for TH/PV 59% of the contacts of TH+ terminals with PV+ neurons were synapses, whereas in sections dual-labeled for TH/CR only 13% of the contacts of TH+ terminals with CR+ cells were synapses. In separate preparations examined in complete serial sections for TH+ basket-like innervation of PV+ perikarya, most (76.2%) of TH+ terminal contacts with PV+ perikarya were synapses. These findings suggest that PV+ interneurons, but not CR+ interneurons, are prominent synaptic targets of dopaminergic terminals in the BLC.

Strong coupling between pyramidal cell activity and network oscillations in the olfactory cortex

Oscillatory activity is a prominent characteristic of electrophysiological recordings in the olfactory system and has been proposed to play a key role in encoding olfactory representations. Studies in several systems have shown that some aspects of information coding involve characteristics that intertwine spikes and fast oscillations (in the beta and gamma range) of local field potentials (LFP). In the insect olfactory system, it has been proposed that oscillatory activity could provide a temporal link between cells. Following previous data, we have proposed that gamma band oscillations in mammals could subserve a gating function for the transfer of information between the olfactory bulb (OB) and the anterior piriform cortex (aPC), which are functionally coupled. In this study, we used an electrophysiological approach to investigate the temporal relationship between LFP gamma oscillations and single-unit activity by simultaneously recording LFP and single unit discharges in the rat aPC during odor evoked activity. Our data showed that mean spike discharges and gamma oscillatory bursts were synchronized with the same respiratory cycle epoch (around the inspiration/expiration transition). Temporal correlations between spikes and LFP revealed that cortical cell spikes were tightly phase-coupled with the peak of gamma oscillations and that this phase-coupling was not odor-dependent. Our results suggest that gamma oscillation may act as a temporal filter. Oscillatory phase-coupled spikes in the OB could act in increasing the probability of spike emission in the aPC cell during a narrow time-window, explaining the tight phase-coupling observed in the aPC. The role of spike-LFP phase-coupling as a binding function between odor features is discussed.

(R)-roscovitine, a cyclin-dependent kinase inhibitor, enhances tonic GABA inhibition in rat hippocampus

Pharmacological agents that mediate a persistent GABAergic conductance are of considerable interest for treatment of epilepsy. (R)-roscovitine is a membrane permeable cyclin-dependent kinase inhibitor, designed to block cell division. It is currently undergoing a phase II clinical trial as an anticancer drug. We show that (R)-roscovitine increases a tonic GABA-mediated current in rat hippocampal neurons. This enhanced tonic current appears independent of synaptic GABA release and requires functional transmembrane GABA transport. The effect of (R)-roscovitine is associated with neither modification of GABA A receptors nor protein kinase activity, but is associated with a significant increase in intracellular GABA concentration in hippocampal GABAergic neurons. (R)-roscovitine-induced tonic inhibition significantly suppresses spontaneous spiking activity of hippocampal pyramidal cells. Therefore, (R)-roscovitine is a potent modulator of neuronal activity in rat hippocampus and may provide a tool for preventing paroxysmal activity.

Cortical source estimates of gamma band amplitude and phase are different in schizophrenia

Reductions in gamma band phase synchrony and evoked power have been reported in schizophrenic subjects in response to auditory stimuli. These results have been observed in the EEG at one or two electrode sites. We wished to extend these results using magnetic field data to estimate the responses at the neural generators themselves in each hemisphere. Whole head magnetoencephalographic (MEG) recordings were used to estimate the phase and amplitude behavior of sources in primary auditory cortex in both hemispheres of schizophrenic and comparison subjects. Both ipsi- and contralateral cases were evaluated using a driving (40 Hz modulated 1 kHz carrier) and a non-driving (1 kHz tone) stimulus. We used source space projection (SSP) to collapse the magnetic field data into estimates of the time course of source strengths in individual trials. Complex wavelet based time–frequency decomposition was used to compute inter-trial phase locking factor (PLF), and mean evoked and induced amplitude for each cortical generator. Schizophrenic subjects showed reduced SSP PLF and evoked source strength for contralateral generators responding to the driving stimulus in both hemispheres. For the pure tone stimulus, only the left hemisphere PLF's in the transient window were reduced. In contrast, subjects with schizophrenia exhibited higher induced 40 Hz power to both stimulus types, consistent with the reduced PLF findings. The method of SSP combined with wavelet based complex demodulation produces a significant improvement in signal-to-noise ratio, and directly estimates the activity of the cortical generators responsible for gamma band auditory MEG evoked fields. Schizophrenic subjects exhibit significant impairment of generation and phase locking of this activity in auditory cortex, suggesting an impairment of GABA-ergic inhibitory interneuronal modulation of pyramidal cell activity.

