C1q, a member of the immune complement cascade, is implicated in the selective pruning of synapses by microglial phagocytosis. C1q-mediated synapse elimination has been shown to occur during brain ...development, while increased activation and complement-dependent synapse loss is observed in neurodegenerative diseases. However, the molecular mechanisms underlying C1q-controlled synaptic pruning are mostly unknown. This study addresses distortions in the synaptic proteome leading to C1q-tagged synapses. Our data demonstrated the preferential localization of C1q to the presynapse. Proteomic investigation and pathway analysis of C1q-tagged synaptosomes revealed the presence of apoptotic-like processes in C1q-tagged synapses, which was confirmed experimentally with apoptosis markers. Moreover, the induction of synaptic apoptotic-like mechanisms in a model of sensory deprivation-induced synaptic depression led to elevated C1q levels. Our results unveiled that C1q label-based synaptic pruning is triggered by and directly linked to apoptotic-like processes in the synaptic compartment.
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Information processing in the hippocampus critically relies on its reciprocal interaction with the medial septum (MS). Synchronization of the septo-hippocampal system was demonstrated during both ...major hippocampal activity states, the regular theta rhythm and the large amplitude irregular activity. Previous experimental and modeling data suggest that the MS provides rhythmic drive to the hippocampus, and hippocampo-septal feedback synchronizes septal pacemaker units. However, this view has recently been questioned based on the possibility of intrahippocampal theta genesis. Previously, we identified putative pacemaker neurons expressing parvalbumin (PV) and/or the pacemaker hyperpolarization-activated and cyclic nucleotide-gated nonselective cation channel (HCN) in the MS. In this study, by analyzing the temporal relationship of activity between the PV/HCN-containing medial septal neurons and hippocampal local field potential, we aimed to uncover whether the sequence of events during theta formation supports the classic view of septal drive or the challenging theory of hippocampal pacing of theta. Importantly, by implementing a circular statistical method, a temporal lead of these septal neurons over the hippocampus was observed on the course of theta synchronization. Moreover, the activity of putative hippocampal interneurons also preceded hippocampal local field theta, but by a shorter time period compared with PV/HCN-containing septal neurons. Using the concept of mutual information, the action potential series of PV/HCN-containing neurons shared higher amount of information with hippocampal field oscillation than PV/HCN-immunonegative cells. Thus, a pacemaker neuron population of the MS leads hippocampal activity, presumably via the synchronization of hippocampal interneurons.
Neuropeptides acting on pre- and postsynaptic receptors are coreleased with GABA by interneurons including bistratified and O-LM cells, both expressing somatostatin but innervating segregated ...dendritic domains of pyramidal cells. Neuropeptide release requires high-frequency action potentials, but the firing patterns of most peptide/GABA-releasing interneurons during behavior are unknown. We show that behavioral and network states differentiate the activities of bistratified and O-LM cells in freely moving rats. Bistratified cells fire at higher rates during sleep than O-LM cells and, unlike O-LM cells, strongly increase spiking during sharp wave-associated ripples (SWRs). In contrast, O-LM interneurons decrease firing during sleep relative to awake states and are mostly inhibited during SWRs. During movement, both cell types fire cooperatively at the troughs of theta oscillations but with different frequencies. Somatostatin and GABA are differentially released to distinct dendritic zones of CA1 pyramidal cells during sleep and wakefulness to coordinate segregated glutamatergic inputs from entorhinal cortex and CA3.
•Bistratified and O-LM cells release GABA and somatostatin to distinct dendrites•During movement the two cells cooperate temporally but fire at different frequencies•During sleep bistratified cells are strongly active, O-LM cells decrease firing•Behavior differentiates GABA and somatostatin release to distinct dendritic zones
Katona et al. demonstrate that behavioral and network states differentiate the firing of somatostatin-expressing bistratified and O-LM interneurons in freely moving rats. Segregated glutamatergic inputs to pyramidal cells in CA1 from entorhinal cortex and CA3 are differentially modulated by GABA and somatostatin.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Parvalbumin-expressing basket cells tightly control cortical networks and fire remarkably stereotyped during network oscillations and simple behaviors. How can these cells support multifaceted ...situations with different behavioral options and complex temporal sequences? We recorded from identified parvalbumin-expressing basket cells in prefrontal cortex of freely moving rats performing a multidimensional delayed cue-matching-to-place task, juxtacellularly filled recorded neurons for unequivocal histological identification, and determined their activity during temporally structured task episodes, associative working-memory, and stimulus-guided choice behavior. We show that parvalbumin-expressing basket cells do not fire homogenously, but individual cells were recruited or inhibited during different task episodes. Firing of individual basket cells was correlated with amount of presynaptic VIP (vasoactive intestinal polypeptide)-expressing GABAergic input. Together with subsets of pyramidal neurons, activity of basket cells differentiated for sequential actions and stimulus-guided choice behavior. Thus, interneurons of the same cell type can be recruited into different neuronal ensembles with distinct firing patterns to support multi-layered cognitive computations.
