Jonas-Frederic Sauer

Parvalbumin-positive CA1 interneurons are required for spatial working but not for reference memory

Parvalbumin-positive GABAergic interneurons in cortical circuits are hypothesized to control cognitive function. To test this idea directly, we functionally removed parvalbumin-positive interneurons selectively from hippocampal CA1 in mice. We found that parvalbumin-positive interneurons are dispensable for spatial reference, but are essential for spatial working memory.

Associative Plasticity at Excitatory Synapses Facilitates Recruitment of Fast-Spiking Interneurons in the Dentate Gyrus

Fast-spiking perisomatic-inhibitory interneurons (PIIs) receive convergent excitation and mediate both feedforward and feedback inhibition in cortical microcircuits. However, it remains poorly understood how convergent excitatory inputs recruit PIIs to produce precisely timed inhibition. Here, we analyzed the interaction of inputs from the entorhinal cortex [perforant path (PP)] and from local granule cells [mossy fibers (MFs)] onto PIIs in the rat dentate gyrus (DG). PP stimulation alone activates PIIs with low temporal precision. Interestingly, when PP and MFs are coactivated with a 10 ms delay, PIIs discharge with precise timing. Moreover, repeated coactivation of the two inputs induces associative long-term potentiation (LTP) at MF synapses. Under these conditions, a single potentiated MF input is sufficient to recruit PIIs in a reliable and highly precise manner to provide feedback inhibition. MF-LTP depends on the discharge of PIIs, indicating Hebbian plasticity. However, MF-LTP is preserved when NMDA receptors are blocked but depends on transmission through Ca2+-permeable AMPA receptors (AMPARs). PP–PII synapses, in contrast, lack Ca2+-permeable AMPARs and do not show plasticity on associative activation. Thus, precise recruitment of PIIs requires excitation through MF–PII synapses during feedforward activation. We propose that associative plasticity at these synapses is a central mechanism that adjusts inhibition levels to maintain sparse activity and to improve signal-to-noise ratio in the DG network.

Impaired fast-spiking interneuron function in a genetic mouse model of depression

Rhythmic neuronal activity provides a frame for information coding by co-active cell assemblies. Abnormal brain rhythms are considered as potential pathophysiological mechanisms causing mental disease, but the underlying network defects are largely unknown. We find that mice expressing truncated Disrupted-in-Schizophrenia 1 (Disc1), which mirror a high-prevalence genotype for human psychiatric illness, show depression-related behavior. Theta and low-gamma synchrony in the prelimbic cortex (PrlC) is impaired in Disc1 mice and inversely correlated with the extent of behavioural despair. While weak theta activity is driven by the hippocampus, disturbance of low-gamma oscillations is caused by local defects of parvalbumin (PV)-expressing fast-spiking interneurons (FS-INs). The number of FS-INs is reduced, they receive fewer excitatory inputs, and form fewer release sites on targets. Computational analysis indicates that weak excitatory input and inhibitory output of FS-INs may lead to impaired gamma oscillations. Our data link network defects with a gene mutation underlying depression in humans. DOI: http://dx.doi.org/10.7554/eLife.04979.001

Interneurons Provide Circuit-Specific Depolarization and Hyperpolarization

Perisoma-inhibiting interneurons (PIIs) control fundamental aspects of cortical network function by means of their GABAergic output synapses. However, whether they depolarize or hyperpolarize their target cells in the mature circuitry remains controversial. By using unitary field potential and gramicidin D perforated-patch recordings, we provide evidence that the postsynaptic effect of GABAergic synapses is fundamentally different in two regions of rat hippocampus. Signaling at PII output synapses is hyperpolarizing in CA1 principal cells (PCs) but depolarizing in dentate gyrus (DG) PCs. While the reversal potential of GABAA receptor-mediated currents is identical in both areas, ∼15 mV more negative resting potentials of DG compared with CA1 PCs underlie the opposing effects of perisomatic GABAergic transmission. Thus, the nature of PII output signaling is circuit-dependent and may therefore contribute differentially to information processing in the two brain areas.

Recruitment of Early Postnatal Parvalbumin-Positive Hippocampal Interneurons by GABAergic Excitation

GABAergic synaptic inputs targeting cortical principal cells undergo marked changes in their functional properties from depolarizing at early postnatal life to hyperpolarizing at mature stages. In contrast, the nature of GABAA receptor-mediated signaling in interneurons during maturation of neuronal networks is controversial. By using gramicidin perforated-patch and whole-cell recordings from LIM homeobox 6 (Lhx6)-positive dentate gyrus perisomatic-targeting parvalbumin-expressing interneurons (PV-INs), we show that signaling at first formed GABAergic synapses at postnatal day 3 (P3) is excitatory and switches to shunting during the course of the first to second postnatal week. GABAergic synaptic inputs at P3–P6 reliably evoke action potentials in 65% of Lhx6-EGFP-expressing perisomatic-targeting cells and boost spike induction upon conjoint activation of glutamatergic fibers. Thus, GABAergic inputs change their functional role during maturation. They facilitate the recruitment of perisomatic-targeting INs in early postnatal circuits when network connectivity and synaptic glutamate receptor-mediated excitation are low and control spike timing at later stages when connectivity and glutamate-mediated drive are high.