Cell type-specific firing during ripple oscillations in the hippocampal formation of humans.

High-frequency field ripples occur in the rodent hippocampal formation and are assumed to depend on interneuron type-specific firing patterns, structuring the activity of pyramidal cells. Ripples with similar characteristics are also present in humans, yet their underlying cellular correlates are still unknown. By in vivo recording interneurons and pyramidal cells in the human hippocampal formation, we find that cell type-specific firing patterns and phase-locking on a millisecond timescale can be distinguished during ripples. In particular, pyramidal cells fired preferentially at the highest amplitude of the ripple, but interneurons began to discharge earlier than pyramidal cells. Furthermore, a large fraction of cells were phase-locked to the ripple cycle, but the preferred phase of discharge of interneurons followed the maximum discharge probability of pyramidal neurons. These relationships between human ripples and unit activity are qualitatively similar to that observed in vivo in the rodents, suggesting that their underlying mechanisms are similar.

Aged wild-type and APP, PS1, and APP + PS1 mice present similar deficits in associative learning and synaptic plasticity independent of amyloid load

Wild-type and single-transgenic (APP, PS1) and double-transgenic (APP+PS1) mice were studied at three different (3-, 12-, and 18-month-old) age periods. Transgenic mice had reflex eyelid responses like those of controls, but only 3-month-old mice were able to fully acquire conditioned eyeblinks, using a trace paradigm, whilst 12-month-old wild-type and transgenic mice presented intermediate values, and 18-month-old wild-type and transgenic mice were unable to acquire this type of associative learning. 18-month-old wild-type and transgenic mice presented a normal synaptic activation of CA1 pyramidal cells by the stimulation of Schaffer collaterals, but they did not show any activity-dependent potentiation of the CA3–CA1 synapse across conditioning sessions, as was shown by 3-month-old wild-type mice. Moreover, 18-month-old wild-type and transgenic mice presented a noticeable deficit in long-term potentiation evoked in vivo at the hippocampal CA3–CA1 synapse. The 18-month-old wild-type and transgenic mice also presented a significant deficit in prepulse inhibition as compared with 3-month-old controls. Except for results collected by prepulse inhibition, the above-mentioned deficits were not related with the presence of amyloid β deposits. Thus, learning and memory deficits observed in aged wild-type and transgenic mice are not directly related to the genetic manipulations or to the presence of amyloid plaques.

Changes in hippocampal function of ovariectomized rats after sequential low doses of estradiol to simulate the preovulatory estrogen surge

In adult female rats, robust hippocampal changes occur when estradiol rises on the morning of proestrus. Whether estradiol mediates these changes, however, remains unknown. To address this issue, we used sequential injections of estradiol to simulate two key components of the preovulatory surge: the rapid rise in estradiol on proestrous morning, and the slower rise during the preceding day, diestrus 2. Animals were examined mid-morning of simulated proestrus, and compared to vehicle-treated or intact rats. In both simulated and intact rats, CA1-evoked responses were potentiated in hippocampal slices, and presynaptic mechanisms appeared to contribute. In CA3, multiple population spikes were evoked in response to mossy fiber stimuli, and expression of brain-derived neurotrophic factor was increased. Simulation of proestrous morning also improved performance on object and place recognition tests, in comparison to vehicle treatment. Surprisingly, effects on CA1-evoked responses showed a dependence on estradiol during simulated diestrus 2, as well as a dependence on proestrous morning. Increasing estradiol above the physiological range on proestrous morning paradoxically decreased evoked responses in CA1. However, CA3 pyramidal cell activity increased further, and became synchronized. Together, the results confirm that physiological estradiol levels are sufficient to profoundly affect hippocampal function. In addition: (i) changes on proestrous morning appear to depend on slow increases in estradiol during the preceding day; (ii) effects are extremely sensitive to the peak serum level on proestrous morning; and (iii) there are striking subfield differences within the hippocampus.

