•Adolescence occurs in mammals as a period for acquisition of prefrontal maturity .•Dramatic functional changes occur in the prefrontal cortex during adolescence.•Prefrontal maturation is required to ...support complex behavioral outcomes.•Preventing such maturation leads to an inadequate control of prefrontal output.
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.
Adolescence is a vulnerable period for the onset of mental illnesses including schizophrenia and affective disorders, yet the neurodevelopmental processes underlying this vulnerability remain poorly ...understood. The prefrontal cortex (PFC) and its local GABAergic system are thought to contribute to the core of cognitive deficits associated with such disorders. However, clinical and preclinical end-point analyses performed in adults are likely to give limited insight into the cellular mechanisms that are altered during adolescence but are only manifested in adulthood. This perspective summarizes work regarding the developmental trajectories of the GABAergic system in the PFC during adolescence to provide an insight into the increased susceptibility to psychiatric disorders during this critical developmental period.
The prefrontal cortex (PFC) is a cortical structure involved in a variety of complex functions in the cognitive and affective domains. The intrinsic function of the PFC is defined by the interaction ...of local glutamatergic and GABAergic neurons and their modulation by long-range inputs. The ensuing interactions generate a ratio of excitation and inhibition (E-I) in each output neuron, a balance which is refined during the adolescent to adult transition. In this short review, we aim to describe how an increase in GABAergic transmission during adolescence modifies the E-I ratio in adults. We further discuss how this new setpoint may change the dynamics of PFC networks observed during the transition to adulthood.
•The prefrontal excitatory-inhibitory (E-I) balance is actively changing during adolescence.•A gain of GABA function during late adolescence dictates the prefrontal E-I balance.•Reduced GABA function up to adolescence can permanently alter prefrontal E-I ratio.
In animal models of drug addiction, cocaine exposure has been shown to increase levels of calcium-permeable AMPA receptors (CP-AMPARs) in two brain regions that are critical for motivation and ...reward-the ventral tegmental area (VTA) and the nucleus accumbens (NAc). This review compares CP-AMPAR plasticity in the two brain regions and addresses its functional significance. In VTA dopamine neurons, cocaine exposure results in synaptic insertion of high conductance CP-AMPARs in exchange for lower conductance calcium-impermeable AMPARs (CI-AMPARs). This plasticity is rapid in onset (hours), GluA2-dependent, and can be observed with a single cocaine injection. Whereas it is short-lived after experimenter-administered cocaine, it persists for months after cocaine self-administration. In addition to strengthening synapses and altering Ca(2+) signaling, CP-AMPAR insertion alters subsequent induction of plasticity at VTA synapses. However, CP-AMPAR insertion is unlikely to mediate the increased DA cell activity that occurs during early withdrawal from cocaine exposure. Metabotropic glutamate receptor 1 (mGluR1) exerts a negative influence on CP-AMPAR accumulation in the VTA. Acutely, mGluR1 stimulation elicits a form of LTD resulting from CP-AMPAR removal and CI-AMPAR insertion. In medium spiny neurons (MSNs) of the NAc, extended access cocaine self-administration is required to increase CP-AMPAR levels. This is first detected after approximately a month of withdrawal and then persists. Once present in NAc synapses, CP-AMPARs mediate the expression of incubation of cue-induced cocaine craving. The mechanism of their accumulation may be GluA1-dependent, which differs from that observed in the VTA. However, similar to VTA, mGluR1 stimulation removes CP-AMPARs from MSN synapses. Loss of mGluR1 tone during cocaine withdrawal may contribute to CP-AMPAR accumulation in the NAc. Thus, results in both brain regions point to the possibility of using positive modulators of mGluR1 as treatments for cocaine addiction.