•PV+ basket cells do not fire homogenously during a delayed cue-matching-to-place task•Their firing differentiates between distinct task episodes or choice behavior•Firing of individual basket cells is correlated with their amount of VIP+ input•Firing patterns are impaired during task performance without memory content
Lagler et al. (2016) recorded from identified parvalbumin-expressing basket cells in prefrontal cortex while rats performed a delayed cue-matching-to-place task. They show that these interneurons segregate into neuronal ensembles with different firing patterns and synaptic connectivity differentiating task sequences and choice behavior.
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Cortical information processing is under state-dependent control of subcortical neuromodulatory systems. Although this modulatory effect is thought to be mediated mainly by slow nonsynaptic ...metabotropic receptors, other mechanisms, such as direct synaptic transmission, are possible. Yet, it is currently unknown if any such form of subcortical control exists. Here, we present direct evidence of a strong, spatiotemporally precise excitatory input from an ascending neuromodulatory center. Selective stimulation of serotonergic median raphe neurons produced a rapid activation of hippocampal interneurons. At the network level, this subcortical drive was manifested as a pattern of effective disynaptic GABAergic inhibition that spread throughout the circuit. This form of subcortical network regulation should be incorporated into current concepts of normal and pathological cortical function.
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Pyramidal cells of the ventral hippocampal CA1 area have numerous and diverse distant projections to other brain regions including the temporal and parietal association areas, visual, auditory, ...olfactory, somatosensory, gustatory, and visceral areas, and inputs to the amygdalar and prefrontal-orbital-agranular insular region. In addition, their differential expression of proteins like calbindin provides further indications for cellular diversity. This raises the possibility that the pyramidal cells may form subpopulations participating in different brain circuitries. To address this hypothesis we applied the juxtacellular labeling technique to fill individual pyramidal cells in the ventral hippocampus with neurobiotin in urethane anesthetized rats. For each labeled pyramidal cell we determined soma location, dendritic arborizations and selective expression of calbindin and norbin. Reconstruction and mapping of long-range axonal projections were made with the Neurolucida system. We found three major routes of ventral CA1 pyramidal cell projections. The classical pathway run caudo-ventrally across and innervating the subiculum, further to the parahippocampal regions and then to the deep and superficial layers of entorhinal cortex. The other two pathways avoided subiculum by branching from the main axon close to the soma and either traveled antero- and caudo-ventrally to amygdaloid complex, amygdalopiriform-transition area and parahippocampal regions or run antero-dorsally through the fimbria-fornix to the septum, hypothalamus, ventral striatum and olfactory regions. We found that most pyramidal cells investigated used all three major routes to send projecting axons to other brain areas. Our results suggest that the information flow through the ventral hippocampus is distributed by wide axonal projections from the CA1 area.
Center for Molecular and Behavioral Neuroscience, Rutgers, The
State University of New Jersey, Newark, New Jersey 07102
Henze, Darrell A.,
Zsolt Borhegyi,
Jozsef Csicsvari,
Akira Mamiya,
Kenneth D. ...Harris, and
György Buzsáki.
Intracellular Features Predicted by Extracellular Recordings in
the Hippocampus In Vivo. J. Neurophysiol. 84: 390-400, 2000. Multichannel tetrode array recording in
awake behaving animals provides a powerful method to record the
activity of large numbers of neurons. The power of this method could be
extended if further information concerning the intracellular state of
the neurons could be extracted from the extracellularly recorded
signals. Toward this end, we have simultaneously recorded intracellular and extracellular signals from hippocampal CA1 pyramidal cells and
interneurons in the anesthetized rat. We found that several intracellular parameters can be deduced from extracellular spike waveforms. The width of the intracellular action potential is defined
precisely by distinct points on the extracellular spike. Amplitude
changes of the intracellular action potential are reflected by changes
in the amplitude of the initial negative phase of the extracellular
spike, and these amplitude changes are dependent on the state of the
network. In addition, intracellular recordings from dendrites with
simultaneous extracellular recordings from the soma indicate that, on
average, action potentials are initiated in the perisomatic region and
propagate to the dendrites at 1.68 m/s. Finally we determined that a
tetrode in hippocampal area CA1 theoretically should be able to record
electrical signals from ~1,000 neurons. Of these, 60-100 neurons
should generate spikes of sufficient amplitude to be detectable from
the noise and to allow for their separation using current spatial
clustering methods. This theoretical maximum is in contrast to the
approximately six units that are usually detected per tetrode. From
this, we conclude that a large percentage of hippocampal CA1 pyramidal cells are silent in any given behavioral condition.
