parvalbumin

Metabolic-functional coupling of parvalbmunin-positive GABAergic interneurons in the injured and epileptic brain

Parvalbumin-positive GABAergic interneurons (PV-INs) provide inhibitory control of excitatory neuron activity, coordinate circuit function, and regulate behavior and cognition. PV-INs are uniquely susceptible to loss and dysfunction in traumatic brain injury (TBI) and epilepsy but the cause of this susceptibility is unknown. One hypothesis is that PV-INs use specialized metabolic systems to support their high-frequency action potential firing and that metabolic stress disrupts these systems, leading to their dysfunction and loss. Metabolism-based therapies can restore PV-IN function after injury in preclinical TBI models. Based on these findings, we hypothesize that (1) PV-INs are highly metabolically specialized, (2) these specializations are lost after TBI, and (3) restoring PV-IN metabolic specializations can improve PV-IN function as well as TBI-related outcomes. Using novel single-cell approaches, we can now quantify cell-type-specific metabolism in complex tissues to determine whether PV-IN metabolic dysfunction contributes to the pathophysiology of TBI.

Neuronal plasticity and neurotrophin signaling as the common mechanism for antidepressant effect

Neuronal plasticity has for a long time been considered important for the recovery from depression and for the antidepressant drug action, but how the drug action is translated to plasticity has remained unclear. Brain-derived neurotrophic factor (BDNF) and its receptor TRKB are critical regulators of neuronal plasticity and have been implicated in the antidepressant action. We have recently found that many, if not all, different antidepressants, including serotonin selective SSRIs, tricyclic as well as fast-acting ketamine, directly bind to TRKB, thereby promoting TRKB translocation to synaptic membranes, which increases BDNF signaling. We have previously shown that antidepressant treatment induces a juvenile-like state of activity in the cortex that facilitates beneficial rewiring of abnormal networks. We recently showed that activation of TRKB receptors in parvalbumin-containing interneurons orchestrates cortical activation states and is both necessary and sufficient for the antidepressantinduced cortical plasticity. Our findings open a new framework how the action of antidepressants act: rather than regulating brain monoamine concentrations, antidepressants directly bind to TRKB and allosterically promote BDNF signaling, thereby inducing a state of plasticity that allows re-wiring of abnormal networks for better functionality.

The GluN2A Subunit of the NMDA Receptor and Parvalbumin Interneurons: A Possible Role in Interneuron Development

N-methyl-D-aspartate receptors (NMDARs) are excitatory glutamate-gated ion channels that are expressed throughout the central nervous system. NMDARs mediate calcium entry into cells, and are involved in a host of neurological functions. The GluN2A subunit, encoded by the GRIN2A gene, is expressed by both excitatory and inhibitory neurons, with well described roles in pyramidal cells. By using Grin2a knockout mice, we show that the loss of GluN2A signaling impacts parvalbumin-positive (PV) GABAergic interneuron function in hippocampus. Grin2a knockout mice have 33% more PV cells in CA1 compared to wild type but similar cholecystokinin-positive cell density. Immunohistochemistry and electrophysiological recordings show that excess PV cells do eventually incorporate into the hippocampal network and participate in phasic inhibition. Although the morphology of Grin2a knockout PV cells is unaffected, excitability and action-potential firing properties show age-dependent alterations. Preadolescent (P20-25) PV cells have an increased input resistance, longer membrane time constant, longer action-potential half-width, a lower current threshold for depolarization-induced block of action-potential firing, and a decrease in peak action-potential firing rate. Each of these measures are corrected in adulthood, reaching wild type levels, suggesting a potential delay of electrophysiological maturation. The circuit and behavioral implications of this age-dependent PV interneuron malfunction are unknown. However, neonatal Grin2a knockout mice are more susceptible to lipopolysaccharide and febrile-induced seizures, consistent with a critical role for early GluN2A signaling in development and maintenance of excitatory-inhibitory balance. These results could provide insights into how loss-of-function GRIN2A human variants generate an epileptic phenotypes.

