Kuei Y. Tseng

Periadolescent Exposure to the NMDA Receptor Antagonist MK-801 Impairs the Functional Maturation of Local GABAergic Circuits in the Adult Prefrontal Cortex

A developmental disruption of prefrontal cortical inhibitory circuits is thought to contribute to the adolescent onset of cognitive deficits observed in schizophrenia. However, the developmental mechanisms underlying such a disruption remain elusive. The goal of this study is to examine how repeated exposure to the NMDA receptor antagonist dizocilpine maleate (MK-801) during periadolescence [from postnatal day 35 (P35) to P40] impacts the normative development of local prefrontal network response in rats. In vivo electrophysiological analyses revealed that MK-801 administration during periadolescence elicits an enduring disinhibited prefrontal local field potential (LFP) response to ventral hippocampal stimulation at 20 Hz (beta) and 40 Hz (gamma) in adulthood (P65–P85). Such a disinhibition was not observed when MK-801 was given during adulthood, indicating that the periadolescent transition is indeed a sensitive period for the functional maturation of prefrontal inhibitory control. Accordingly, the pattern of prefrontal LFP disinhibition induced by periadolescent MK-801 treatment resembles that observed in the normal P30–P40 prefrontal cortex (PFC). Additional pharmacological manipulations revealed that these developmentally immature prefrontal responses can be mimicked by single microinfusion of the GABAA receptor antagonist picrotoxin into the normal adult PFC. Importantly, acute administration of the GABAA-positive allosteric modulator Indiplon into the PFC reversed the prefrontal disinhibitory state induced by periadolescent MK-801 to normal levels. Together, these results indicate a critical role of NMDA receptors in regulating the periadolescent maturation of GABAergic networks in the PFC and that pharmacologically induced augmentation of local GABAA-receptor-mediated transmission is sufficient to overcome the disinhibitory prefrontal state associated with the periadolescent MK-801 exposure.

Differential regulation of parvalbumin and calretinin interneurons in the prefrontal cortex during adolescence

Determining the normal developmental trajectory of individual GABAergic components in the prefrontal cortex (PFC) during the adolescent transition period is critical because local GABAergic interneurons are thought to play an important role in the functional maturation of cognitive control that occurs in this developmental window. Based on the expression of calcium-binding proteins, three distinctive subtypes of interneurons have been identified in the PFC: parvalbumin (PV)-, calretinin (CR)-, and calbindin (CB)-positive cells. Using biochemical and histochemical measures, we found that the protein level of PV is lowest in juveniles [postnatal days (PD) 25–35] and increases during adolescence (PD 45–55) to levels similar to those observed in adulthood (PD 65–75). In contrast, the protein expression of CR is reduced in adults compared to juvenile and adolescent animals, whereas CB levels remain mostly unchanged across the developmental window studied here. Semi-quantitative immunostaining analyses revealed that the periadolescent upregulation of PV and the loss of the CR signal appear to be attributable to changes in PV- and CR-positive innervation, which are dissociable from the trajectory of PV- and CR-positive cell number. At the synaptic level, our electrophysiological data revealed that a developmental facilitation of spontaneous glutamatergic synaptic inputs onto PV-positive/fast-spiking interneurons parallels the increase in prefrontal PV signal during the periadolescent transition. In contrast, no age-dependent changes in glutamatergic transmission were observed in PV-negative/non fast-spiking interneurons. Together, these findings emphasize that GABAergic inhibitory interneurons in the PFC undergo a dynamic, cell type-specific remodeling during adolescence and provide a developmental framework for understanding alterations in GABAergic circuits that occur in psychiatric disorders.

Nitric Oxide-Soluble Guanylyl Cyclase-Cyclic GMP Signaling in the Striatum: New Targets for the Treatment of Parkinson's Disease?

Striatal nitric oxide (NO)-producing interneurons play an important role in the regulation of corticostriatal synaptic transmission and motor behavior. Striatal NO synthesis is driven by concurrent activation of NMDA and dopamine (DA) D1 receptors. NO diffuses into the dendrites of medium-sized spiny neurons which contain high levels of NO receptors called soluble guanylyl cyclases (sGC). NO-mediated activation of sGC leads to the synthesis of the second messenger cGMP. In the intact striatum, transient elevations in intracellular cGMP primarily act to increase neuronal excitability and to facilitate glutamatergic corticostriatal transmission. NO–cGMP signaling also functionally opposes the inhibitory effects of DA D2 receptor activation on corticostriatal transmission. Not surprisingly, abnormal striatal NO–sGC–cGMP signaling becomes apparent following striatal DA depletion, an alteration thought to contribute to pathophysiological changes observed in basal ganglia circuits in Parkinsons disease (PD). Here, we discuss recent developments in the field which have shed light on the role of NO–sGC–cGMP signaling pathways in basal ganglia dysfunction and motor symptoms associated with PD and l-DOPA-induced dyskinesias.

