In adult rodents that were exposed to nicotine during adolescence only a handful of proteins show long-term adaptations following adolescent nicotine exposure that persisted into later life. Nicotinic AChR levels in the PFC returned to baseline 5 weeks following adolescent nicotine exposure (Counotte et al., 2012
). In contrast, mGluR2 levels show a strong down-regulation at this time (Counotte et al., 2011
). Reduced mGluR2 function in mPFC synapses resulted in impaired attention performance. Stimulating mGluR2s with specific agonists improved attention performance in animals that were exposed to nicotine during adolescence (Counotte et al., 2011
). Interestingly, the association between changes in mGluR2 signalling and nicotine exposure is not limited to the PFC. Also in other brain areas involved in reward processing such as ventral tegmental area (VTA) and the nucleus accumbens (NAcc) lasting adaptations in mGluR2 function follow nicotine exposure and were found to affect rewarding properties of nicotine (Helton et al., 1997
; Kenny et al., 2003
; Kenny and Markou, 2004
; Liechti et al., 2007
). In these brain areas, activation of mGlu2/3 receptors decreases nicotine self-administration (Liechti et al., 2007
), and they play an important role in the development of drug dependence and the expression of the negative affective state observed during withdrawal (Pilc et al., 2008
). However, the role of group II mGlu receptors in withdrawal appears complex and most likely depends on changes in multiple brain areas.
Although the sequence of events linking mGluR2 adaptations to nAChR activation is unknown, it seems that the reasons for its up- and down-regulation pattern after adolescent nicotine exposure may lie in its function. Metabotropic GluR2 receptors are located on presynaptic glutamatergic terminals where they are activated by glutamate spill over to inhibit glutamate release (Mateo and Porter, 2007
). It was shown that activation of mGluR2s can also regulate release of other neurotransmitters: it can inhibit GABA release via a presynaptic mechanism (Bradley et al., 2000
; Pilc et al., 2008
). Given the inhibitory role of mGluR2 in neurotransmitter release, its function seems to counteract that of nAChR, which enhances both excitatory and inhibitory synaptic transmission (Lambe et al., 2003
; Couey et al., 2007
; Poorthuis et al., 2012
). The short-term effects of adolescent nicotine exposure most likely involve enhanced levels of inhibition in prefrontal network. Accordingly, we found an initial and transient upregulation of inhibitory mGluR2 receptor directly following nicotine exposure during adolescence (Counotte et al., 2011
), which would contribute to the same effect.
In general, factors that lead to enhanced excitation can cause alterations in mGluR2 transmission and cause cognitive deficits (Melendez et al., 2004
; Pozzi et al., 2011
). Enhanced glutamate release in PFC was found to be associated with attention deficit and loss of impulse control (Pozzi et al., 2011
). MGluR2 agonists are effective in improving cognitive deficits if enhanced glutamate release is caused by NMDA receptor antagonists (Pozzi et al., 2011
). Furthermore, the important role of prefrontal mGluR2 signaling in cognition is stressed by its link to brain disorders such as depression and schizophrenia. Activation of this receptor has even been proposed as a novel treatment approach for these disorders (Gupta et al., 2005
; Palucha and Pilc, 2005
; Pilc et al., 2008
; Conn et al., 2009
). Thus, mGluR2 signalling seems to be a good candidate for shaping cognitive behavior and its impairment leads to disturbances in cognitive function.