Optimising spiking interneuron circuits for compartment-specific feedback

Cortical circuits process information by rich recurrent interactions between excitatory neurons and inhibitory interneurons. One of the prime functions of interneurons is to stabilize the circuit by feedback inhibition, but the level of specificity on which inhibitory feedback operates is not fully resolved. We hypothesized that inhibitory circuits could enable separate feedback control loops for different synaptic input streams, by means of specific feedback inhibition to different neuronal compartments. To investigate this hypothesis, we adopted an optimization approach. Leveraging recent advances in training spiking network models, we optimized the connectivity and short-term plasticity of interneuron circuits for compartment-specific feedback inhibition onto pyramidal neurons. Over the course of the optimization, the interneurons diversified into two classes that resembled parvalbumin (PV) and somatostatin (SST) expressing interneurons. The resulting circuit can be understood as a neural decoder that inverts the nonlinear biophysical computations performed within the pyramidal cells. Our model provides a proof of concept for studying structure-function relations in cortical circuits by a combination of gradient-based optimization and biologically plausible phenomenological models

Synapse and Circuit Development

The symposium will start with A/Prof Jenny Gunnersen who will present “New insights into mechanisms of excitatory synapse development”. Then, Dr Tommas Ellender will deal with the “Embryonic neural progenitor pools and the generation of fine-scale neural circuits” and Dr Thomas Marissal will talk about “Parvalbumin interneurons: the missing link between the micro and macroscopic alterations related to neurodevelopmental disorders?"”.

All optical interrogation of developing GABAergic circuits in vivo

The developmental journey of cortical interneurons encounters several activity-dependent milestones. During the early postnatal period in developing mice, GABAergic neurons are transient preferential recipients of thalamic inputs and undergo activity-dependent migration arrest, wiring and programmed cell-death. But cortical GABAergic neurons are also specified by very early developmental programs. For example, the earliest born GABAergic neurons develop into hub cells coordinating spontaneous activity in hippocampal slices. Despite their importance for the emergence of sensory experience, their role in coordinating network dynamics, and the role of activity in their integration into cortical networks, the collective in vivo dynamics of GABAergic neurons during the neonatal postnatal period remain unknown. Here, I will present data related to the coordinated activity between GABAergic cells of the mouse barrel cortex and hippocampus in non-anesthetized pups using the recent development of all optical methods to record and manipulate neuronal activity in vivo. I will show that the functional structure of developing GABAergic circuits is remarkably patterned, with segregated assemblies of prospective parvalbumin neurons and highly connected hub cells, both shaped by sensory-dependent processes.

Cellular/circuit dysfunction across development in a model of Dravet syndrome

Dravet syndrome (DS) is a neurodevelopmental disorder caused by heterozygous loss-of-function of the gene SCN1A encoding the voltage-gated sodium channel subunit Nav1.1, and is defined by treatment-resistant epilepsy, intellectual impairment, and sudden death. However, disease mechanisms remain unclear, as previously-identified deficiency in action potential generation of Nav1.1-expressing parvalbumin-positive fast-spiking GABAergic interneurons (PV-INs) in DS (Scn1a+/-) mice normalizes during development. We used a novel approach that facilitated the assessment of PV-IN function at both early (post-natal day (P) 16-21) and late (P35-56) time points in the same mice. We confirmed that PV-IN spike generation was impaired at P16-21 in all mice (those deceased from SUDEP by P35 and those surviving to P35-56). However, unitary synaptic transmission assessed in PV-IN:principal cell paired recordings was severely dysfunctional selectively in mice recorded at P16-21 that did not survive to P35. Spike generation in surviving mice had normalized by P35-56; yet we again identified abnormalities in synaptic transmission in surviving mice. We propose that early dysfunction of PV-IN spike propagation drives epilepsy severity and risk of sudden death, while persistent dysfunction of spike propagation contributes to chronic DS pathology.

Inhibitory neural circuit mechanisms underlying neural coding of sensory information in the neocortex

Neural codes, such as temporal codes (precisely timed spikes) and rate codes (instantaneous spike firing rates), are believed to be used in encoding sensory information into spike trains of cortical neurons. Temporal and rate codes co-exist in the spike train and such multiplexed neural code-carrying spike trains have been shown to be spatially synchronized in multiple neurons across different cortical layers during sensory information processing. Inhibition is suggested to promote such synchronization, but it is unclear whether distinct subtypes of interneurons make different contributions in the synchronization of multiplexed neural codes. To test this, in vivo single-unit recordings from barrel cortex were combined with optogenetic manipulations to determine the contributions of parvalbumin (PV)- and somatostatin (SST)-positive interneurons to synchronization of precisely timed spike sequences. We found that PV interneurons preferentially promote the synchronization of spike times when instantaneous firing rates are low (<12 Hz), whereas SST interneurons preferentially promote the synchronization of spike times when instantaneous firing rates are high (>12 Hz). Furthermore, using a computational model, we demonstrate that these effects can be explained by PV and SST interneurons having preferential contribution to feedforward and feedback inhibition, respectively. Overall, these results show that PV and SST interneurons have distinct frequency (rate code)-selective roles in dynamically gating the synchronization of spike times (temporal code) through preferentially recruiting feedforward and feedback inhibitory circuit motifs. The inhibitory neural circuit mechanisms we uncovered here his may have critical roles in regulating neural code-based somatosensory information processing in the neocortex.

