Parvalbumin interneuron mediated feedforward inhibition controls signal output in the deep layers of the perirhinal-entorhinal cortex.
ABSTRACT: The perirhinal (PER) and lateral entorhinal (LEC) cortex form an anatomical link between the neocortex and the hippocampus. However, neocortical activity is transmitted through the PER and LEC to the hippocampus with a low probability, suggesting the involvement of the inhibitory network. This study explored the role of interneuron mediated inhibition, activated by electrical stimulation in the agranular insular cortex (AiP), in the deep layers of the PER and LEC. Activated synaptic input by AiP stimulation rarely evoked action potentials in the PER-LEC deep layer excitatory principal neurons, most probably because the evoked synaptic response consisted of a small excitatory and large inhibitory conductance. Furthermore, parvalbumin positive (PV) interneurons-a subset of interneurons projecting onto the axo-somatic region of principal neurons-received synaptic input earlier than principal neurons, suggesting recruitment of feedforward inhibition. This synaptic input in PV interneurons evoked varying trains of action potentials, explaining the fast rising, long lasting synaptic inhibition received by deep layer principal neurons. Altogether, the excitatory input from the AiP onto deep layer principal neurons is overruled by strong feedforward inhibition. PV interneurons, with their fast, extensive stimulus-evoked firing, are able to deliver this fast evoked inhibition in principal neurons. This indicates an essential role for PV interneurons in the gating mechanism of the PER-LEC network.
Project description:Stimulus processing in fear conditioning is constrained by parvalbumin interneurons (PV-INs) through inhibition of principal excitatory neurons. However, the contributions of PV-IN microcircuits to input gating and long-term plasticity in the fear system remain unknown. Here we interrogate synaptic connections between afferent pathways, PV-INs, and principal excitatory neurons in the basolateral amygdala. We find that subnuclei of this region are populated two functionally distinct PV-IN networks. PV-INs in the lateral (LA), but not the basal (BA), amygdala possess complex dendritic arborizations, receive potent excitatory drive, and mediate feedforward inhibition onto principal neurons. After fear conditioning, PV-INs exhibit nucleus- and target-selective plasticity, resulting in persistent reduction of their excitatory input and inhibitory output in LA but not BA. These data reveal previously overlooked specializations of amygdala PV-INs and indicate specific circuit mechanisms for inhibitory plasticity during the encoding of associative fear memories.
Project description:In the neocortex, large layer 5B pyramidal neurons implement a high-density firing code. In contrast, other subtypes of pyramidal neurons, including those in layer 2/3, are functionally characterized by their sparse firing rate. Here, we investigate the synaptic basis of this behavior by comparing the properties of the postsynaptic responses evoked by cortical inputs in layer 5B and layer 2/3 pyramidal neurons in vitro. We demonstrate that a major determinant of the larger responsiveness of layer 5B with respect to layer 2/3 pyramidal neurons is the different properties in their inhibitory postsynaptic currents (IPSCs): layer 5B pyramidal neurons have IPSCs of lower amplitude and the temporal delay between the excitatory and inhibitory synaptic components is also larger in these cells. Our data also suggest that this difference depends on the lower gain of the cortical response of layer 5 parvalbumin-positive fast-spiking (PV-FS) interneurons with respect to PV-FS cells from layer 2/3. We propose that, while superficial PV-FS interneurons are well suited to provide a powerful feed-forward inhibitory control of pyramidal neuron responses, layer 5 PV-FS interneurons are mainly engaged in a feedback inhibitory loop and only after a substantial recruitment of surrounding pyramidal cells do they respond to an external input.
Project description:Synaptic dysfunction is widely proposed as an initial insult leading to the neurodegeneration observed in Alzheimer's disease (AD). We hypothesize that the initial insult originates in the lateral entorhinal cortex (LEC) due to deficits in key interneuronal functions and synaptic signaling mechanisms, in particular, Wnt (Wingless/integrated). To investigate this hypothesis, we utilized the first knock-in mouse model of AD (AppNL-F/NL-F), expressing a mutant form of human amyloid-? (A?) precursor protein. This model shows an age-dependent accumulation of A?, neuroinflammation, and neurodegeneration. Prior to the typical AD pathology, we showed a decrease in canonical Wnt signaling activity first affecting the LEC in combination with synaptic hyperexcitation and severely disrupted excitatory-inhibitory inputs onto principal cells. This synaptic imbalance was consistent with a reduction in the number of parvalbumin-containing (PV) interneurons, and a reduction in the somatic inhibitory axon terminals in the LEC compared with other cortical regions. However, targeting GABAA receptors on PV cells using allosteric modulators, diazepam, zolpidem, or a nonbenzodiazepine, L-838,417 (modulator of ?2/3 subunit-containing GABAA receptors), restored the excitatory-inhibitory imbalance observed at principal cells in the LEC. These data support our hypothesis, providing a rationale for targeting the synaptic imbalance in the LEC for early stage therapeutic intervention to prevent neurodegeneration in AD.