High-dose glycine inhibits the loudness dependence of the auditory evoked potential (LDAEP) in healthy humans

The loudness dependence of the auditory evoked Potential (LDAEP) has been suggested to be a putative marker of central serotonin function, with reported abnormalities in clinical disorders presumed to reflect serotonin dysfunction. Despite considerable research, very little is known about the LDAEP's sensitivity to other neurotransmitter systems. Given the role of N-methyl-D-aspartate (NMDA) receptors in modulating pyramidal cell activity in cortico-cortico and thalamo-cortical loops, we examined the effect of targeting the glycine modulatory site of the NMDA receptor with high-dose glycine on the LDAEP in healthy subjects. The study was a double-blind, placebo-controlled repeated-measures design in which 14 healthy participants were tested under two acute treatment conditions, placebo and oral glycine (0.8 g/kg). Changes in the amplitude of the N1/P2 at varying intensities (60, 70, 80, 90, 100 dB) were examined at C(Z). Compared to placebo, high-dose glycine induced a weaker LDAEP (a pronounced decrease in the slope of the N1/P2 with increasing tone loudness; p < 0.02). While the exact mechanism responsible for the effects of glycine on the LDAEP are not known, the findings suggest an inhibitory effect in the cortex, possibly via activation of NMDA receptors on GABA interneurons or inhibitory glycine receptors. The findings add to the growing literature exhibiting modulation of the LDAEP by multiple neurochemical systems in addition to the serotonergic system.

EEG Sharp Waves and Sparse Ensemble Unit Activity in the Macaque Hippocampus

Neural unit activity and EEGs were recorded from inferior temporal regions of three rhesus macaques chronically implanted with "hyperdrives" holding 12 individually movable tetrodes. Recordings were made from each monkey over a period of approximately 3 mo, while the electrodes were moved by small increments through the hippocampus and neighboring structures. After recording, the monkeys were necropsied, and the brains were sectioned and Nissl-stained, permitting identification of individual electrode tracks. The results establish that hippocampal pyramidal cells are "complex spike cells," firing at overall average rates of approximately 0.3 Hz, with spike trains consisting of long periods of silence interspersed with bursts of activity. The results also establish that the monkey hippocampal EEG shows "sharp wave" events consisting of a high-frequency "ripple" oscillation ( approximately 110 Hz) together with a large slow-wave EEG deflection lasting several hundred milliseconds. The evidence suggests that monkey sharp waves are probably generated mainly in the CA1 region and that sharp waves are associated with an inactive/drowsy-or-sleeping behavioral state, which is also associated with increased hippocampal pyramidal cell activity and increased hippocampal EEG amplitude. The results of this initial study of ensembles of primate hippocampal neurons are consistent with previous studies in rodents and consistent with the hypothesis that theories and models of hippocampal memory function developed on the basis of rat data may be applicable to a wide range of mammalian species.

Spike Timing of Lacunosom-Moleculare Targeting Interneurons and CA3 Pyramidal Cells During High-Frequency Network Oscillations In Vitro