Self-organisation in interneuron circuits

Inhibitory interneurons come in different classes and form intricate circuits. While our knowledge of these circuits has advanced substantially over the last decades, it is not fully understood how the structure of these circuits relates to their function. I will present some of our recent attempts to “understand” the structure of interneuron circuits by means of computational modeling. Surprisingly (at least for us), we found that prominent features of inhibitory circuitry can be accounted for by an optimisation for excitation-inhibition (E/I) balance. In particular, we find that such an optimisation generates networks that resemble mouse V1 in terms of the structure of synaptic efficacies between principal cells and parvalbumin-positive interneurons. Moreover, an optimisation for E/I balance across neuronal compartments promotes a functional diversification of interneurons into two classes that resemble parvalbumin and somatostatin-positive interneurons. Time permitting, I may briefly touch on recent work in which we link E/I balance to prediction error coding in V1.

The integration of parvalbumin and somatostatin interneurons into cortical networks:both nature and nurture

Circuit dysfunction and sensory processing in Fragile X Syndrome

To uncover the circuit-level alterations that underlie atypical sensory processing associated with autism, we have adopted a symptom-to-circuit approach in theFmr1-/- mouse model of Fragile X syndrome (FXS). Using a go/no-go task and in vivo 2-photon calcium imaging, we find that impaired visual discrimination in Fmr1-/- mice correlates with marked deficits in orientation tuning of principal neurons in primary visual cortex, and a decrease in the activity of parvalbumin (PV) interneurons. Restoring visually evoked activity in PV cells in Fmr1-/- mice with a chemogenetic (DREADD) strategy was sufficient to rescue their behavioural performance. Strikingly, human subjects with FXS exhibit similar impairments in visual discrimination as Fmr1-/- mice. These results suggest that manipulating inhibition may help sensory processing in FXS. More recently, we find that the ability of Fmr1-/- mice to perform the visual discrimination task is also drastically impaired in the presence of visual or auditory distractors, suggesting that sensory hypersensitivity may affect perceptual learning in autism.

Circuit and synaptic mechanisms of plasticity in neural ensembles

Inhibitory microcircuits play an important role regulating cortical responses to sensory stimuli. Interneurons that inhibit dendritic or somatic integration are gatekeepers for neural activity, synaptic plasticity and the formation of sensory representations. We have been investigating the synaptic plasticity mechanisms underlying the formation of ensembles in olfactory and orbitofrontal cortex. We have been focusing on the roles of three inhibitory neuron classes in gating excitatory synaptic plasticity in olfactory cortex- somatostatin (SST-INs), parvalbumin (PV-INs), and vasoactive intestinal polypeptide (VIP-INs) interneurons. Further, we are investigating the rules for inhibitory plasticity and a potential role in stabilizing ensembles in associative cortices. I will present new findings to support distinct roles for different interneuron classes in the gating and stabilization of ensemble representations of olfactory responses.

Cellular/circuit dysfunction in a model of Dravet syndrome - a severe childhood epilepsy

Dravet syndrome is a severe childhood epilepsy due to heterozygous loss-of-function mutation of the gene SCN1A, which encodes the type 1 neuronal voltage gated sodium (Na+) channel alpha-subunit Nav1.1. Prior studies in mouse models of Dravet syndrome (Scn1a+/- mice) at early developmental time points indicate that, in cerebral cortex, Nav1.1 is predominantly expressed in GABAergic interneurons (INs) and, in particular, in parvalbumin-positive fast-spiking basket cells (PV-INs). This has led to a model of Dravet syndrome pathogenesis whereby Nav1.1 mutation leads to preferential IN dysfunction, decreased synaptic inhibition, hyperexcitability, and epilepsy. We found that, at later developmental time points, the intrinsic excitability of PV-INs has essentially normalized, via compensatory reorganization of axonal Na+ channels. Instead, we found persistent and seemingly paradoxical dysfunction of putative disinhibitory INs expressing vasoactive intestinal peptide (VIP-INs). In vivo two-photon calcium imaging in neocortex during temperature-induced seizures in Scn1a+/- mice showed that mean activity of both putative principal cells and PV-INs was higher in Scn1a+/- relative to wild-type controls during quiet wakefulness at baseline and at elevated core body temperature. However, wild-type PV-INs showed a progressive synchronization in response to temperature elevation that was absent in PV-INs from Scn1a+/- mice immediately prior to seizure onset. We suggest that impaired PV-IN synchronization, perhaps via persistent axonal dysfunction, may contribute to the transition to the ictal state during temperature induced seizures in Dravet syndrome.