At the level of synapse function, alterations in mGluR2 levels affect both short-term synaptic plasticity as well as STDP in later life. Short-term depression (STD) is reduced in adult animals as a result of nicotine exposure during adolescence (Counotte et al., 2011
). In control animals, blocking mGluR2 signalling with mGluR2 antagonists also results in reduced STD. Reduced mGluR2 signalling after nicotine exposure has a similar effect on STD as mGluR2 block by antagonist (Figure ). Thereby, mGluR2 may act as an inhibitory feedback mechanism in conditions of excessive excitation and high glutamate release, as occurs when a neuron fires a train of action potentials. Especially at high frequency stimulation the effect of mGluR2 on STD was most prominent at excitatory synapses on layer V pyramidal neurons in the PFC (Counotte et al., 2011
). The lasting reduction of mGluR2 levels and function after adolescent nicotine exposure leads to reduced inhibitory feedback on pyramidal cells and reduces the regulatory role of this receptor in short-term plasticity. Most likely, activation of mGluR2s affects presynaptic calcium channel function as was found in the calyx of Held, by direct electrophysiological recordings from presynaptic terminals (Takahashi et al., 1996
). Agonists of metabotropic glutamate receptors (mGluRs) suppressed high voltage-activated P/Q-type calcium channels in the presynaptic terminal, thereby inhibiting transmitter release (Takahashi et al., 1996
). Since presynaptic Ca2+
dynamics play a key role in short—term plasticity (Zucker and Regehr, 2002
), decrease in Ca2+
current may explain mGluR-dependent modulation of STD.
STD may equip the synapse with low-pass filtering properties, by which the synapse will pass on the first of stimulus in a train of stimuli unaltered, while the rest are attenuated. In this manner it shapes the information transfer by synaptic networks and gives rise to sensory and behavioral phenomena (Zucker, 1989
). For example, in somatosensory cortex of rat, in vivo
whole-cell recordings in cortical neurons during whisker deflection directly demonstrated that synaptic depression of thalamic input to the cortex contributes to rapid adaptation of sensory responses (Chung et al., 2002
). Selective attention, the ability of an organism to filter out relevant information in the face of distractors, can build upon just such synaptic process. Layer V pyramidal neurons in PFC handle diverse incoming information from mediodorsal thalamus and from local neurons and these connections are important in mediating executive functions such as for example working memory (Floresco et al., 1999
). STD on this level may represent a higher level of sensory adaptation that can be expressed as decreased levels of attention and responsiveness. Reduced short-term plasticity after nicotine exposure compromises the ability of prefrontal neurons to efficiently filter out irrelevant information.
We recently found that glutamatergic synapses in the PFC show increased spike-timing-dependent LTP 5 weeks after nicotine exposure during adolescence (Figure ) (Goriounova and Mansvelder, 2012
). This was not the case when animals were exposed to nicotine during adulthood, indicating that adolescence is a vulnerable period for these lasting changes to occur. The long-term effects on LTP 5 weeks after nicotine exposure during adolescence were opposite to the effects immediately following nicotine exposure during adolescence, where spike-timing-dependent LTP is supressed. Thus, nicotine exposure during adolescence has lasting effects on the mechanisms of STDP and persistent synaptic alterations that increase LTP.
What is the mechanism underlying the long-term effects of nicotine exposure during adolescence on STDP? We hypothesized that altered levels of mGluR2 receptors can explain the lasting effects on STDP. Reduced mGluR2 signalling in adult rats after nicotine exposure (Counotte et al., 2011
) may contribute to the decreased plasticity we observed. Blocking mGluR2 receptors with MPPG resulted in increased LTP comparable to levels observed in adult rats treated with nicotine during adolescence (Goriounova and Mansvelder, 2012
). In nicotine-treated rats, where the synaptic mGluR2 receptor levels are reduced (Counotte et al., 2011
), enhancing mGluR2 activity by applying mGluR2 agonist LY379268 completely abolished LTP (Goriounova and Mansvelder, 2012
). Thereby, mGluR2 signalling bidirectionally influences spike-timing-dependent LTP: reducing mGluR2-dependent inhibition leads to increased LTP, while enhancing mGluR2 activation blocked LTP. Thus, immediately following adolescent nicotine exposure, increased levels of mGluR2s may be responsible for reduced LTP induction, and 5 weeks following adolescent nicotine exposure, the lasting reduction in mGluR2 signalling can explain the increased LTP in the adult mPFC.
STDP depends on the precise timing of the synaptic input and the postsynaptic action potential and this temporal relationship resembles typical features of associative learning (Letzkus et al., 2007
). Although STDP has not been directly linked to attention performance, the ability to associate goal-relevant information is crucial for any cognitive behavior. In nicotine-treated rats the same amount of pre- and postsynaptic activity leads to more synaptic potentiation. This may suggest that the PFC network would even associate irrelevant stimuli.