Interneurons In Prefrontal Cortex Research Articles

Long-term adaptation of prefrontal circuits in a mouse model of NMDAR hypofunction

Pharmacological approaches to induce N-methyl-d-aspartate receptor (NMDAR) hypofunction have been intensively used to understand the aetiology and pathophysiology of schizophrenia. Yet, the precise cellular and molecular mechanisms that relate to brain network dysfunction remain largely unknown. Here, we used a set of complementary approaches to assess the functional network abnormalities present in male mice that underwent a 7-day subchronic phencyclidine (PCP 10 mg/kg, subcutaneously, once daily) treatment. Our data revealed that pharmacological intervention with PCP affected cognitive performance and auditory evoked gamma oscillations in the prefrontal cortex (PFC) mimicking endophenotypes of some schizophrenia patients. We further assessed PFC cellular function and identified altered neuronal intrinsic membrane properties, reduced parvalbumin (PV) immunostaining and diminished inhibition onto L5 PFC pyramidal cells. A decrease in the strength of optogenetically-evoked glutamatergic current at the ventral hippocampus to PFC synapse was also demonstrated, along with a weaker shunt of excitatory transmission by local PFC interneurons. On a macrocircuit level, functional ultrasound measurements indicated compromised functional connectivity within several brain regions particularly involving PFC and frontostriatal circuits. Herein, we reproduced a panel of schizophrenia endophenotypes induced by subchronic PCP application in mice. We further recapitulated electrophysiological signatures associated with schizophrenia and provided an anatomical reference to critical elements in the brain circuitry. Together, our findings contribute to a better understanding of the physiological underpinnings of deficits induced by subchronic NMDAR antagonist regimes and provide a test system for characterization of pharmacological compounds.

Selective ablation of VIP interneurons in the rodent prefrontal cortex results in increased impulsivity.

It has been well-established that novelty-seeking and impulsivity are significant risk factors for the development of psychological disorders, including substance use disorder and behavioral addictions. While dysfunction in the prefrontal cortex is at the crux of these disorders, little is known at the cellular level about how alterations in neuron activity can drive changes in impulsivity and novelty seeking. We harnessed a cre-dependent caspase-3 ablation in both male and female mice to selectively ablate vasoactive intestinal peptide (VIP)-expressing interneurons in the prefrontal cortex to better explore how this microcircuit functions during specific behavioral tasks. Caspase-ablated animals had no changes in anxiety-like behaviors or hedonic food intake but had a specific increase in impulsive responding during longer trials in the three-choice serial reaction time test. Together, these data suggest a circuit-level mechanism in which VIP interneurons function as a gate to selectively respond during periods of high expectation.

LPS-induced acute neuroinflammation, involving interleukin-1 beta signaling, leads to proteomic, cellular, and network-level changes in the prefrontal cortex of mice

Neuroinflammation induced by peripheral infections leads to various neuropsychiatric symptoms both in humans and laboratory animals, e.g., to the manifestation of sickness behavior that resembles some features of clinical depression. However, in addition to depression-like behavior, there are other symptoms of acute systemic inflammation that can be associated with the impairment of prefrontal cortex (PFC)-regulated cognitive functions. Thus, we investigated the electrophysiological and proteomic alterations of the PFC using brain slices and the lipopolysaccharide (LPS) model of acute peripheral infection in male mice. Based on the gene expression differences of the coreceptor (Il1rap) of interleukin-1 beta (IL-1β) between neuron types in our previous single-cell sequencing dataset, we first compared the electrophysiological effects of IL-1β on PFC pyramidal cells and interneurons. We found that pyramidal cells are more responsive to IL-1β, as could be presumed from our transcriptomic data. To examine the possible circuit-level correlates of the cellular changes, frontal electroencephalographic (EEG) activity and fronto-occipital functional connectivity were analyzed in LPS-treated mice and significant changes were found in the fronto-occipital EEG correlation and coherence in the delta and high-gamma frequency bands. The upregulation of the prefrontal IL-1 system (IL-1β and its receptor) after LPS treatment was revealed by immunoassays simultaneously with the observed EEG changes. Furthermore, we investigated the LPS-induced alterations of the synaptic proteome in the PFC using 2-D differential gel electrophoresis and mass spectrometry and found 48 altered proteins mainly related to cellular signaling, cytoskeletal organization, and carbohydrate/energy metabolism. Thus, our results indicate remarkable electrophysiological and molecular changes in the PFC related to acute systemic inflammation that may explain some of the concomitant behavioral and physiological symptoms.