SPATIAL TRANSCRIPTOMIC PROFILING REVEALS MOLECULAR SIGNATURES OF PERINEURONAL NET-ASSOCIATED PARVALBUMIN INTERNEURONS

FENS Forum 2026

GENETIC RISK ANALYSES HIGHLIGHT PARVALBUMIN-EXPRESSING INTERNEURON WIRING DURING DEVELOPMENT AS A VULNERABLE PROCESS IN SCHIZOPHRENIA

FENS Forum 2026

PARVALBUMIN-SPECIFIC LOSS OF COMPLEXIN I DISRUPTS INHIBITORY SYNAPTIC FUNCTION AND HIPPOCAMPAL OUTPUT

FENS Forum 2026

PSYCHEDELIC-INDUCED REMODELING OF PERINEURONAL NETS AND PARVALBUMIN NEURONS ACROSS THE MOUSE BRAIN

FENS Forum 2026

EXCITATORY SYNAPTIC INPUT TO PARVALBUMIN INTERNEURONS PREFERENTIALLY SHAPES GAMMA OSCILLATION DYNAMICS AND PLASTICITY IN ACUTE BRAIN SLICES OF HUMAN NEOCORTEX

FENS Forum 2026

<EM>DLX5/6</EM> REGULATE PARVALBUMIN-POSITIVE NEURONS FUNCTION THROUGH PERINEURONAL NET STRUCTURE MODULATIONS IN THE CEREBRAL CORTEX

FENS Forum 2026

MGLUR7 MODULATION OF PARVALBUMIN-CA1 SYNAPSES CONTROLS SPATIAL MEMORY AND ANTI-EPILEPTIC ACTIVITY

FENS Forum 2026

LAMINAR PARVALBUMIN AND SOMATOSTATIN ACTIVATION IN ACC TRACKS MEDIODORSAL THALAMUS CONTROL OF PAIN BEHAVIOR

FENS Forum 2026

KV3.1 MODULATION RESTORES FAST-SPIKING IN PARVALBUMIN INTERNEURONS DESPITE REDUCED EXCITATORY SYNAPTIC INPUT IN CHRONIC EPILEPSY

FENS Forum 2026

DIVERSITY OF FAST-SPIKING PARVALBUMIN-CONTAINING INTERNEURONS IN THE DENTATE GYRUS

FENS Forum 2026

WHOLE BRAIN MAP OF DEVELOPING PARVALBUMIN INTERNEURON NETWORKS IN MOUSE MODELS OF SCHIZOPHRENIA

FENS Forum 2026

ATTENTION TRANSFORMS THE IMPACT OF PARVALBUMIN-POSITIVE INTERNEURON ACTIVITY IN MOUSE PRIMARY VISUAL CORTEX

FENS Forum 2026

<B DATA-OLK-COPY-SOURCE="MESSAGEBODY">CCP1 REGULATE FUNCTIONAL PROPERTIES OF CORTICAL PARVALBUMIN INTERNEURONS </B>

FENS Forum 2026

SOMA-LOCATION OF PARVALBUMIN-EXPRESSING INTERNEURONS DEFINES THEIR CONTRIBUTION TO FEEDFORWARD AND FEEDBACK INHIBITION

FENS Forum 2026

LOSS OF THE <EM >MECP2</EM> GENE IN PARVALBUMIN INTERNEURONS LEADS TO AN INHIBITORY DEFICIT IN THE AMYGDALA AND AFFECTS ITS FUNCTIONAL CONNECTIVITY

FENS Forum 2026

MICROGLIA GABA<SUB>B1</SUB> SIGNALING LINKS PARVALBUMIN INTERNEURON HYPERACTIVITY TO SYNAPTIC PATHOLOGY IN ALZHEIMER DISEASE

