The dorsal raphe (DR) constitutes a major serotonergic input to the forebrain and modulates diverse functions and brain states, including mood, anxiety, and sensory and motor functions. Most functional studies to date have treated DR serotonin neurons as a single population. Using viral-genetic methods, we found that subcortical- and cortical-projecting serotonin neurons have distinct cell-body distributions within the DR and differentially co-express a vesicular glutamate transporter. Further, amygdala- and frontal-cortex-projecting DR serotonin neurons have largely complementary whole-brain collateralization patterns, receive biased inputs from presynaptic partners, and exhibit opposite responses to aversive stimuli. Gain- and loss-of-function experiments suggest that amygdala-projecting DR serotonin neurons promote anxiety-like behavior, whereas frontal-cortex-projecting neurons promote active coping in the face of challenge. These results provide compelling evidence that the DR serotonin system contains parallel sub-systems that differ in input and output connectivity, physiological response properties, and behavioral functions.

Elucidating the prefrontal cortical microcircuit has been challenging, given its role in multiple complex behaviors, including working memory, cognitive flexibility, attention, social interaction and emotional regulation. Additionally, previous methodological limitations made it difficult to parse out the contribution of certain neuronal subpopulations in refining cortical representations. However, growing evidence supports a fundamental role of fast-spiking parvalbumin (PV) GABAergic interneurons in regulating pyramidal neuron activity to drive appropriate behavioral responses. Further, their function is heavily diminished in the prefrontal cortex (PFC) in numerous psychiatric diseases, including schizophrenia and autism. Previous research has demonstrated the importance of the optimal balance of excitation and inhibition (E/I) in cortical circuits in maintaining the efficiency of cortical information processing. Although we are still unraveling the mechanisms of information representation in the PFC, the E/I balance seems to be crucial, as pharmacological, chemogenetic and optogenetic approaches for disrupting E/I balance induce impairments in a range of PFC-dependent behaviors. In this review, we will explore two key hypotheses. First, PV interneurons are powerful regulators of E/I balance in the PFC, and help optimize the representation and processing of supramodal information in PFC. Second, diminishing the function of PV interneurons is sufficient to generate an elaborate symptom sequelae corresponding to those observed in a range of psychiatric diseases. Then, using this framework, we will speculate on whether this circuitry could represent a platform for the development of therapeutic interventions in disorders of PFC function.

Background The mediodorsal (MD) thalamus plays a critical role in cognition through its extensive innervation of the medial prefrontal cortex (mPFC), but how the two structures cooperate at the single-cell level to generate associated cognitive functions and other mPFC-dependent behaviors remains elusive. A principal importance for organizing cortical activity is maintaining the proper balance between excitation and inhibition (E/I balance). Further, the PFC E/I balance has been implicated in successful execution of multiple PFC-dependent behaviors in both animal research and the context of human psychiatric disorders. Methods Here, we utilized a pharmacogenetic strategy to decrease MD activity in adult male rats, and evaluated the consequences for E/I balance in PFC pyramidal neurons, as well as cognition, social interaction and anxiety. Results We found that dampening MD activity caused significant reductions in GABAergic signaling, increased E/I balance in the mPFC, and was concomitant with abnormalities in these behaviors. Further, by selectively activating parvalbumin (PV) interneurons in the mPFC with a novel pharmacogenetic approach, we restored GABAergic signaling and E/I balance, as well as ameliorated all behavioral impairments. Conclusions These findings underscore the importance of thalamocortical activation of mPFC GABAergic interneurons in a broad range of mPFC-dependent behaviors. Further, it highlights this circuitry as a platform for therapeutic investigation in psychiatric diseases that involve impairments in PFC-dependent behaviors.

The mediodorsal thalamus (MD) represents a fundamental subcortical relay to the prefrontal cortex (PFC), and is thought to be highly implicated in modulation of cognitive performance. Additionally, it undergoes highly conserved developmental stages, which, when dysregulated, can have detrimental consequences. Embryonically, the MD experiences a tremendous surge in neurogenesis and differentiation, and disruption of this process may underlie the pathology in certain neurodevelopmental disorders. However, during the postnatal period, a vast amount of cell loss in the MD occurs. These together may represent an extended critical period for postnatal development, in which disturbances in the normal growth or reduction of the MD afferents to the PFC, can result in PFC-dependent cognitive, affective, or psychotic abnormalities. In this review, we explore the current knowledge supporting this hypothesis of a protracted critical period, and propose how developmental changes in the MD contribute to successful prefrontal cortical development and function. Specifically, we elaborate on the unique properties of MD-PFC connections compared with other thalamocortical afferents in sensory cortices, examine how MD-PFC innervation modulates synaptic transmission in the local prefrontal circuitry, and speculate on what occurs during postnatal development, particularly within the early neonatal stage, as well as juvenile and adolescent periods. Finally, we discuss the questions that remain and propose future experiments in order to provide perspective and novel insights into the cause of neuropsychiatric disorders associated with MD-PFC development.