Project description:Parvalbumin (PV) positive interneurons exert strong effects on the neocortical excitatory network, but it remains unclear how they impact the spatiotemporal dynamics of sensory processing in the somatosensory cortex. Here, we characterized the effects of optogenetic inhibition and activation of PV interneurons on spontaneous and sensory-evoked activity in mouse barrel cortex in vivo. Inhibiting PV interneurons led to a broad-spectrum power increase both in spontaneous and sensory-evoked activity. Whisker-evoked responses were significantly increased within 20 ms after stimulus onset during inhibition of PV interneurons, demonstrating high temporal precision of PV-shaped inhibition. Multiunit activity was strongly enhanced in neighboring cortical columns, but not at the site of transduction, supporting a central and highly specific role of PV interneurons in lateral inhibition. Inversely, activating PV interneurons drastically decreased spontaneous and whisker-evoked activity in the principal column and exerted strong lateral inhibition. Histological assessment of transduced cells combined with quantitative modeling of light distribution and spike sorting revealed that only a minor fraction (~10%) of the local PV population comprising no more than a few hundred neurons is optogenetically modulated, mediating the observed prominent and widespread effects on neocortical processing.
Project description:The basolateral amygdala (BLA) plays a vital role in associating sensory stimuli with salient valence information. Excitatory principal neurons (PNs) undergo plastic changes to encode this association; however, local BLA inhibitory interneurons (INs) gate PN plasticity via feedforward inhibition (FFI). Despite literature implicating parvalbumin expressing (PV+) INs in FFI in cortex and hippocampus, prior anatomical experiments in BLA implicate somatostatin expressing (Sst+) INs. The lateral entorhinal cortex (LEC) projects to BLA where it drives FFI. In the present study, we explored the role of interneurons in this circuit. Using mice, we combined patch clamp electrophysiology, chemogenetics, unsupervised cluster analysis, and predictive modeling and found that a previously unreported subpopulation of fast-spiking Sst+ INs mediate LEC?BLA FFI.
Project description:We developed and applied a Cre-dependent, genetically modified rabies-based tracing system to map direct synaptic connections to specific CA1 neuron types in the mouse hippocampus. We found common inputs to excitatory and inhibitory CA1 neurons from CA3, CA2, the entorhinal cortex (EC), the medial septum (MS), and, unexpectedly, the subiculum. Excitatory CA1 neurons receive inputs from both cholinergic and GABAergic MS neurons, whereas inhibitory neurons receive a great majority of inputs from GABAergic MS neurons. Both cell types also receive weaker input from glutamatergic MS neurons. Comparisons of inputs to CA1 PV+ interneurons versus SOM+ interneurons showed similar strengths of input from the subiculum, but PV+ interneurons received much stronger input than SOM+ neurons from CA3, the EC, and the MS. Thus, rabies tracing identifies hippocampal circuit connections and maps how the different input sources to CA1 are distributed with different strengths on each of its constituent cell types.
Project description:Memories are believed to be encoded by changes in the synaptic connections between neurons. Although many forms of synaptic plasticity have been identified, it remains unknown how such changes affect local circuits. Feedforward inhibitory networks are a common type of local circuitry and occur when principal neurons and their afferent inhibitory interneurons receive the same input. Using slices of cerebellar cortex, we explored how synaptic plasticity at multiple sites within a feedforward inhibitory network consisting of parallel fibers, interneurons, and Purkinje neurons alters the output of this circuit. We found that stimuli resembling baseline activity potentiated feedforward excitatory and simultaneously depressed feedforward inhibitory pathways. In contrast, stimuli resembling sensory-evoked patterns of firing potentiated both types of feedforward connections. These distinct forms of ensemble plasticity change the way Purkinje neurons subsequently respond to inputs. Such concerted changes in the circuitry of cerebellar cortex may contribute to certain forms of sensorimotor learning.