Maternal immune activation alters fetal and neonatal microglia phenotype and disrupts neurogenesis in mice.

Activation of microglia, increase in cortical neuron density, and reduction in GABAergic interneurons are some of the key findings in postmortem autism spectrum disorders (ASD) subjects. The aim of this study was to investigate how maternal immune activation (MIA) programs microglial phenotypes and abnormal neurogenesis in offspring mice. MIA was induced by injection of lipopolysaccharide (LPS, i.p.) to pregnant mice at embryonic (E) day 12.5. Microglial phenotypes and neurogenesis were investigated between E15.5 to postnatal (P) day 21 by immunohistochemistry, flow cytometry, and cytokine array. MIA led to a robust increase in fetal and neonatal microglia in neurogenic regions. Homeostatic E15.5 and P4 microglia are heterogeneous, consisting of M1 (CD86+/CD206-) and mixed M1/M2 (CD86+/CD206+)-like subpopulations. MIA significantly reduced M1 but increased mixed M1/M2 microglia, which was associated with upregulation of numerous cytokines with pleotropic property. MIA resulted in a robust increase in Ki67+/Nestin+ and Tbr2+ neural progenitor cells in the subventricular zone (SVZ) of newborn mice. At juvenile stage, a male-specific reduction of Parvalbumin+ but increase in Reelin+ interneurons in the medial prefrontal cortex was found in MIA offspring mice. MIA programs microglia towards a pleotropic phenotype that may drive excessive neurogenesis in ASD patients. Maternal immune activation (MIA) alters microglial phenotypes in the brain of fetal and neonatal mouse offspring. MIA leads to excessive proliferation and overproduction of neural progenitors in the subventricular zone (SVZ). MIA reduces parvalbumin+ while increases Reelin+ interneurons in the prefrontal cortex. Our study sheds light on neurobiological mechanisms of abnormal neurogenesis in certain neurodevelopmental disorders, such as autism spectrum disorder (ASD).

Impact of adolescent intermittent ethanol exposure on interneurons and their surrounding perineuronal nets in adulthood.

Binge alcohol exposure during adolescence results in long-lasting alterations in the brain and behavior. For example, adolescent intermittent ethanol (AIE) exposure in rodents results in long-term loss of functional connectivity among prefrontal cortex (PFC) and striatal regions as well as a variety of neurochemical, molecular, and epigenetic alterations. Interneurons in the PFC and striatum play critical roles in behavioral flexibility and functional connectivity. For example, parvalbumin (PV) interneurons are known to contribute to neural synchrony and cholinergic interneurons contribute to strategy selection. Furthermore, extracellular perineuronal nets (PNNs) that surround some interneurons, particularly PV+ interneurons, further regulate cellular plasticity. The effect of AIE exposure on the expression of these markers within the PFC is not well understood. The present study tested the hypothesis that AIE exposure reduces the expression of PV+ and choline acetyltransferase (ChAT)+ interneurons in the adult PFC and striatum and increases the related expression of PNNs (marked by binding of Wisteria floribunda agglutinin lectin) in adulthood. Male rats were exposed to AIE (5g/kg/day, 2-days-on/2-days-off, i.e., P25 to P54) or water (CON), and brain tissue was harvested in adulthood (>P80). Immunohistochemistry and co-immunofluorescence were used to assess the expression of ChAT, PV, and PNNs within the adult PFC and striatum following AIE exposure. ChAT and PV interneuron densities in the striatum and PFC were unchanged after AIE exposure. However, PNN density in the PFC of AIE-exposed rats was greater than in CON rats. Moreover, significantly more PV neurons were surrounded by PNNs in AIE-exposed subjects than controls in both PFC subregions assessed: orbitofrontal cortex (CON=34%; AIE=40%) and medial PFC (CON=10%; AIE=14%). These findings indicate that, following AIE exposure, PV interneuron expression in the adult PFC and striatum is unaltered, while PNNs surrounding these neurons are increased. This increase in PNNs may restrict the plasticity of the ensheathed neurons, thereby contributing to impaired microcircuitry in frontostriatal connectivity and related behavioral impairments.