Septo-hippocampal GABAergic neurons immunoreactive for parvalbumin are thought to play a crucial role in the generation of hippocampal theta oscillations associated with a specific stage of memory ...formation. Here we use in vivo juxtacellular recording and filling in the medial septum followed by immunocytochemical identification of the recorded cells containing parvalbumin to determine their firing pattern, phase relationship with hippocampal theta, morphology, and to thereby reveal their involvement in the generation of hippocampal theta activity. We have demonstrated that GABAergic medial septal neurons form two distinct populations exhibiting highly regular bursting activity that is tightly coupled to either the trough (178 degrees ) or the peak (330 degrees ) of hippocampal theta waves. Additionally, different types of bursting as well as nonbursting activity patterns were also observed. The morphological reconstruction of theta-bursting neurons revealed extensive axon arbors of these cells with numerous local collaterals establishing symmetrical synapses; thus, synchrony among the septal pacemaker units may be brought about by their recurrent collateral interactions. Long projecting axons could also be found running dorsally toward the hippocampus and ventrally in the direction of basal forebrain regions. We conclude that GABAergic neurons in the medial septum, which are known to selectively innervate hippocampal interneurons, are in a position to induce rhythmic disinhibition in the hippocampus and other theta-related subcortical areas at two different phases of hippocampal theta.
The medial septum (MS) is an indispensable component of the subcortical network which synchronizes the hippocampus at theta
frequency during specific stages of information processing. GABAergic ...neurons exhibiting highly regular firing coupled to
the hippocampal theta rhythm are thought to form the core of the MS rhythm-generating network. In recent studies the hyperpolarization-activated,
cyclic nucleotide-gated non-selective cation (HCN) channel was shown to participate in theta synchronization of the medial
septum. Here, we tested the hypothesis that HCN channel expression correlates with theta modulated firing behaviour of MS
neurons by a combined anatomical and electrophysiological approach. HCN-expressing neurons represented a subpopulation of
GABAergic cells in the MS partly overlapping with parvalbumin (PV)-containing neurons. Rhythmic firing in the theta frequency
range was characteristic of all HCN-expressing neurons. In contrast, only a minority of HCN-negative cells displayed theta
related activity. All HCN cells had tight phase coupling to hippocampal theta waves. As a group, PV-expressing HCN neurons
had a marked bimodal phase distribution, whereas PV-immunonegative HCN neurons did not show group-level phase preference despite
significant individual phase coupling. Microiontophoretic blockade of HCN channels resulted in the reduction of discharge
frequency, but theta rhythmic firing was perturbed only in a few cases. Our data imply that HCN-expressing GABAergic neurons
provide rhythmic drive in all phases of the hippocampal theta activity. In most MS theta cells rhythm genesis is apparently
determined by interactions at the level of the network rather than by the pacemaking property of HCN channels alone.
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The nucleus accumbens (NAc) is positioned to integrate signals originating from limbic and cortical areas and to modulate reward-related motor output of various goal-directed behaviours. The major ...target of the NAc GABAergic output neurons is the ventral pallidum (VP). VP is part of the reward circuit and controls the ascending mesolimbic dopamine system, as well as the motor output structures and the brainstem. The excitatory inputs governing this system converge in the NAc from the prefrontal cortex (PFC), ventral hippocampus (vHC), midline and intralaminar thalamus (TH) and basolateral nucleus of the amygdala (BLA). It is unclear which if any of these afferents innervate the medium spiny neurons of the NAc, that project to the VP. To identify the source of glutamatergic afferents that innervate neurons projecting to the VP, a dual-labelling method was used:
Phaseolus vulgaris leucoagglutinin
for anterograde and EGFP-encoded adenovirus for retrograde tract-tracing. Within the NAc, anterogradely labelled BLA terminals formed asymmetric synapses on dendritic spines that belonged to medium spiny neurons retrogradely labelled from the VP. TH terminals also formed synapses on dendritic spines of NAc neurons projecting to the VP. However, dendrites and dendritic spines retrogradely labelled from VP received no direct synaptic contacts from afferents originating from mPFC and vHC in the present material, despite the large number of fibres labelled by the anterograde tracer injections. These findings represent the first experimental evidence for a selective glutamatergic innervation of NAc neurons projecting to the VP. The glutamatergic inputs of different origin (i.e. mPFC, vHC, BLA, TH) to the NAc might thus convey different types of reward-related information during goal-directed behaviour, and thereby contribute to the complex regulation of nucleus accumbens functions.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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