Network activity in the 200- to 600-Hz range termed high-frequency oscillations (HFOs) has been detected in epileptic tissue from both humans and rodents and may underlie the mechanism of epileptogenesis in experimental rodent models. Slower network oscillations including theta and gamma oscillations as well as ripples are generated by the complex spike timing and interactions between interneurons and pyramidal cells of the hippocampus. We determined the activity of CA3 pyramidal cells, stratum oriens lacunosum-moleculare (O-LM) and s. radiatum lacunosum-moleculare (R-LM) interneurons during HFO in the in vitro low-Mg(2+) model of epileptiform activity in GIN mice. In these animals, interneurons can be identified prior to cell-attached recordings by the expression of green-fluorescent protein (GFP). Simultaneous local field potential recordings from s. pyramidale and on-cell recordings of individual interneurons and principal cells revealed three primary firing behaviors of the active cells: 36% of O-LM interneurons and 60% of pyramidal cells fired action potentials at high frequencies during the HFO. R-LM interneurons were biphasic in that they fired at high frequency at the beginning of the HFO but stopped firing before its end. When considering only the highest frequency component of the oscillations most pyramidal cells fired on the rising phase of the oscillation. These data provide evidence for functional distinction during HFOs within otherwise homogeneous groups of O-LM interneurons and pyramidal cells.

Theta phase precession emerges from a hybrid computational model of a CA3 place cell

The origins and functional significance of theta phase precession in the hippocampus remain obscure, in part, because of the difficulty of reproducing hippocampal place cell firing in experimental settings where the biophysical underpinnings can be examined in detail. The present study concerns a neurobiologically based computational model of the emergence of theta phase precession in which the responses of a single model CA3 pyramidal cell are examined in the context of stimulation by realistic afferent spike trains including those of place cells in entorhinal cortex, dentate gyrus, and other CA3 pyramidal cells. Spike-timing dependent plasticity in the model CA3 pyramidal cell leads to a spatially correlated associational synaptic drive that subsequently creates a spatially asymmetric expansion of the model cell's place field. Following an initial training period, theta phase precession can be seen in the firing patterns of the model CA3 pyramidal cell. Through selective manipulations of the model it is possible to decompose theta phase precession in CA3 into the separate contributing factors of inheritance from upstream afferents in the dentate gyrus and entorhinal cortex, the interaction of synaptically controlled increasing afferent drive with phasic inhibition, and the theta phase difference between dentate gyrus granule cell and CA3 pyramidal cell activity. In the context of a single CA3 pyramidal cell, the model shows that each of these factors plays a role in theta phase precession within CA3 and suggests that no one single factor offers a complete explanation of the phenomenon. The model also shows parallels between theta phase encoding and pattern completion within the CA3 autoassociative network.