Schizophrenia (SCZ) is a neurodevelopmental psychiatric disorder, in which cognitive function becomes disrupted at early stages of the disease. Although the mechanisms underlying cognitive impairments remain unclear, N-methyl-D-aspartate receptors (NMDAR) hypofunctioning in the prefrontal cortex (PFC) has been implicated. Moreover, cognitive symptoms in SCZ are usually unresponsive to treatment with current antipsychotics and by onset, disruption of the dopamine system, not NMDAR hypofunctioning, dominates the symptoms. Therefore, treating cognitive deficits at an early stage is a realistic approach. In this study, we tested whether an early treatment targeting mGluR2 would be effective in ameliorating cognitive impairments in the methylazoxymethanol acetate (MAM) model of SCZ. We investigated the effects of an mGluR2 agonist/mGluR3 antagonist, LY395756 (LY39), on the NMDAR expression and function in juveniles, as well as cognitive deficits in adult rats after juvenile treatment. We found that gestational MAM exposure induced a significant decrease in total protein levels of the NMDAR subunit, NR2B, and a significant increase of pNR2BTyr1472 in the juvenile rat PFC. Treatment with LY39 in juvenile MAM-exposed rats effectively recovered the disrupted NMDAR expression. Furthermore, a subchronic LY39 treatment in juvenile MAM-exposed rats also alleviated the learning deficits and cognitive flexibility impairments when tested with a cross-maze based set-shifting task in adults. Therefore, our study demonstrates that targeting dysfunctional NMDARs with an mGluR2 agonist during the early stage of SCZ could be an effective strategy in preventing the development and progression in addition to ameliorating cognitive impairments of SCZ.

Targeting group II metabotropic glutamate receptors (mGluR2/3) has been proposed to correct the dysfunctional glutamatergic system, particularly NMDA receptor (NMDAR) hypofunction, for treatment of schizophrenia. However, how activation of mGluR2/3 affects NMDAR function in adult animals remains elusive. Here we show the effects of LY395756 (LY39), a compound acting as both an mGluR2 agonist and mGluR3 antagonist, on the NMDAR expression and function of normal adult rat prefrontal cortex (PFC) as well as working memory function in the MK801 model of schizophrenia. We found that in vivo administration of LY39 significantly increased the total protein levels of NMDAR subunits and NR2B phosphorylation in the PFC, along with the amplitude of NMDAR-mediated miniature excitatory postsynaptic currents (mEPSC) in the prefrontal cortical neurons. Moreover, LY39 also significantly increased mTOR and pmTOR expression, but not ERK1/2, Akt, and GSK3β, suggesting an activation of mTOR signaling. Indeed, the mTOR inhibitor rapamycin, and actinomycin-D, a transcription inhibitor, blocked the enhanced effects of LY39 on NMDAR-mEPSCs. These results indicate that LY39 regulates NMDAR expression and function through unidentified mTOR-mediated protein synthesis in the normal adult rat PFC. However, this change is insufficient to affect working memory function in normal animals, nor to reverse the MK801-induced working memory deficit. Our data provide the first evidence of an in vivo effect of a novel compound that acts as both an mGluR2 agonist and mGluR3 antagonist on synaptic NMDAR expression and function in the adult rat PFC, although its effect on PFC-dependent cognitive function remains to be explored.

Glycogen synthase kinase 3β (GSK3β) is a highly conserved serine/threonine kinase that has been implicated in both psychiatric and neurodegenerative diseases including schizophrenia, bipolar disorder, and Alzheimer's disease; therefore regulating its activity has become an important strategy for treatment of cognitive impairments in these disorders. This study examines the effects of lithium on GSK3β and its interaction with β-catenin and NMDA receptors within the prefrontal cortex. Lithium, a clinically relevant drug commonly prescribed as a mood stabilizer for psychiatric disorders, significantly increased levels of phosphorylated GSK3β serine 9, an inhibitory phosphorylation site, and decreased β-catenin ser33/37/thr41 phosphorylation in vitro, indicating GSK3β inhibition and reduced β-catenin degradation. GluN2A subunit levels were concurrently increased following lithium treatment. Similar alterations were also demonstrated in vivo; lithium administration increased GSK3β serine 9 phosphorylation and GluN2A levels, suggesting a reduced GSK3β activity and augmented GluN2A expression. Correspondingly, we observed that the amplitudes of evoked GluN2A-mediated excitatory postsynaptic currents in mPFC pyramidal neurons were significantly increased following lithium administration. Our data suggest that GSK3β activity negatively regulates GluN2A expression, likely by mediating upstream β-catenin phosphorylation, in prefrontal cortical neurons. Furthermore, our biochemical and electrophysiological experiments demonstrate that lithium mediates a specific increase in GluN2A subunit expression, ultimately augmenting GluN2A-mediated currents in the prefrontal cortex.

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