Lateralized Changes in Language Associated Auditory and Somatosensory Cortices in Autism.

Lateralized specialization of the two cerebral hemispheres is a fundamental structural hallmark of the human brain and underlies many cognitive functions and behavioral abilities. In typical developing individuals the influence of handedness on performance of various sensory modalities and the cortical processing has been well recognized. Increasing evidence suggests that several neurodevelopmental and psychiatric disorders such as bipolar disorder, schizophrenia, and autism spectrum disorders (ASD) are associated with abnormal patterns of cerebral lateralization. Individuals with ASD exhibit abnormal structural and functional lateralization of circuits subserving motor, auditory, somatosensory, visual face processing, and language-related functions. Furthermore, a high prevalence of atypical handedness has been reported in ASD individuals. While the hemispheric dominance is also related to functions other than handedness, there is a clear relationship between handedness and language-related cortical dominance. This minireview summarizes these recent findings on asymmetry in somatosensory and auditory cortical structures associated with language processing in ASD. I will also discuss the importance of cortical dominance and interhemispheric disruption of balance between excitatory and inhibitory synapses as pathophysiological mechanisms in ASD.

Lateralized Decrease of Parvalbumin+ Cells in the Somatosensory Cortex of ASD Models Is Correlated with Unilateral Tactile Hypersensitivity.

Inhibitory control of excitatory networks contributes to cortical functions. Increasing evidence indicates that parvalbumin (PV+)-expressing basket cells (BCs) are a major player in maintaining the balance between excitation (E) and inhibition (I). Disruption of E/I balance in cortical networks is believed to be a hallmark of autism spectrum disorder (ASD). Here, we report a lateralized decrease in the number of PV+ BCs in L2/3 of the somatosensory cortex in the dominant hemisphere of Shank3-/- and Cntnap2-/- mouse models of ASD. The dominant hemisphere was identified during a reaching task to establish each animal's dominant forepaw. Double labeling with anti-PV antibody and a biotinylated lectin (Vicia villosa lectin [VVA]) showed that the number of BCs was not different but rather, some BCs did not express PV (PV-), resulting in an elevated number of PV- VVA+ BCs. Finally, we showed that dominant hindpaws had higher mechanical sensitivity when compared with the other hindpaws. This mechanical hypersensitivity in the dominant paw strongly correlated with the decrease in the number of PV+ interneurons and reduced PV expression in the corresponding cortex. Together, these results suggest that the hypersensitivity in ASD patients could be due to decreased inhibitory inputs to the dominant somatosensory cortex.

Neuron-astrocyte networking: astrocytes orchestrate and respond to changes in neuronal network activity across brain states and behaviors.

Astrocytes are known to play many important roles in brain function. However, research underscoring the extent to which astrocytes modulate neuronal activity is still underway. Here we review the latest evidence regarding the contribution of astrocytes to neuronal oscillations across the brain, with a specific focus on how astrocytes respond to changes in brain state (e.g., sleep, arousal, stress). We then discuss the general mechanisms by which astrocytes signal to neurons to modulate neuronal activity, ultimately driving changes in behavior, followed by a discussion of how astrocytes contribute to respiratory rhythms in the medulla. Finally, we contemplate the possibility that brain stem astrocytes could modulate brainwide oscillations by communicating the status of oxygenation to higher cortical areas.

Astrocytes integrate and drive action potential firing in inhibitory subnetworks.

Many brain functions depend on the ability of neural networks to temporally integrate transient inputs to produce sustained discharges. This can occur through cell-autonomous mechanisms in individual neurons and through reverberating activity in recurrently connected neural networks. We report a third mechanism involving temporal integration of neural activity by a network of astrocytes. Previously, we showed that some types of interneurons can generate long-lasting trains of action potentials (barrage firing) following repeated depolarizing stimuli. Here we show that calcium signaling in an astrocytic network correlates with barrage firing; that active depolarization of astrocyte networks by chemical or optogenetic stimulation enhances; and that chelating internal calcium, inhibiting release from internal stores, or inhibiting GABA transporters or metabotropic glutamate receptors inhibits barrage firing. Thus, networks of astrocytes influence the spatiotemporal dynamics of neural networks by directly integrating neural activity and driving barrages of action potentials in some populations of inhibitory interneurons.

Serotonin selectively enhances perception and sensory neural responses to stimuli generated by same-sex conspecifics.

Centrifugal serotonergic fibers innervating sensory brain areas are seen ubiquitously across systems and species but their function remains unclear. Here we examined the functional role of serotonergic innervation onto electrosensory neurons in weakly electric fish by eliciting endogenous release through electrical stimulation as well as exogenous focal application of serotonin in the vicinity of the cell being recorded from. Both approaches showed that the function of serotonergic input onto electrosensory pyramidal neurons is to render them more excitable by reducing the spike afterhyperpolarization amplitude and thereby promoting burst firing. Further, serotonergic input selectively improved neuronal responses to stimuli that occur during interactions between same-sex conspecifics but not to stimuli associated with either prey or that occur during interactions between opposite-sex conspecifics. Finally, we tested whether serotonin-mediated enhanced pyramidal neuron responses to stimuli associated with same-sex conspecifics actually increase perception by the animal. Our behavioral experiments show that exogenous injection and endogenous release of serotonin both increase the magnitude of behavioral responses to stimuli associated with same-sex conspecifics as well as simultaneously decrease aggressive behaviors. Thus, our data indicate that the serotonergic system inhibits aggressive behavior toward same-sex conspecifics, while at the same time increasing perception of stimuli associated with these individuals. This function is likely to be conserved across systems and species.