Stepping test in mice: A reliable approach in determining forelimb akinesia in MPTP-induced Parkinsonism

Currently existing behavioral measures for motor impairments in rodent models with bilateral dopamine depletion have demonstrated to be difficult to assess due to the degree of task complexity. There is clearly a need for a behavioral test that is simplistic in design and does not require the animal to learn a specific task, in particular for mice. Here we adapted the stepping test, originally designed for assessing asymmetric motor deficits in rats (Olsson, M., Nikkhah, G., Bentlage, C., Bjorklund, A., 1995. Forelimb akinesia in the rat Parkinson model: differential effects of dopamine agonists and nigral transplants as assessed by a new stepping test. J. Neurosci. 15, 3863-3875; Schallert, T., De Ryck, M., Whishaw, I.Q., Ramirez, V.D., Teitelbaum, P., 1979. Excessive bracing reactions and their control by atropine and l-DOPA in an animal analog of Parkinsonism. Exp. Neurol. 64, 33-43), into a mouse-friendly version for bilateral dopamine lesion induced by subacute MPTP injection. We found that MPTP-treated mice exhibit a significant and persistent reduction in the number of adjusting steps when compared to saline-treated animals. Typically, MPTP-induced stepping deficit becomes apparent by the fourth MPTP injection. The number of adjusting steps continues to decline throughout the injections, and by day 10 from the last MPTP injection, the stepping deficit observed is associated with approximately 65% TH positive cells loss in the SN. Importantly, L-DOPA administration significantly improved stepping performance in MPTP-treated mice. Thus, stepping test in mice is a reliable and simple behavioral measure for assessing forelimb akinesia induced by systemic MPTP.

Developmental Disruption of Gamma-Aminobutyric Acid Function in the Medial Prefrontal Cortex by Noncontingent Cocaine Exposure During Early Adolescence

BACKGROUND Drug experimentation during adolescence is associated with increased risk of drug addiction relative to any other age group. To further understand the neurobiology underlying such liability, we investigate how early adolescent cocaine experience impacts medial prefrontal cortex (mPFC) network function in adulthood. METHODS A noncontingent administration paradigm was used to assess the impact of early adolescent cocaine treatment (rats; postnatal days [PD] 35-40) on the overall inhibitory regulation of mPFC activity in adulthood (PD 65-75) by means of histochemical and in vivo electrophysiological measures combined with pharmacologic manipulations. RESULTS Cocaine exposure during early adolescence yields a distinctive hypermetabolic prefrontal cortex state that was not observed in adult-treated rats (PD 75-80). Local field potential recordings revealed that early adolescent cocaine exposure is associated with an attenuation of mPFC gamma-aminobutyric acid (GABA)ergic inhibition evoked by ventral hippocampal stimulation at beta and gamma frequencies that endures throughout adulthood. Such cocaine-induced mPFC disinhibition was not observed in adult-exposed animals. Furthermore, the normal developmental upregulation of parvalbumin immunoreactivity observed in the mPFC from PD 35 to PD 65 is lacking following early adolescent cocaine treatment. CONCLUSIONS Our data indicate that repeated cocaine exposure during early adolescence can elicit a state of mPFC disinhibition resulting from a functional impairment of the local prefrontal GABAergic network that endures through adulthood. A lack of acquisition of prefrontal GABAergic function during adolescence could trigger long-term deficits in the mPFC that may increase the susceptibility for the onset of substance abuse and related psychiatric disorders.

Late Adolescent Expression of GluN2B Transmission in the Prefrontal Cortex Is Input-Specific and Requires Postsynaptic Protein Kinase A and D1 Dopamine Receptor Signaling

BACKGROUND Refinement of mature cognitive functions, such as working memory and decision making, typically takes place during adolescence. The acquisition of these functions is linked to the protracted development of the prefrontal cortex (PFC) and dopamine facilitation of glutamatergic transmission. However, the mechanisms that support these changes during adolescence remain elusive. METHODS Electrophysiological recordings (in vitro and in vivo) combined with pharmacologic manipulations were employed to determine how N-methyl-D-aspartate transmission in the medial PFC changes during the adolescent transition to adulthood. The relative contribution of GluN2B transmission and its modulation by postsynaptic protein kinase A and D1 receptor signaling were determined in two distinct age groups of rats: postnatal day (P)25 to P40 and P50 to P80. RESULTS We found that only N-methyl-D-aspartate receptor transmission onto the apical dendrite of layer V pyramidal neurons undergoes late adolescent remodeling due to a functional emergence of GluN2B function after P40. Both protein kinase A and dopamine D1 receptor signaling are required for the functional expression of GluN2B transmission and to sustain PFC plasticity in response to ventral hippocampal, but not basolateral amygdala, inputs. CONCLUSIONS Thus, the late adolescent acquisition of GluN2B function provides a mechanism for dopamine D1-mediated regulation of PFC responses in an input-specific manner.

Mechanisms contributing to prefrontal cortex maturation during adolescence.

Adolescence is defined as a transitional period between childhood and adulthood characterized by changes in social interaction and acquisition of mature cognitive abilities. These changes have been associated with the maturation of brain regions involved in the control of motivation, emotion, and cognition. Among these regions, the protracted development of the human prefrontal cortex during adolescence has been proposed to underlie the maturation of cognitive functions and the regulation of affective responses. Studies in animal models allow us to test the causal contribution of specific neural processes in the development of the prefrontal cortex and the acquisition of adult behavior. This review summarizes the cellular and synaptic mechanisms occurring in the rodent prefrontal cortex during adolescence as a model for understanding the changes underlying human prefrontal development.