Inhibition and Timing in Cortical Neural Circuits

Back to table of contents Previous article Next article Images in NeuroscienceFull AccessInhibition and Timing in Cortical Neural CircuitsGuillermo Gonzalez-Burgos PH.D.Takanori Hashimoto M.D., PH.D.David A. Lewis M.D.,Guillermo Gonzalez-Burgos PH.D.Search for more papers by this authorTakanori Hashimoto M.D., PH.D.Search for more papers by this authorDavid A. Lewis M.D.Search for more papers by this author,Published Online:1 Jan 2007AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail Excitatory pyramidal cells convey to other brain regions the neural signals generated by the local circuits in each cortical area. Pyramidal cell activity is strongly modulated by interneurons that utilize the inhibitory neurotransmitter GABA. Subclasses of cortical interneurons are defined by several characteristics. Biochemically, some interneurons express the calcium-binding proteins parvalbumin (PV) or calretinin (CR), whereas others contain the neuropeptide somatostatin (SST). Morphologically, the axons of SST neurons target pyramidal cell dendrites, whereas the GABA synapses formed by PV neurons are found at or close to pyramidal cell bodies (panel A). For example, as shown in panel B, the axons of PV-containing chandelier neurons (black arrow) make multiple synaptic contacts (small arrows) at the pyramidal cell axon initial segment (red arrow). Anatomically, these three subclasses of interneurons have differential distributions across the six layers of the neocortex, as illustrated by the distinctive expression patterns of their messenger RNAs (panel C). Electrophysiologically, PV neurons are called fast-spiking (FS), since during sustained stimulation they fire fast action potentials at a constant interval (panel D). In contrast, non-FS neurons, such as the SST neurons, fire slower action potentials at progressively longer intervals.In interneurons, the discharge of an action potential (black traces in panel E) triggers synaptic GABA release, which activates GABA-A receptors in the targeted pyramidal cell and produces an inhibitory postsynaptic potential (IPSP). The IPSPs generated by FS/PV neurons have a large amplitude and fast time course (top red trace), reflecting the perisomatic location of the synaptic contacts. In contrast, IPSPs generated by dendrite-targeting non-FS/SST neurons are small and slow at the pyramidal cell body (bottom red trace), indicating that their physiological inhibitory effect is strongest in the dendrites. Interneuron-mediated inhibition does not simply constrain pyramidal cell excitation but precisely controls the timing of pyramidal cell firing, causing large groups of nearby pyramidal cells to oscillate between active and silent states. GABA neuron activity induces rhythms of different frequencies, with each oscillation frequency apparently involving different interneuron subclasses. The synaptic signaling by cell body-targeting PV neurons and by dendritic-targeting SST neurons appears to be impaired in schizophrenia, suggesting that the alterations in circuit oscillations and neuronal synchrony observed in the illness are due, at least in part, to selective disturbances in GABA transmission mediated by these interneuron subtypes. Because neuronal synchrony increases the efficacy of synaptic communication within and between cortical areas, interneuron alterations in schizophrenia are likely to have substantial effects on cognitive processes that are dependent on the integration of neural signals across the neocortex. Pittsburgh, Pa.Address reprint requests to Dr. Tamminga, UT Southwestern Medical Center, Department of Psychiatry, 5323 Harry Hines Blvd., #NE5.110, Dallas, TX 75390-9070; [email protected] (e-mail). FiguresReferencesCited byDetailsCited ByPLOS ONE, Vol. 10, No. 6Neuroscience, Vol. 189Neuropsychopharmacology, Vol. 33, No. 1 Volume 164Issue 1 January, 2007Pages 12-12THE AMERICAN JOURNAL OF PSYCHIATRY January 2007 Volume 164 Number 1 Metrics PDF download History Published online 1 January 2007 Published in print 1 January 2007

Homosynaptic and heterosynaptic modes of endocannabinoid action at hippocampal CCK+ basket cell synapses