Mechanisms of retroaxonal barrage firing in hippocampal interneurons.

We recently described a new form of neural integration and firing in a subset of interneurons, in which evoking hundreds of action potentials over tens of seconds to minutes produces a sudden barrage of action potentials lasting about a minute beyond the inciting stimulation. During this persistent firing, action potentials are generated in the distal axon and propagate retrogradely to the soma. To distinguish this from other forms of persistent firing, we refer to it here as 'retroaxonal barrage firing', or 'barrage firing' for short. Its induction is blocked by chemical inhibitors of gap junctions and curiously, stimulation of one interneuron in some cases triggers barrage firing in a nearby, unstimulated interneuron. Beyond these clues, the mechanisms of barrage firing are unknown. Here we report new results related to these mechanisms. Induction of barrage firing was blocked by lowering extracellular calcium, as long as normal action potential threshold was maintained, and it was inhibited by blocking L-type voltage-gated calcium channels. Despite its calcium dependence, barrage firing was not prevented by inhibiting chemical synaptic transmission. Furthermore, loading the stimulated/recorded interneuron with BAPTA did not block barrage firing, suggesting that the required calcium entry occurs in other cells. Finally, barrage firing was normal in mice with deletion of the primary gene for neuronal gap junctions (connexin36), suggesting that non-neuronal gap junctions may be involved. Together, these findings suggest that barrage firing is probably triggered by a multicellular mechanism involving calcium signalling and gap junctions, but operating independently of chemical synaptic transmission.

Sub- and suprathreshold adaptation currents have opposite effects on frequency tuning.

Natural stimuli are often characterized by statistics that can vary over orders of magnitude. Experiments have shown that sensory neurons continuously adapt their responses to changes in these statistics, thereby optimizing information transmission. However, such adaptation can also alter the neuronal transfer function by attenuating if not eliminating responses to the low frequency components of time varying stimuli,which can create ambiguity in the neural code. We recorded from electrosensory pyramidal neurons before and after pharmacological inactivation of either calcium-activated (I(AHP)) or KCNQ voltage-gated potassium currents (I(M)). We found that blocking each current decreased adaptation in a similar fashion but led to opposite changes in the neuronal transfer function. Indeed, blocking I(AHP) increased while blocking I(M) instead decreased the response to low temporal frequencies. To understand this surprising result, we built a mathematical model incorporating each channel type. This model predicted that these differential effects could be accounted for by differential activation properties. Our results show that the mechanisms that mediate adaptation can either increase or decrease the response to low frequency stimuli. As such, they suggest that the nervous system resolves ambiguity resulting from adaptation through independent control of adaptation and the neuronal transfer function.

Inhibition of SK and M channel-mediated currents by 5-HT enables parallel processing by bursts and isolated spikes.

Although serotonergic innervation of sensory brain areas is ubiquitous, its effects on sensory information processing remain poorly understood. We investigated these effects in pyramidal neurons within the electrosensory lateral line lobe (ELL) of weakly electric fish. Surprisingly, we found that 5-HT is present at different levels across the different ELL maps; the presence of 5-HT fibers was highest in the map that processes intraspecies communication signals. Electrophysiological recordings revealed that 5-HT increased excitability and burst firing through a decreased medium afterhyperpolarization resulting from reduced small-conductance calcium-activated (SK) currents as well as currents mediated by an M-type potassium channel. We next investigated how 5-HT alters responses to sensory input. 5-HT application decreased the rheobase current, increased the gain, and decreased first spike latency. Moreover, it reduced discriminability between different stimuli, as quantified by the mutual information rate. We hypothesized that 5-HT shifts pyramidal neurons into a burst-firing mode where bursts, when considered as events, can detect the presence of particular stimulus features. We verified this hypothesis using signal detection theory. Our results indeed show that serotonin-induced bursts of action potentials, when considered as events, could detect specific stimulus features that were distinct from those detected by isolated spikes. Moreover, we show the novel result that isolated spikes transmit more information after 5-HT application. Our results suggest a novel function for 5-HT in that it enables differential processing by action potential patterns in response to current injection.

Effect of sertraline on ouabain-induced arrhythmia in isolated guinea-pig atria.