Inhibition of striatal soluble guanylyl cyclase-cGMP signaling reverses basal ganglia dysfunction and akinesia in experimental parkinsonism.

Objective There is clearly a necessity to identify novel non-dopaminergic mechanisms as new therapeutic targets for Parkinsons disease (PD). Among these, the soluble guanylyl cyclase (sGC)-cGMP signaling cascade is emerging as a promising candidate for second messenger-based therapies for the amelioration of PD symptoms. In the present study, we examined the utility of the selective sGC inhibitor 1H-[1], [2], [4] oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ) for reversing basal ganglia dysfunction and akinesia in animal models of PD. Methods The utility of the selective sGC inhibitor ODQ for reversing biochemical, electrophysiological, histochemical, and behavioral correlates of experimental PD was performed in 6-OHDA-lesioned rats and mice chronically treated with MPTP. Results We found that one systemic administration of ODQ is sufficient to reverse the characteristic elevations in striatal cGMP levels, striatal output neuron activity, and metabolic activity in the subthalamic nucleus observed in 6-OHDA-lesioned rats. The latter outcome was reproduced after intrastriatal infusion of ODQ. Systemic administration of ODQ was also effective in improving deficits in forelimb akinesia induced by 6-OHDA and MPTP. Interpretation Pharmacological inhibition of the sGC-cGMP signaling pathway is a promising non-dopaminergic treatment strategy for restoring basal ganglia dysfunction and attenuating motor symptoms associated with PD.

Emergence of GABAergic-dependent regulation of input-specific plasticity in the adult rat prefrontal cortex during adolescence

ObjectiveThe prefrontal cortex (PFC) receives multiple cortical and subcortical afferents that regulate higher order cognitive functions, many of which emerge late in adolescence. However, it remains unclear how these afferents influence PFC processing, especially in light of the protracted, late adolescent maturation of prefrontal GABAergic function. Here we investigated the role of PFC GABAergic transmission in regulating plasticity elicited from the ventral hippocampus and basolateral amygdala, and how such modulation undergoes functional changes during adolescence in rats.MethodsIn vivo local field potential recordings, combined with prefrontal microinfusion of the GABA-A receptor antagonist picrotoxin, were employed to study the impact of ventral hippocampal and basolateral amygdala high-frequency stimulation on PFC plasticity.ResultsVentral hippocampal-induced PFC plasticity begins to appear only by postnatal days (P) 45–55 with a transient suppression of the evoked response. A switch from transient to long-lasting depression (LTD) of the PFC response emerges after P55 and throughout adulthood (P65–120). Recordings conducted in the presence of picrotoxin revealed that PFC GABAergic transmission is critical for the expression of LTD. In contrast, basolateral amygdala stimulation resulted in PFC long-term potentiation, a form of plasticity that is already enabled by P30 and is insensitive to picrotoxin.ConclusionsThe development of ventral hippocampal-dependent PFC LTD is contingent upon the recruitment of local prefrontal GABAergic transmission during adolescence whereas plasticity elicited from the basolateral amygdala is not. Thus, different mechanisms contribute to the refinement of prefrontal plasticity during adolescence as inputs from these two regions are critical for shaping PFC functions.

Early adolescent MK-801 exposure impairs the maturation of ventral hippocampal control of basolateral amygdala drive in the adult prefrontal cortex.

The adolescent susceptibility to the onset of psychiatric disorders is only beginning to be understood when factoring in the development of the prefrontal cortex (PFC). The functional maturation of the PFC is dependent upon proper integration of glutamatergic inputs from the ventral hippocampus (vHipp) and the basolateral amygdala (BLA). Here we assessed how transient NMDAR blockade during adolescence alters the functional interaction of vHipp–BLA inputs in regulating PFC plasticity. Local field potential recordings were used to determine changes in long-term depression (LTD) and long-term potentiation (LTP) of PFC responses resulting from vHipp and BLA high-frequency stimulation in adult rats that received repeated injections of saline or the NMDAR antagonist MK-801 from postnatal day 35 (P35) to P40. We found that early adolescent MK-801 exposure elicited an age- and input-specific dysregulation of vHipp–PFC plasticity, characterized by a shift from LTD to LTP without altering the BLA-induced LTP. Data also showed that the vHipp normally resets the LTP state of BLA transmission; however, this inhibitory regulation is absent following early adolescent MK-801 treatment. This deficit was reminiscent of PFC responses seen in drug-naive juveniles. Notably, local prefrontal upregulation of GABAAα1 function completely restored vHipp functionality and its regulation of BLA plasticity in MK-801-treated rats. Thus, NMDAR signaling is critical for the periadolescent acquisition of a GABA-dependent hippocampal control of PFC plasticity, which enables the inhibitory control of the prefrontal output by the vHipp. A dysregulation of this pathway can alter PFC processing of other converging afferents such as those from the BLA.