Theta activity paradoxically boosts gamma and ripple frequency sensitivity in prefrontal interneurons

Fast oscillations in cortical circuits critically depend on GABAergic interneurons. Which interneuron types and populations can drive different cortical rhythms, however, remains unresolved and may depend on brain state. Here, we measured the sensitivity of different GABAergic interneurons in prefrontal cortex under conditions mimicking distinct brain states. While fast-spiking neurons always exhibited a wide bandwidth of around 400 Hz, the response properties of spike-frequency adapting interneurons switched with the background input's statistics. Slowly fluctuating background activity, as typical for sleep or quiet wakefulness, dramatically boosted the neurons' sensitivity to gamma and ripple frequencies. We developed a time-resolved dynamic gain analysis and revealed rapid sensitivity modulations that enable neurons to periodically boost gamma oscillations and ripples during specific phases of ongoing low-frequency oscillations. This mechanism predicts these prefrontal interneurons to be exquisitely sensitive to high-frequency ripples, especially during brain states characterized by slow rhythms, and to contribute substantially to theta-gamma cross-frequency coupling.

Attenuated NMDAR signaling on fast-spiking interneurons in prefrontal cortex contributes to age-related decline of cognitive flexibility

Ionotropic glutamate receptors of the NMDA and AMPA subtypes transduce excitatory signaling on neurons in the prefrontal cortex (PFC) in support of cognitive flexibility. Cognitive flexibility is reliably observed to decline at advanced ages, coinciding with changes in PFC glutamate receptor expression and neuronal physiology. However, the relationship between age-related impairment of cognitive flexibility and changes to excitatory signaling on distinct classes of PFC neurons is not known. In this study, one cohort of young adult (4 months) and aged (20 months) male F344 rats were characterized for cognitive flexibility on an operant set-shifting task. Expression of the essential NMDAR subunit, NR1, was correlated with individual differences in set-shifting abilities such that lower NR1 in the aged PFC was associated with worse set-shifting. In contrast, lower expression of two AMPAR subunits, GluR1 and GluR2, was not associated with set-shift abilities in aging. As NMDARs are expressed by both pyramidal cells and fast-spiking interneurons (FSI) in PFC, whole-cell patch clamp recordings were performed in a second cohort of age-matched rats to compare age-associated changes on these neuronal subtypes. Evoked excitatory postsynaptic currents were generated using a bipolar stimulator while AMPAR vs. NMDAR-mediated components were isolated using pharmacological tools. The results revealed a clear increase in AMPA/NMDA ratio in FSIs that was not present in pyramidal neurons. Together, these data indicate that loss of NMDARs on interneurons in PFC contributes to age-related impairment of cognitive flexibility.

\u0394-9-Tetrahydrocannabinol treatment during adolescence and alterations in the inhibitory networks of the adult prefrontal cortex in mice subjected to perinatal NMDA receptor antagonist injection and to postweaning social isolation

The prefrontal cortex (PFC) continues its development during adolescence and alterations in its structure and function, particularly of inhibitory networks, have been detected in schizophrenic patients. Since cannabis use during adolescence is a risk factor for this disease, our main objective was to investigate whether THC administration during this period might exacerbate alterations in prefrontocortical inhibitory networks in mice subjected to a perinatal injection of MK801 and postweaning social isolation. This double-hit model (DHM) combines a neurodevelopmental manipulation and the exposure to an aversive experience during early life; previous work has shown that DHM mice have important alterations in the structure and connectivity of PFC interneurons. In the present study we found that DHM had reductions in prepulse inhibition of the startle reflex (PPI), GAD67 expression and cingulate 1 cortex volume. Interestingly, THC by itself induced increases in PPI and decreases in the dendritic complexity of somatostatin expressing interneurons. Both THC and DHM reduced the density of parvalbumin expressing cells surrounded by perineuronal nets and, when combined, they disrupted the ratio between the density of puncta expressing excitatory and inhibitory markers. Our results support previous work showing alterations in parameters involving interneurons in similar animal models and schizophrenic patients. THC treatment does not modify further these parameters, but changes some others related also to interneurons and their plasticity, in some cases in the opposite direction to those induced by the DHM, suggesting a protective effect.