The expression of the calcium binding protein parvalbumin (PV) has been observed in several cortical regions during development in a temporal pattern consistent with increased afferent-dependent ...activity. In the prefrontal cortex (PFC), PV expression appears last and continues to substantially increase throughout adolescence, yet the significance of this increase remains unclear. Because of the expression of PV in fast-spiking GABAergic interneurons, we hypothesized that PV upregulation during adolescence is necessary to sustain the increase in GABAergic activity observed in the PFC during this period. To test this hypothesis, we utilized an RNAi strategy to directly downregulate PV levels in the PFC during adolescence and examined its impact on prefrontal GABAergic function, plasticity, and associated behaviors during adulthood. The data indicate that a mere 25% reduction of adult PV levels in the PFC was sufficient to reduce local GABAergic transmission onto pyramidal neurons, disrupt prefrontal excitatory-inhibitory balance, and alter processing of afferent information from the ventral hippocampus. Accordingly, these animals displayed an impairment in the level of extinction learning of a trace fear conditioning response, a behavioral paradigm that requires intact PFC-ventral hippocampus connectivity. These results indicate the PV upregulation observed in the PFC during adolescence is necessary for refinement of prefrontal GABAergic function, the absence of which results in immature afferent processing and a hypofunctional state. Importantly, these results suggest there is a critical window of plasticity during which PV upregulation supports the acquisition of mature GABAergic phenotype necessary to sustain adult PFC functions.
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.
Relapse to cocaine use after prolonged abstinence is an important clinical problem. This relapse is often induced by exposure to cues associated with cocaine use. To account for the persistent ...propensity for relapse, it has been suggested that cue-induced cocaine craving increases over the first several weeks of abstinence and remains high for extended periods. We and others identified an analogous phenomenon in rats that was termed 'incubation of cocaine craving': time-dependent increases in cue-induced cocaine-seeking over the first months after withdrawal from self-administered cocaine. Cocaine-seeking requires the activation of glutamate projections that excite receptors for -amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) in the nucleus accumbens. Here we show that the number of synaptic AMPA receptors in the accumbens is increased after prolonged withdrawal from cocaine self-administration by the addition of new AMPA receptors lacking glutamate receptor 2 (GluR2). Furthermore, we show that these new receptors mediate the incubation of cocaine craving. Our results indicate that GluR2-lacking AMPA receptors could be a new target for drug development for the treatment of cocaine addiction. We propose that after prolonged withdrawal from cocaine, increased numbers of synaptic AMPA receptors combined with the higher conductance of GluR2-lacking AMPA receptors causes increased reactivity of accumbens neurons to cocaine-related cues, leading to an intensification of drug craving and relapse.
Although the importance of dopamine (DA) for prefrontal cortical (PFC) cognitive functions is widely recognized, the nature of DA actions in the PFC remains controversial. A critical component in DA ...actions is its modulation of glutamate transmission, which can be different when specific receptors are activated. To obtain a clear picture of cellular mechanisms involved in these interactions, we studied the effects of DA-glutamate coactivation on pyramidal cell excitability in brain slices obtained from developmentally mature rats using whole-cell patch-clamp recordings. Bath application of NMDA, AMPA, and the D1 agonist SKF38393 induced concentration-dependent excitability increases, whereas bath application of the D2 receptor agonist quinpirole induced a concentration-dependent excitability decrease. The NMDA-mediated response was potentiated by SKF38393. This NMDA-D1 synergism required postsynaptic intracellular Ca2+ and protein kinase A (PKA) and was independent of membrane depolarization. On the other hand, the excitatory effects of both NMDA and AMPA were attenuated by a D2 agonist. Surprisingly, the D2-NMDA interaction was also blocked by the GABA(A) antagonists bicuculline and picrotoxin, suggesting that the inhibitory action of D2 receptors on NMDA-induced responses in the PFC may be mediated by GABAergic interneurons. In contrast, the D2-AMPA interaction involves inhibition of PKA and activation of phospholipase lipase C-IP3 and intracellular Ca2+ at a postsynaptic level. Thus, the modulatory actions of D1 and D2 receptors on PFC pyramidal cell excitability are mediated by multiple intracellular mechanisms and by activation of GABA(A) receptors, depending on the glutamate receptor subtypes involved.