Hippocampal interneuron subtypes exhibit remarkable diversity in their morphological, intrinsic and synaptic properties, converging to yield precision in the dynamics of firing during in vivo oscillatory activity (Somogyi & Klausberger, 2005). The basket cell, a type of interneuron specialized to innervate the perisomatic regions of principal cells, comprises two neurochemically distinct and mutually exclusive cell populations, which are either parvalbumin positive (PV+) or cholecystokinin positive (CCK+). Though morphologically similar in dendritic and axonal arborizations, profound immunocytochemical, physiological and synaptic differences exist between CCK+ and PV+ basket cell populations (Hefft & Jonas, 2005; Glickfeld & Scanziani, 2006). In response to afferent stimulation of the Schaeffer collaterals in vitro, PV+ basket cells are readily entrained to provide fast feedfoward GABAergic transmission to principal cell targets (Glickfeld & Scanziani, 2006). In contrast, afferent excitation of CCK+ basket cells is weaker and more transient, often requiring the integration of independent afferent pathways to engage CCK+ basket cells in feedback inhibition (Glickfeld & Scanziani, 2006). These differences fit with the suggestion that PV+ basket cells are well suited to provide rapid, reliable feedforward inhibition to pyramidal cells for sustaining intrinsic network oscillations (‘rhythm’). In contrast, CCK+ basket cells may act as an interface between the intrinsic hippocampal hardware and emotional centres of the brain; their extrinsic neuromodulation would confer emotional context to the spatial information being processed (‘mood’; Freund, 2003). A striking feature of CCK+ basket cells is their capacity to be modulated by endogenous endocannabinoids, which are generated in postsynaptic pyramidal cells upon depolarization, or through activation of G-protein coupled receptors (GPCRs) such as muscarinic (mAChRs) or metabotropic glutamate receptors (mGluRs). Once produced, endocannabioids are liberated to diffuse retrogradely across the synapse to bind CB1 receptors present on presynaptic CCK+ terminals, resulting in the inhibition of GABA release. In contrast, CB1 receptors are largely absent from PV+ basket cell terminals. This phasic mechanism, termed depolarization-induced suppression of inhibition (DSI), is well understood (Wilson & Nicoll, 2002), but less is known about whether endocannabinoids might also tonically modulate CCK+ interneurons. In the current issue of The Journal of Physiology, Neu et al. (2007) offer unprecedented resolution of how single CA1 CCK+ basket cells might be tonically modulated by endocannabinoids. In a series of technically demanding experiments, the authors performed whole cell recordings between pairs of neurochemically identified, monosynaptically connected CCK+ basket cells and CA1 pyramidal cells, thereby avoiding the confounding influence of PV+ cells and other cell types. The authors definitively showed that basal levels of endocannabinoids present tonically modulate GABAergic transmission at a subset of CCK+ basket cell terminals. Interestingly, the CB1 receptor-dependent tonic modulation was completely blocked by buffering calcium in the postsynaptic cell with 10 mm BAPTA, pointing to the postsynaptic cell as the sole source of endocannabinoid generation (Fig. 1). Apparently, basal levels of endocannabinoids released from nearby pyramidal cells cannot diffuse to the recorded CCK basket cell to tonically block presynaptic CB1 receptors. This homosynaptic mechanism contrasts sharply with the findings of Wilson & Nicoll (2001), who demonstrated through simultaneous pyramidal cell recordings that depolarizing one pyramidal cell caused a heterosynaptic depression of GABA release onto an adjacent non-depolarized pyramidal cell. Under different circumstances, Neu et al. (2007) also find evidence for heterosynaptic depression: with 10 mm BAPTA in the postsynaptic cell, exogenous activation of mAChRs induces presynaptic CB1 receptor activation, suggesting that mAChR activation induces ‘spill over’ of endocannabinoids from neighbouring pyramidal cells (Fig. 1). One alternative interpretation is that mAChR-induced release of endocannabinoids is relatively calcium-independent. Future experiments may distinguish between heterosynaptic and calcium-independent homosynaptic mechanisms by preventing GPCR-dependent endocannabinoid generation postsynaptically. In any case, regardless of whether GPCRs utilize a different route for endocannabinoid synthesis, global GPCR activation would be expected to strongly depolarize many CA1 pyramidal cells, which could then induce heterosynaptic effects via a classic calcium-dependent, DSI-like mechanism. Figure 1 Homosynaptic vs. heterosynaptic modes of endocannabinoid action Homosynaptic and heterosynaptic modes of endocannabinoid action pose intriguing questions regarding the impact of CCK+ basket cell-mediated inhibition in the context of other interneuronal networks, as well as their overall effect on excitability in the hippocampal network. How do tonic, DSI-like, and GPCR-mediated endo-cannabinoid signalling modes alter the balance of GABAergic inhibition? Are each of these modes associated with dynamic shifts in how CCK+ and PV+ basket cells shape the oscillatory activity of pyramidal cells? Finally, are these modes of endo-cannabinoid mobilization operative under in vivo conditions? Although the answers to these questions await further investigation, the findings of Neu et al. provide a useful framework for understanding how different conditions and possibly sources of endo-cannabinoids might be mobilized to alter CCK+ interneuron-mediated inhibition within the hippocampal network.

The activation of prefrontal cortical neurons in aggression—A double labeling study