S189. PREFRONTAL PARVALBUMIN INTERNEURONS REQUIRE JUVENILE SOCIAL EXPERIENCE TO ESTABLISH ADULT SOCIAL BEHAVIOR

BackgroundSocial isolation during developmental critical windows could be highly detrimental to proper functioning of mature prefrontal cortex (PFC) and establishment of appropriate adult behaviors. However, the specific circuits that undergo social experience-dependent maturation to regulate social behavior development are poorly understood. Social processing is a domain that is commonly dysregulated in psychiatric disorders including Schizophrenia, and is poorly treated by available psychiatric medications. In humans and rodents, portions of the evolutionarily conserved medial prefrontal cortex (mPFC) are part of a network that regulates social behavior. Many disorders with shared social processing deficits show impairments in inhibitory neurotransmission within the brain, particularly in the mPFC, suggesting a role for PFC inhibitory action in regulating social behavior. Parvalbumin expressing interneurons (PVIs) are one of the major subclasses of inhibitory neurons, implicated in psychiatric disorders. Here we aim to examine a contribution of PVIs in mPFC for social behavior development in mice.MethodsWe use juvenile social isolation (jSI) during a 2-week sensitive window immediately following weaning and test social behavior in adult mice using the 3-chamber test and reciprocal interaction test. To investigate the causal contribution of mPFC-PVIs in social behavior of adult mice, we leveraged chemogenetic technologies. We selectively expressed hM4Di, an inhibitory DREADD (Designer Receptor Exclusively Activated by Designer Drugs), or hM3Dq an excitatory DREADD in the adult mPFC-PVIs and manipulated mPFC-PVI activity acutely using the selective DREADD agonist, Clozapine-N-oxide (CNO). To test the activity of mPFC-PVIs in response to social experience we used in vivo imaging of calcium transients by fiber photometry.ResultsWe identified a specific activation pattern of parvalbumin-positive interneurons (PVIs) in dorsal-medial PFC (dmPFC) prior to an active bout, or a bout initiated by the focal mouse, but not during a passive bout when mice are explored by a stimulus mouse. Optogenetic and chemogenetic manipulation revealed that brief dmPFC-PVI activation triggers an active social approach to promote sociability. Juvenile social isolation critically decoupled dmPFC-PVI activation from subsequent active social approach by “freezing” the functional maturation process of dmPFC-PVIs during the juvenile-to-adult transition. Chemogenetic activation of dmPFC-PVI activity in the adult animal mitigated juvenile isolation-induced social deficits.DiscussionThese results demonstrate that PVI development in the juvenile mPFC is critically linked to long-term impacts on social behavior. Our study implicates mPFC PVIs as promising cellular targets for future therapeutic development on social impairments in psychiatric disorders such as Schizophrenia.

Computational Investigation of Contributions from Different Subtypes of Interneurons in Prefrontal Cortex for Information Maintenance

Interneurons play crucial roles in neocortex associated with high-level cognitive functions; however, the specific division of labor is still under investigation. Interneurons are exceptionally diverse in their morphological appearance and functional properties. In this study, we modify a prefrontal multicolumn circuit in which five subtypes of inhibitory interneurons play distinct roles in the maintenance of transient information. These interneurons are classified according to the extending range of axonal projections. Our work simplifies the division of labor between different types of interneurons for the maintenance of information and the principle of functional redundancy of the brain from the perspective of computational modeling. This model presents a framework to understand the cooperation between different interneurons in a recurrent cortical circuit.