Understanding how disruption of prefrontal cortex (PFC) maturation during adolescence is crucial to reveal which neural processes could contribute to the onset of psychiatric disorders that display ...frontal cortical deficits. Of particular interest is the gain of GABAergic function in the PFC during adolescence and its susceptibility to the impact of transient blockade of NMDA receptor function. Here we assessed whether exposure to MK-801 during adolescence in male rats triggers a state of excitatory-inhibitory imbalance in the PFC that limits its functional capacity to regulate behavior in adulthood. Recordings from PFC brain slices revealed that MK-801 exposure during adolescence preferentially reduces the presynaptic functionality of GABAergic activity over that of excitatory synapses. As a result, an imbalance of excitatory-inhibitory synaptic activity emerges in the PFC that correlates linearly with the GABAergic deficit. Notably, the data also suggest that the diminished prefrontal GABAergic function could arise from a deficit in the recruitment of fast-spiking interneurons by excitatory inputs during adolescence. At the behavioral level, MK-801 exposure during adolescence did not disrupt the acquisition of trace fear conditioning, but markedly increased the level of freezing response during extinction testing. Infusion of the GABA
receptor-positive allosteric modulator Indiplon into the PFC before extinction testing reduced the level of freezing response in MK-801-treated rats to control levels. Collectively, the results indicate NMDA receptor signaling during adolescence enables the gain of prefrontal GABAergic function, which is required for maintaining proper excitatory-inhibitory balance in the PFC and its control of behavioral responses.
A developmental disruption of prefrontal cortex maturation has been implicated in the pathophysiology of cognitive deficits in psychiatric disorders. Of particular interest is the susceptibility of the local GABAergic circuit to the impact of transient disruption of NMDA receptors. Here we found that NMDA receptor signaling is critical to enable the gain of prefrontal GABAergic transmission during adolescence for maintaining proper levels of excitatory-inhibitory balance in the PFC and its control of behavior.
Cue-induced cocaine craving in rodents intensifies or “incubates” during the first months of withdrawal from long access cocaine self-administration. This incubation phenomenon is relevant to human ...users who achieve abstinence but exhibit persistent vulnerability to cue-induced relapse. It is well established that incubation of cocaine craving involves complex neuronal circuits. Here we will focus on neuroadaptations in the nucleus accumbens (NAc), a region of convergence for pathways that control cocaine seeking. A key adaptation is a delayed (∼3–4 weeks) accumulation of Ca2+-permeable AMPAR receptors (CP-AMPARs) in synapses on medium spiny neurons (MSN) of the NAc. These CP-AMPARs mediate the expression of incubation after prolonged withdrawal, although different mechanisms must be responsible during the first weeks of withdrawal, prior to CP-AMPAR accumulation. The cascade of events leading to CP-AMPAR accumulation is still unclear. However, several candidate mechanisms have been identified. First, mGluR1 has been shown to negatively regulate CP-AMPAR levels in NAc synapses, and it is possible that a withdrawal-dependent decrease in this effect may help explain CP-AMPAR accumulation during incubation. Second, an increase in phosphorylation of GluA1 subunits (at the protein kinase A site) within extrasynaptic homomeric GluA1 receptors (CP-AMPARs) may promote their synaptic insertion and oppose their removal. Finally, elevation of brain-derived neurotrophic factor (BDNF) levels in the NAc may contribute to maintenance of incubation after months of withdrawal, although incubation-related increases in BDNF accumulation do not account for CP-AMPAR accumulation. Receptors and pathways that negatively regulate incubation, such as mGluR1, are promising targets for the development of therapeutic strategies to help recovering addicts maintain abstinence.
This article is part of a Special Issue entitled ‘NIDA 40th Anniversary Issue’.
•Incubation of cocaine craving is relevant to cue-induced relapse in abstinent users.•CP-AMPARs in the NAc mediate expression of incubation after prolonged withdrawal.•Decreased mGluR1 negative regulatory tone may promote CP-AMPAR accumulation.•CP-AMPAR synaptic insertion may be enhanced by increased GluA1 phosphorylation.•NAc BDNF does not mediate incubation but may contribute to its maintenance.
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