Project description:Dissecting the functional roles of excitatory and inhibitory neurons in cortical circuits is a fundamental goal in neuroscience. Of particular interest are their roles in emergent cortical computations such as binocular integration in primary visual cortex (V1). We measured the binocular response selectivity of genetically defined subpopulations of excitatory and inhibitory neurons. Parvalbumin (PV+) interneurons received strong inputs from both eyes but lacked selectivity for binocular disparity. Because broad selectivity could result from heterogeneous synaptic input from neighboring neurons, we examined how individual PV+ interneuron selectivity compared to that of the local neuronal network, which is primarily composed of excitatory neurons. PV+ neurons showed functional similarity to neighboring neuronal populations over spatial distances resembling measurements of synaptic connectivity. On the other hand, excitatory neurons expressing CaMKII? displayed no such functional similarity with the neighboring population. Our findings suggest that broad selectivity of PV+ interneurons results from nonspecific integration within local networks. VIDEO ABSTRACT.
Project description:Huntington's disease (HD) is a heritable neurological disorder that affects cognitive and motor performance in patients carrying the mutated huntingtin (HTT) gene. In mouse models of HD, previous reports showed a significant increase in spontaneous GABAA receptor-mediated synaptic activity in striatal spiny projection neurons (SPNs). In this study, using optogenetics and slice electrophysiology, we examined the contribution of ?-aminobutyric acid (GABA)-ergic parvalbumin (PV)- and somatostatin (SOM)-expressing interneurons to the increase in GABA neurotransmission using the Q175 (heterozygote) mouse model of HD. Patch clamp recordings in voltage-clamp mode were performed on SPNs from brain slices of presymptomatic (2 months) and symptomatic (8 and 12 months) Q175 mice and wildtype (WT) littermates. While inhibitory postsynaptic currents (IPSCs) evoked in SPNs following optical activation of PV- and SOM-expressing interneurons differed in amplitude, no genotype-dependent differences were observed at all ages from both interneuron types; however, responses evoked by either type were found to have faster kinetics in symptomatic mice. Since SOM-expressing interneurons are constitutively active in striatal brain slices, we then examined the effects of acutely silencing these neurons in symptomatic mice with enhanced Natronomonas pharaonis halorhodopsin (eNpHR). Optically silencing SOM-expressing interneurons resulted in a greater decrease in the frequency of spontaneous IPSCs (sIPSCs) in a subset of SPNs from Q175 mice compared to WTs, suggesting that SOM-expressing interneurons are the main contributors to the overall increased GABA synaptic activity in HD SPNs. Additionally, the effects of activating GABAB and cannabinoid (CB1) receptors were investigated to determine whether these receptors were involved in modulating interneuron-specific GABA synaptic transmission and if this modulation differed in HD mice. When selectively activating PV- and SOM-expressing interneurons in the presence of the CB1 receptor agonist WIN-55,212, the magnitudes of the evoked IPSCs in SPNs decreased for both interneuron types although this change was less prominent in symptomatic Q175 SPNs during SOM-expressing interneuron activation. Overall, these findings show that dysfunction of SOM-expressing interneurons contributes to the increased GABA synaptic activity found in HD mouse models and that dysregulation of the endocannabinoid system may contribute to this effect.
Project description:Accumulation of amyloid ? oligomers (A?O) in Alzheimer's disease (AD) impairs hippocampal theta and gamma oscillations. These oscillations are important in memory functions and depend on distinct subtypes of hippocampal interneurons such as somatostatin-positive (SST) and parvalbumin-positive (PV) interneurons. Here, we investigated whether A?O causes dysfunctions in SST and PV interneurons by optogenetically manipulating them during theta and gamma oscillations in vivo in A?O-injected SST-Cre or PV-Cre mice. Hippocampal in vivo multi-electrode recordings revealed that optogenetic activation of channelrhodopsin-2 (ChR2)-expressing SST and PV interneurons in A?O-injected mice selectively restored A?O-induced reduction of the peak power of theta and gamma oscillations, respectively, and resynchronized CA1 pyramidal cell (PC) spikes. Moreover, SST and PV interneuron spike phases were resynchronized relative to theta and gamma oscillations, respectively. Whole-cell voltage-clamp recordings in CA1 PC in ex vivo hippocampal slices from A?O-injected mice revealed that optogenetic activation of SST and PV interneurons enhanced spontaneous inhibitory postsynaptic currents (IPSCs) selectively at theta and gamma frequencies, respectively. Furthermore, analyses of the stimulus-response curve, paired-pulse ratio, and short-term plasticity of SST and PV interneuron-evoked IPSCs ex vivo showed that A?O increased the initial GABA release probability to depress SST/PV interneuron's inhibitory input to CA1 PC selectively at theta and gamma frequencies, respectively. Our results reveal frequency-specific and interneuron subtype-specific presynaptic dysfunctions of SST and PV interneurons' input to CA1 PC as the synaptic mechanisms underlying A?O-induced impairments of hippocampal network oscillations and identify them as potential therapeutic targets for restoring hippocampal network oscillations in early AD.