Violence is associated with prefrontal deficits in humans, suggesting that this brain area inhibits aggressiveness. Its role, however, remains controversial, as certain subdivisions of the prefrontal cortex become activated by fights in rodents. Disparate human findings also show that this area is acutely activated by aggression under certain conditions. We explored prefrontal neuronal activation patterns in resident rats exposed to psychosocial (sensory contact with the intruder) and aggressive encounters. Both psychosocial and aggressive encounters increased c-Fos activation in the prelimbic (PrL), anterior cingular (Cg1), agranular insular (AI), ventral (VO) and lateral orbital (LO) cortices. The infralimbic (IL) and medial orbital (MO) cortices were activated significantly by aggressive encounters only. No other prefrontal regions were activated by psychosocial or aggressive encounters. The overwhelming majority of activated cells were pyramidal (glutamatergic) cells in the Cg1, IL, PrL, MO, and VO, whereas interneuron and pyramidal cell activation was similar in AI and LO. When rats showed violent aggression, the activation of GABAergic inhibitory cells decreased in these two, and two other areas (IL and MO). Notably, the latter two areas appeared to be specifically involved in aggressive behavior. The change occurred in a recently developed model of violent aggression. In this model, pyramidal cell activation in the above mentioned four areas (IL, MO, AI, and LO) predicted over 95% of variation in attack counts in general and violent attacks in particular. Based on these data, we present a tentative hypothesis on the involvement of the prefrontal cortex in the control of aggression.

GABAA receptor diversity and pharmacology

Because of its control of spike-timing and oscillatory network activity, gamma-aminobutyric acid (GABA)-ergic inhibition is a key element in the central regulation of somatic and mental functions. The recognition of GABA(A) receptor diversity has provided molecular tags for the analysis of distinct neuronal networks in the control of specific pharmacological and physiological brain functions. Neurons expressing alpha(1)GABA(A) receptors have been found to mediate sedation, whereas those expressing alpha(2)GABA(A) receptors mediate anxiolysis. Furthermore, associative temporal and spatial memory can be regulated by modulating the activity of hippocampal pyramidal cells via extrasynaptic alpha(5)GABA(A) receptors. In addition, neurons expressing alpha(3)GABA(A) receptors are instrumental in the processing of sensory motor information related to a schizophrenia endophenotype. Finally, during the postnatal development of the brain, the maturation of GABAergic interneurons seems to provide the trigger for the experience-dependent plasticity of neurons in the visual cortex, with alpha(1)GABA(A) receptors setting the time of onset of a critical period of plasticity. Thus, particular neuronal networks defined by respective GABA(A) receptor subtypes can now be linked to the regulation of various clearly defined behavioural patterns. These achievements are of obvious relevance for the pharmacotherapy of certain brain disorders, in particular sleep dysfunctions, anxiety disorders, schizophrenia and diseases associated with memory deficits.

Hippocampal CA1 spiking during encoding and retrieval: Relation to theta phase

The hippocampal theta rhythm is a prominent oscillation in the field potential observed throughout the hippocampus as a rat investigates stimuli in the environment. A recent computational model [Hasselmo, M. E., Bodelon, C., & Wyble, B. P. (2002a). A proposed function for hippocampal theta rhythm: separate phases of encoding and retrieval enhance reversal of prior learning. Neural Computation, 14, 793–817. Neuromodulation, theta rhythm and rat spatial navigation. Neural Networks, 15, 689–707] suggested that the theta rhythm allows the hippocampal formation to alternate rapidly between conditions that promote memory encoding (strong synaptic input from entorhinal cortex to areas CA3 and CA1) and conditions that promote memory retrieval (strong synaptic input from CA3 to CA1). That model predicted that the preferred theta phase of CA1 spiking should differ for information being encoded versus information being retrieved. In the present study, the spiking activity of CA1 pyramidal cells was recorded while rats performed either an odor-cued delayed nonmatch-to-sample recognition memory test or an object recognition memory task based on the animal’s spontaneous preference for novelty. In the test period of both tasks, the preferred theta phase exhibited by CA1 pyramidal cells differed between moments when the rat inspected repeated (match) and non-repeated (nonmatch) items. Also in the present study, additional modeling work extended the previous model to address the mean phase of CA1 spiking associated with stimuli inducing varying levels of retrieval relative to encoding, ranging from novel nonmatch stimuli with no retrieval to highly familiar repeated stimuli with extensive retrieval. The modeling results obtained here demonstrated that the experimentally observed phase differences are consistent with different levels of CA3 synaptic input to CA1 during recognition of repeated items.