FENS Forum 2026

AUTAPTIC SELF-INHIBITION OF PARVALBUMIN INTERNEURONS DRIVES NETWORK HYPEREXCITABILITY IN GABAA RECEPTOR GAIN-OF-FUNCTION ENCEPHALOPATHY

FENS Forum 2026

EARLY PARVALBUMIN INHIBITION SHAPES THE DEVELOPMENT OF CORTICAL INTERHEMISPHERIC EXCITATORY CONNECTIVITY

FENS Forum 2026

RECEPTOR PROTEIN TYROSINE PHOSPHATASE (RPTP) Β/Ζ MODULATES PERINEURONAL NETS AND PARVALBUMIN INTERNEURONS IN THE HIPPOCAMPUS OF APP/PS1 MICE

FENS Forum 2026

CHANGES IN THE POPULATION OF PARVALBUMIN-EXPRESSING INTERNEURONS IN THE HUMAN HIPPOCAMPAL FORMATION IN ALZHEIMER'S DISEASE: A ROSTROCAUDAL STUDY

FENS Forum 2026

CHLORIDE REGULATION AND POST-SYNAPTIC GABA RECEPTOR SIGNALLING IN CORTICAL PARVALBUMIN-EXPRESSING INTERNEURONS

FENS Forum 2026

PARVALBUMIN INTERNEURONS WITHIN THE POSTERIOR DORSOMEDIAL STRIATUM REGULATE UPDATING OF ACTION–OUTCOME ASSOCIATIONS DURING REVERSAL LEARNING

FENS Forum 2026

ELECTROPHYSIOLOGICAL AND MORPHOLOGICAL CHARACTERIZATION OF PARVALBUMIN POSITIVE INTERNEURONS ALONG THE CA1-SUBICULUM AXIS IN RODENT

FENS Forum 2026

NEUROPHYSIOLOGICAL DEVELOPMENT OF LAYER 3 PYRAMIDAL AND PARVALBUMIN NEURONS IN THE MOUSE PREFRONTAL CORTEX ACROSS ADOLESCENCE

FENS Forum 2026

MITOCHONDRIAL DYNAMICS ARE SELECTIVELY ALTERED IN PARVALBUMIN NEURONS DURING GREY MATTER DEMYELINATION

FENS Forum 2026

A PROXIMODISTAL GRADIENT OF CA3 PARVALBUMIN<SUP>+ </SUP>INTERNEURON PROPERTIES, MORPHOLOGY AND CONNECTIVITY

FENS Forum 2026

EPHB2 FORWARD SIGNALING REGULATES PARVALBUMIN INTERNEURON INHIBITORY STRENGTH, NETWORK EXCITABILITY, AND BEHAVIOR

FENS Forum 2026

Myelination of Parvalbumin interneurons is critical to maintain high-frequency firing and self-inhibitory neurotransmission

Layer-specific stimulations of parvalbumin-positive interneurons in mice entrain brain rhythms to different frequencies

Dlx5/6 levels in mouse GABAergic neurons affect adult Parvalbumin-positive neuronal density and control anxiety/compulsive behaviours

Involvement of parvalbumin-positive GABAergic neurons in basal forebrain modulation in a mouse model of neuropathic pain

Involvement of nucleus accumbens parvalbumin interneurons in cocaine seeking behavior

Abnormal changes in hippocampal synaptic plasticity are accompanied by parvalbumin reductions in the TgF344 rat model for Alzheimer’s disease

Investigating the mechanisms underlying the beneficial effects of exercise on cognitive impairment associated with schizophrenia - focus on parvalbumin interneurons and perineuronal nets

Increased excitability of parvalbumin-positive interneurons in premotor cortical area in a mouse model of obsessive-compulsive disorder

Impact of early disruption of parvalbumin interneuron-OPC interactions on prefrontal-dependent cognitive processes

Hyperpolarization-activated cyclic nucleotide-gated channels regulate response probability in the terminals of parvalbumin positive basket cells

Continuous stress affects kainate receptor-dependent inhibition by parvalbumin neurons in the mouse amygdala

Retrosplenial Parvalbumin Interneurons Gate the Egocentric Vector Coding of Environmental Geometry

COSYNE 2025

Parvalbumin-positive interneuron regulation of maternal pup retrieval behavior

COSYNE 2022