Psychostimulant-induced alteration of dendritic spines on dopaminoceptive neurons in nucleus accumbens (NAcc) has been hypothesized as an adaptive neuronal response that is linked to longlasting addictive behaviors. NAcc is largely composed of two distinct subpopulations of medium-sized spiny neurons expressing high levels of either dopamine D1 or D2 receptors. In the present study, we analyzed dendritic spine density after chronic cocaine treatment in distinct D1 or D2 receptor-containing medium-sized spiny neurons in NAcc. These studies made use of transgenic mice that expressed EGFP under the control of either the D1 or D2 receptor promoter (Drd1-EGFP or Drd2-EGFP). After 28 days of cocaine treatment and 2 days of withdrawal, spine density increased in both Drd1-EGFP-and Drd2-EGFP-positive neurons. However, the increase in spine density was maintained only in Drd1-EGFP-positive neurons 30 days after drug withdrawal. Notably, increased ⌬FosB expression also was observed in Drd1-EGFP-and Drd2-EGFP-positive neurons after 2 days of drug withdrawal but only in Drd1-EGFP-positive neurons after 30 days of drug withdrawal. These results suggest that the increased spine density observed after chronic cocaine treatment is stable only in D1-receptor-containing neurons and that ⌬FosB expression is associated with the formation and͞or the maintenance of dendritic spines in D1 as well as D2 receptor-containing neurons in NAcc.T he mesolimbic dopaminergic pathway is composed of neurons in the ventral tegmental area that innervate the nucleus accumbens (NAcc), olfactory tubercle, prefrontal cortex, and amygdala (1), whereas nigrostriatal dopaminergic neurons in the substantia nigra (pars compacta) provide an ascending projection to dorsal striatum (2). Psychostimulants elevate synaptic concentrations of dopamine in NAcc: cocaine, by blocking dopamine uptake from the synaptic cleft, and amphetamine, by promoting dopamine release from nerve terminals (3-5). Repeated, intermittent administration of psychostimulants results in augmented behavioral responses (sensitization) to the acute stimulatory effects of these drugs (6-8). Most lines of evidence suggest that adaptive changes in the ventral tegmental areaNAcc dopaminergic system are central to alterations in the experience-dependent plasticity that underlies drug-induced behavior.In addition to dopamine, glutamate is required for the development of behavioral sensitization in response to psychostimulants (9, 10). Medium-sized spiny neurons (MSNs) in ventral striatum receive excitatory glutamatergic projections from prefrontal cortex that synapse onto the heads of dendritic spines. MSNs also are the major target for dopaminergic axons that synapse onto spine necks (1,11,12). Therefore, dendritic spines in MSNs represent the cellular compartment where dopaminergic and glutamatergic transmission are initially integrated. Dopamine acts on two major receptor subfamilies, the D1 subfamily (D1 and D5 subtypes) and the D2 subfamily (D2, D3, and D4 subtypes) (13). In dorsal striatum, ...

Mood disorders and antidepressant therapy involve alterations of monoaminergic and glutamatergic transmission. The protein S100A10 (p11) was identified as a regulator of serotonin receptors, and has been implicated in the etiology of depression and in mediating the antidepressant actions of selective serotonin reuptake inhibitors (SSRIs). Here we report that p11 can also regulate depression-like behaviors via regulation of a glutamatergic receptor in mice. p11 directly binds to the cytoplasmic tail of metabotropic glutamate receptor 5 (mGluR5). p11 and mGluR5 mutually facilitate their accumulation at the plasma membranes, and p11 increases cell surface availability of the receptor. While p11 overexpression potentiates mGluR5 agonist-induced calcium responses, overexpression of mGluR5 mutant, which does not interact with p11, diminishes the calcium responses in cultured cells. Knockout of mGluR5 or p11 specifically in glutamatergic neurons in mice causes depression-like behaviors. Conversely, knockout of mGluR5 or p11 in GABAergic neurons causes antidepressant-like behaviors. Inhibition of mGluR5 with an antagonist, MPEP, induces antidepressant-like behaviors in a p11-dependent manner. Notably, the antidepressant-like action of MPEP is mediated by parvalbumin-positive GABAergic interneurons, resulting in a decrease of inhibitory neuronal firing with a resultant increase of excitatory neuronal firing. These results identify a molecular and cellular basis by which mGluR5 antagonism achieves its antidepressant-like activity.

Hypofunction of NMDA receptors has been considered a possible cause for the pathophysiology of schizophrenia. More recently, indirect ways to regulate NMDA that would be less disruptive have been proposed and metabotropic glutamate receptor subtype 5 (mGluR5) represents one such candidate. To characterize the cell populations involved, we demonstrated here that knock-out (KO) of mGluR5 in cholinergic, but not glutamatergic or parvalbumin (PV)-positive GABAergic, neurons reduced prepulse inhibition of the startle response (PPI) and enhanced sensitivity to MK801-induced locomotor activity. Inhibition of cholinergic neurons in the medial septum by DREADD (designer receptors exclusively activated by designer drugs) resulted in reduced PPI further demonstrating the importance of these neurons in sensorimotor gating. Volume imaging and quantification were used to compare PV and cholinergic cell distribution, density, and total cell counts in the different cell-type-specific KO lines. Electrophysiological studies showed reduced NMDA receptormediated currents in cholinergic neurons of the medial septum in mGluR5 KO mice. These results obtained from male and female mice indicate that cholinergic neurons in the medial septum represent a key cell type involved in sensorimotor gating and are relevant to pathologies associated with disrupted sensorimotor gating such as schizophrenia.The mechanistic complexity underlying psychiatric disorders remains a major challenge that is hindering the drug discovery process. Here, we generated genetically modified mouse lines to better characterize the involvement of the receptor mGluR5 in the fine-tuning of NMDA receptors, specifically in the context of sensorimotor gating. We evaluated the importance of knocking-out mGluR5 in three different cell types in two brain regions and performed different sets of experiments including behavioral testing and electrophysiological recordings. We demonstrated that cholinergic neurons in the medial septum represent a key cell-type involved in sensorimotor gating. We are proposing that pathologies associated with disrupted sensorimotor gating, such as with schizophrenia, could benefit from further evaluating strategies to modulate specifically cholinergic neurons in the medial septum.