Prefrontal parvalbumin interneurons require juvenile social experience to establish adult social behavior

Social isolation during the juvenile critical window is detrimental to proper functioning of the prefrontal cortex (PFC) and establishment of appropriate adult social behaviors. However, the specific circuits that undergo social experience-dependent maturation to regulate social behavior are poorly understood. We identify a specific activation pattern of parvalbumin-positive interneurons (PVIs) in dorsal-medial PFC (dmPFC) prior to an active bout, or a bout initiated by the focal mouse, but not during a passive bout when mice are explored by a stimulus mouse. Optogenetic and chemogenetic manipulation reveals that brief dmPFC-PVI activation triggers an active social approach to promote sociability. Juvenile social isolation decouples dmPFC-PVI activation from subsequent active social approach by freezing the functional maturation process of dmPFC-PVIs during the juvenile-to-adult transition. Chemogenetic activation of dmPFC-PVI activity in the adult animal mitigates juvenile isolation-induced social deficits. Therefore, social experience-dependent maturation of dmPFC-PVI is linked to long-term impacts on social behavior.

L-type Ca2+ channels and charybdotoxin-sensitive Ca2+-activated K+ channels are required for reduction of GABAergic activity induced by β2-adrenoceptor in the prefrontal cortex

Whereas β2-adrenoceptor (β2-AR) has been reported to reduce GABAergic activity in the prefrontal cortex (PFC), the underlying cellular and molecular mechanisms have not been completely determined. Here, we showed that β2-AR agonist Clenbuterol (Clen) decreased GABAergic transmission onto PFC layer V/VI pyramidal neurons via a presynaptic mechanism without altering postsynaptic GABA receptors. Clen decreased the action potential firing rate but increased the burst afterhyperpolarization (AHP) amplitude in PFC interneurons. Application of L-type Ca2+ channel or charybdotoxin-sensitive Ca2+-activated K+ channel inhibitors blocked Clen-induced decreases in action potential firing rate, spontaneous inhibitory postsynaptic current (sIPSC) frequency and Clen-induced enhancement of AHP amplitude, suggesting that the effects of Clen involves L-type Ca2+ Channels and charybdotoxin-sensitive Ca2+-activated K+ channels. Our results provide a potential cellular mechanism by which Clen controls GABAergic neuronal activity in PFC.

The Thalamus Regulates Retinoic Acid Signaling and Development of Parvalbumin Interneurons in Postnatal Mouse Prefrontal Cortex.

GABAergic inhibitory neurons in the prefrontal cortex (PFC) play crucial roles in higher cognitive functions. Despite the link between aberrant development of PFC interneurons and a number of psychiatric disorders, mechanisms underlying the development of these neurons are poorly understood. Here we show that the retinoic acid (RA)-degrading enzyme CYP26B1 (cytochrome P450 family 26, subfamily B, member 1) is transiently expressed in the mouse frontal cortex during postnatal development, and that medial ganglionic eminence (MGE)-derived interneurons, particularly in parvalbumin (PV)-expressing neurons, are the main cell type that has active RA signaling during this period. We found that frontal cortex-specific Cyp26b1 knock-out mice had an increased density of PV-expressing, but not somatostatin-expressing, interneurons in medial PFC, indicating a novel role of RA signaling in controlling PV neuron development. The initiation of Cyp26b1 expression in neonatal PFC coincides with the establishment of connections between the thalamus and the PFC. We found that these connections are required for the postnatal expression of Cyp26b1 in medial PFC. In addition to this region-specific role in postnatal PFC that regulates RA signaling and PV neuron development, the thalamocortical connectivity had an earlier role in controlling radial dispersion of MGE-derived interneurons throughout embryonic neocortex. In summary, our results suggest that the thalamus plays multiple, temporally separate roles in interneuron development in the PFC.

Effects of Low Doses of Ketamine on Pyramidal Neurons in Rat Prefrontal Cortex

Indirect evidence suggests that low doses of ketamine disinhibit (excite) pyramidal neurons in the prefrontal cortex (PFC). In this study, we directly examined the effect of ketamine on PFC pyramidal neurons using simultaneous single-cell and local-field-potential (LFP) recording in chloral hydrate-anesthetized rats. In all animals studied, PFC LFPs showed oscillations (0.3–1.5 Hz) between the active UP state and the relatively quiescent DOWN state, and pyramidal neurons fired preferentially during the UP state. Ketamine (1.25–20 mg/kg, i.v.) inhibited 80% of cells tested and consistently shifted PFC LFPs toward the DOWN state. The inhibitory effect of ketamine was mimicked by MK801, but not by the NR2B-selective NMDA receptor antagonist Ro25-6981. It was not blocked by the dopamine receptor antagonist fluphenazine, the GABAA receptor antagonist picrotoxinin, or the GABAB receptor antagonist CGP46381. These results are consistent with the high density of NMDA receptors expressed on PFC pyramidal neurons and our previous studies showing that blockade of NMDA receptors by ketamine inhibits dendritic NMDA receptor-mediated bursting in PFC pyramidal neurons. Thus, in addition to the previously proposed disinhibitory effect mediated through PFC interneurons, our data suggest that ketamine has an inhibitory effect on PFC pyramidal neurons. Our evidence further suggests that the effect is mediated through non-NR2B-containing NMDA receptors, independent of ketamine’s effect on dopamine and GABA transmission. Further understanding of the two opposing effects of ketamine on PFC pyramidal neurons may provide important new insights into its mechanism of action.