Organization of prefrontal network activity by respiration-related oscillations

The medial prefrontal cortex (mPFC) integrates information from cortical and sub-cortical areas and contributes to the planning and initiation of behaviour. A potential mechanism for signal integration in the mPFC lies in the synchronization of neuronal discharges by theta (6–12 Hz) activity patterns. Here we show, using in vivo local field potential (LFP) and single-unit recordings from awake mice, that prominent oscillations in the sub-theta frequency band (1–5 Hz) emerge during awake immobility in the mPFC. These oscillation patterns are distinct from but phase-locked to hippocampal theta activity and occur synchronized with nasal respiration (hence termed prefrontal respiration rhythm [PRR]). PRR activity modulates the amplitude of prefrontal gamma rhythms with greater efficacy than theta oscillations. Furthermore, single-unit discharges of putative pyramidal cells and GABAergic interneurons are entrained by prefrontal PRR and nasal respiration. Our data thus suggest that PRR activity contributes to information processing in the prefrontal neuronal network.

Postnatal differentiation of cortical interneuron signalling.

Most GABAergic interneurons in the cortex are born at embryonic stages in the ganglionic eminences and migrate tangentially to their final destination. They continue, however, to differentiate and functionally integrate in the circuitry until later postnatal stages of the rodent brain. Recent investigations show that interneurons undergo marked changes in their morphological, intrinsic and synaptic properties as they mature. Action potential shape and its propagation, the period of transmitter release and the time course of the postsynaptic GABAA receptor‐mediated conductance become faster during the first three to four postnatal weeks, resulting in a developmental switch of interneurons from slow to fast signalling units. At the same time, the nature of GABAergic signalling is classically considered to shift from depolarizing to hyperpolarizing. However, recent studies oppose this view as interneuron synapses can be shunting, excitatory or hyperpolarizing in the mature cortex, demonstrating the coexistence of diverse developmental rules for the emerging effects of GABAergic synapses. Thus, mature interneuron signalling comes in many forms and is apparently optimized to the network in which the neurons are embedded.

Seed‐induced Aβ deposition is modulated by microglia under environmental enrichment in a mouse model of Alzheimer's disease

Alzheimers disease (AD) is characterized by severe neuronal loss as well as the accumulation of amyloid‐β (Aβ), which ultimately leads to plaque formation. Although there is now a general agreement that the aggregation of Aβ can be initiated by prion‐like seeding, the impact and functional consequences of induced Aβ deposits (Aβ seeding) on neurons still remain open questions. Here, we find that Aβ seeding, representing early stages of plaque formation, leads to a dramatic decrease in proliferation and neurogenesis in two APP transgenic mouse models. We further demonstrate that neuronal cell death occurs primarily in the vicinity of induced Aβ deposits culminating in electrophysiological abnormalities. Notably, environmental enrichment and voluntary exercise not only revives adult neurogenesis and reverses memory deficits but, most importantly, prevents Aβ seeding by activated, phagocytic microglia cells. Our work expands the current knowledge regarding Aβ seeding and the consequences thereof and attributes microglia an important role in diminishing Aβ seeding by environmental enrichment.

Fast and Slow GABAergic Transmission in Hippocampal Circuits

Cortical neuronal networks consist of excitatory glutamatergic principal cells and a heterogeneous group of GABAergic inhibitory interneurons. Interneurons are embedded in feedforward and feedback microcircuits and control key aspects of cortical network function including the timing of the activation of principal cells and the generation of network oscillations (Freund and Buzsaki, 1996; McBain and Fisahn, 2001; Klausberger and Somogyi, 2008). Although interneurons comprise only 10% of the neuronal population, they are highly diverse and can be subdivided into several types on the basis of various criteria, such as intrinsic physiological properties, neurochemical marker content, morphological features, including the laminar distribution of the axon, and finally the postsynaptic target profile of their output (Freund and Buzsaki, 1996; Avoli et al., 2006). On the basis of synaptic targets, interneurons have been classified into two major groups, perisomatic- and dendrite-targeting cells.

Distance-dependent inhibition facilitates focality of gamma oscillations in the dentate gyrus

Gamma oscillations (30–150 Hz) in neuronal networks are associated with the processing and recall of information. We measured local field potentials in the dentate gyrus of freely moving mice and found that gamma activity occurs in bursts, which are highly heterogeneous in their spatial extensions, ranging from focal to global coherent events. Synaptic communication among perisomatic-inhibitory interneurons (PIIs) is thought to play an important role in the generation of hippocampal gamma patterns. However, how neuronal circuits can generate synchronous oscillations at different spatial scales is unknown. We analyzed paired recordings in dentate gyrus slices and show that synaptic signaling at interneuron-interneuron synapses is distance dependent. Synaptic strength declines whereas the duration of inhibitory signals increases with axonal distance among interconnected PIIs. Using neuronal network modeling, we show that distance-dependent inhibition generates multiple highly synchronous focal gamma bursts allowing the network to process complex inputs in parallel in flexibly organized neuronal centers.Perisomatic-inhibitory interneurons (PIIs) contribute to the generation of gamma oscillations in the hippocampus. Here the authors demonstrate distance-dependent inhibition between PIIs in freely moving mice, and use computational analysis to show that distance-dependent inhibition supports the emergence of focal gamma bursts.