BACKGROUND: The effect of sertraline a selective serotonin reuptake inhibitor antidepressant was studied on ouabain-induced toxicity (arrhythmia) in spontaneously beating isolated guinea-pig atria. METHODS: The guinea-pig atrium was dissected out and suspended in modified Krebs solution under physiological conditions. Drugs were added into solutions. The changes in rate and force of contractions were measured using a physiograph. RESULTS: Sertraline (2-16 microg/mL) caused a dose-dependent decrease in the rate of contractions (17-46%) and in the contractile force (26-48%). Ouabain alone (1.2 microg/mL) produced arrhythmia at 7.8 min and asystole at 22 min. Pre- administration of the atria with sertraline (8 microg/mL) significantly increased the time required to produce arrhythmia by ouabain to 20.5 min, prolonged the beating of atria to more than 64.5 min and delayed the occurrence of asystolia. The pattern of contractile force induced by sertraline + ouabain was more regular than that produced by ouabain alone. CONCLUSIONS: These findings indicate that sertraline produces direct cardiac action, probably due to the inhibition of cardiac Na(+) and Ca(2+) channels. Our results suggest that sertraline may reduce the membrane conduction through inhibition of ionic channels which decrease ouabain-induced arrhythmia.

A preliminary study on the interaction of fluvoxamine and adenosine receptor on isolated Guinea-pig atria.

Fluvoxamine (FLV), a selective serotonin reuptake inhibitor (SSRI) antidepressant, caused a dose-dependent decrease in rate and contractile force of the isolated guinea-pig atria. These effects significantly blocked by DPCPX, a specific A(1) receptor antagonist. Theophylline, an A(1)/A(2A) receptor antagonist, also prevented the inotropic and chronotropic effect of FLV. The atrium was dissected out and suspended in modified Krebs solution under physiologic conditions. Drug was added to the solution. The changes in rate and contractions were measured using a physiograph. The data indicate that DPCPX and theophylline prevent the inotropic and chronotropic effects of FLV on atria, but these effects were not prevented by atropine and DMPX, an A(2) receptor antagonist. Adenosine A(1) receptor blockade attenuates FLV effects in isolated guinea-pig atria.

Involvement of adenosine in the effect of fluoxetine on isolated guinea-pig atria.

The effect of fluoxetine (FL) a selective serotonin reuptake inhibitor antidepressant was studied on the rate and force of contractions of isolated guinea-pig atria. FL (2-16 microg/ml) caused a decrease in the rate (13-45%) and contractile force (41-53%) of isolated guinea-pig atria in a dose-dependent manner. These negative inotropic and chronotropic effect of FL (4 microg/ml) were not prevented by atropine (1 microg/ml) and 3,7-dimethyl-1-propargylxanthine (DMPX; 1.5 microg/ml), an adenosine A(2) receptor antagonist, but 1,3-dipropargyl-8-cyclopentylxanthine (DPCPX;12 microg/ml), a specific adenosine A(1) receptor antagonist significantly blocked these effects (P < 0.001) and theophylline (30 microg/ml) a non- selective adenosine A(1)/A(2A) receptor antagonist also prevented the inotropic and chronotropic effects of FL. These results suggest that the negative chronotropic and inotropic effect of FL on isolated guinea-pig atria is probably mediated through an inhibition of the reuptake of adenosine or the A(1) receptor mechanism.

The effect of fluvoxamine on ouabain-induced arrhythmia in isolated guinea-pig atria.

The effect of fluvoxamine (FLV) a selective serotonin reuptake inhibitor agent was studied on ouabain-induced arrhythmia in spontaneously beating isolated guinea-pig atria. FLV (8-64 microM) caused a dose-dependent decrease in the rate of contractions (7-52%) and in the contractile force (11-57%). Ouabain alone (2 microM) produced arrhythmia at 4.6 min and asystole at 17.4 min. Pre-administration of the atria with FLV (32 microM) significantly increased the time required to produce arrhythmia by ouabain to 14.6 min, prolonged the beating of atria to more than 58.6 min and delayed the occurrence of asystolia. The pattern of contractile force induced by FLV+ouabain was more regular than that produced by ouabain alone. These findings indicate that FLV produces direct cardiac action, probably due to the inhibition of cardiac Na+ and Ca2+ channels. Our results suggest that FLV may reduce the membrane conduction through inhibition of ionic channels which decrease ouabain-induced arrhythmia.

Mechanism of inhibitory effect of citalopram on isolated guinea-pig atria in relation to adenosine receptor.

The effect of citalopram (CTP), a selective serotonin reuptake inhibitor antidepressant was studied on the rate and force of contractions of isolated guinea-pig atria. CTP (2-32 microg/ml) caused a dose-dependent decrease in the contractile force (7%-62%) and in the rate of contractions (11%-72%). These negative inotropic and chronotropic effects of CTP (8 microg/ml) were not prevented by atropine (1 microg/ml) and 3,7 dimethyl-1-propargylxanthine (DMPX; 1.5 microg/ml), an adenosine A(2) receptor antagonist, but 1,3 dipropargyl-8-cyclopentylxanthine (DPCPX; 12 microg/ml), a specific adenosine A(1) receptor antagonist significantly blocked these effects (p < 0.001) and theophylline (30 microg/ml) a non-selective adenosine A(1)/A(2A) receptor antagonist also prevented the inotropic and chronotropic effects of CTP. These results suggest that the negative inotropic and chronotropic effect of CTP on isolated guinea-pig atria is probably mediated through an inhibition of the uptake of adenosine or the A(1) receptor mechanism.