Input Convergence, Synaptic Plasticity and Functional Coupling Across Hippocampal-Prefrontal-Thalamic Circuits.

Executive functions and working memory are long known to involve the prefrontal cortex (PFC), and two PFC-projecting areas: midline/paramidline thalamus (MLT) and cornus ammonis 1 (CA1)/subiculum of the hippocampal formation (HF). An increasing number of rodent electrophysiology studies are examining these substrates together, thus providing circuit-level perspectives on input convergence, synaptic plasticity and functional coupling, as well as insights into cognition mechanisms and brain disorders. Our review article puts this literature into a method-oriented narrative. As revisited throughout the text, limbic thalamic and hippocampal afferents to the PFC gate one another’s inputs, which in turn are modulated by PFC interneurons and ascending monoaminergic projections. In addition, long-term synaptic plasticity, paired-pulse facilitation (PPF), and event-related potentials (ERP) dynamically vary across PFC-related circuits during learning paradigms and drug effects. Finally, thalamic-prefrontal loops, which have been shown to amplify both cognitive processes and limbic seizures, are also being implicated as relays in the prefrontal-hippocampal feedback, contributing to spatial navigation and decision making. Based on these issues, we conclude the review with a critical synthesis and some research directions.

The Number of Chandelier and Basket Cells Are Differentially Decreased in Prefrontal Cortex in Autism.

An interneuron alteration has been proposed as a source for the modified balance of excitation / inhibition in the cerebral cortex in autism. We previously demonstrated a decreased number of parvalbumin(PV)-expressing interneurons in prefrontal cortex in autism. PV-expressing interneurons include chandelier (Ch) and basket (Bsk) cells. We asked whether the decreased PV+ interneurons affected both Ch cells and Bsk cells in autism. The lack of single markers to specifically label Ch cells or Bsk cells presented an obstacle for addressing this question. We devised a method to discern between PV-Ch and PV-Bsk cells based on the differential expression of Vicia villosa lectin (VVA). VVA binds to N-acetylgalactosamine, that is present in the perineuronal net surrounding some cell types where it plays a role in intercellular communication. N-acetylgalactosamine is present in the perineuronal net surrounding Bsk but not Ch cells. We found that the number of Ch cells is consistently decreased in the prefrontal cortex of autistic (n=10) when compared with control (n=10) cases, while the number of Bsk cells is not as severely affected. This finding expand our understanding of GABAergic system functioning in the human cerebral cortex in autism, which will impact translational research directed towards providing better treatment paradigms for individuals with autism.

Nerve growth factor-induced plasticity in medial prefrontal cortex interneurons of aged Wistar rats

The medial prefrontal cortex (mPFC) has been identified as a critical center for working and long-term memory. In this study, we have examined the expression of neuropeptide Y (NPY) and vasoactive intestinal polypeptide (VIP) in mPFC interneurons and the density of the mPFC cholinergic and dopaminergic innervation in cognitively-impaired aged Wistar rats. We also tested the possibility that the potential age-related changes might rely on insufficient neurotrophic support. The total number of NPY- and VIP-immunoreactive neurons and the density of vesicular acetylcholine transporter (VAChT)- and tyrosine hydroxylase (TH)-immunoreactive varicosities were estimated using stereological methods. The number of NPY-immunoreactive neurons was significantly reduced in aged rats, whereas the number of VIP-immunoreactive neurons was unaltered. The decreased expression of NPY was fully reversed by intracerebroventricular administration of nerve growth factor. No differences in the density of VAChT- and TH-immunoreactive varicosities were found among all groups. Our results indicate that the reduced expression of NPY in the mPFC of aged rats can be ascribed to the age-associated loss of neurotrophic support, and raise the possibility that these changes might contribute for the cognitive decline that occurs during non-pathological aging.

Effects of early adolescent environmental enrichment on cognitive dysfunction, prefrontal cortex development, and inflammatory cytokines after early life stress.

Early postnatal stress such as maternal separation causes cognitive dysfunction later in life, including working memory deficits that are largely mediated by the prefrontal cortex. Maternal separation in male rats also yields a loss of parvalbumin-containing prefrontal cortex interneurons in adolescence, which may occur via inflammatory or oxidative stress mechanisms. Environmental enrichment can prevent several effects of maternal separation; however, effects of enrichment on prefrontal cortex development are not well understood. Here, we report that enrichment prevented cognitive dysfunction in maternally separated males and females, and prevented elevated circulating pro-inflammatory cytokines that was evident in maternally separated males, but not females. However, enrichment did not prevent parvalbumin loss or adolescent measures of oxidative stress. Significant correlations indicated that adolescents with higher oxidative damage and less prefrontal cortex parvalbumin in adolescence committed more errors on the win-shift task; therefore, maternal separation may affect cognitive dysfunction via aberrant interneuron development. © 2015 Wiley Periodicals, Inc. Dev Psychobiol 58: 482-491, 2016.

Streptozotocin diabetic mice display depressive-like behavior and alterations in the structure, neurotransmission and plasticity of medial prefrontal cortex interneurons

Diabetes mellitus patients are at increased risk of developing depression, although the neurobiological bases of this comorbidity are not yet fully understood. These patients show CNS alterations, similar to those found in major depression, including changes in the structure and neurotransmission of excitatory neurons. However, although depressive patients and animal models also display alterations in inhibitory networks, little is known about the effects of diabetes on interneurons. Our main objective was to study the impact of diabetes on interneurons of the medial prefrontal cortex (mPFC), one of the regions most affected by major depression. For this purpose we have induced diabetes with high-dose streptozotozin in transgenic mice displaying fluorescent interneurons. These animals showed a depressive-like behavior (increased immobility time in tail suspension test) in parallel with reductions in interneuronal dendritic arborization and in the expression of GAD67, the enzyme that synthetizes the inhibitory neurotransmitter GABA. However, the levels of PSA-NCAM, a plasticity-related molecule exclusively expressed by interneurons in the mPFC, were unaltered in the different regions and layers of this cortical area. Interestingly, diabetic mice also showed increased levels of synaptophysin, a synaptic vesicle protein. These results indicate that the structure and neurotransmission of interneurons is altered in the mPFC of diabetic mice and suggest that these changes may play a key role in the depressive symptoms associated to diabetes.

Gamma Rhythms Link Prefrontal Interneuron Dysfunction with Cognitive Inflexibility in Dlx5/6+/− Mice

Abnormalities in GABAergic interneurons, particularly fast-spiking interneurons (FSINs) that generate gamma (γ; ∼30-120 Hz) oscillations, are hypothesized to disrupt prefrontal cortex (PFC)-dependent cognition in schizophrenia. Although γ rhythms are abnormal in schizophrenia, it remains unclear whether they directly influence cognition. Mechanisms underlying schizophrenia's typical post-adolescent onset also remain elusive. We addressed these issues using mice heterozygous for Dlx5/6, which regulate GABAergic interneuron development. In Dlx5/6(+/-) mice, FSINs become abnormal following adolescence, coinciding with the onset of cognitive inflexibility and deficient task-evoked γ oscillations. Inhibiting PFC interneurons in control mice reproduced these deficits, whereas stimulating them at γ-frequencies restored cognitive flexibility in adult Dlx5/6(+/-) mice. These pro-cognitive effects were frequency specific and persistent. These findings elucidate a mechanism whereby abnormal FSIN development may contribute to the post-adolescent onset of schizophrenia endophenotypes. Furthermore, they demonstrate a causal, potentially therapeutic, role for PFC interneuron-driven γ oscillations in cognitive domains at the core of schizophrenia.