Homer1a Expression Research Articles

Homer proteins accelerate Ca2+ clearance mediated by the plasma membrane Ca2+ pump in hippocampal neurons

The plasma membrane Ca2+ ATPase (PMCA) is responsible for maintaining basal intracellular Ca2+ concentration ([Ca2+]i) and returning small increases in [Ca2+]i back to resting levels. The carboxyl terminus of some PMCA splice variants bind Homer proteins; how binding affects PMCA function is unknown. Here, we examined the effects of altered expression of Homer proteins on PMCA-mediated Ca2+ clearance from rat hippocampal neurons in culture. The kinetics of PMCA-mediated recovery from the [Ca2+]i increase evoked by a brief train of action potentials was determined in the soma of single neurons using indo-1-based photometry. Exogenous expression of Homer 1a, Homer 1c or Homer 2a did not affect PMCA function. However, shRNA mediated knockdown of Homer 1 slowed PMCA mediated Ca2+ clearance by 28% relative to cells expressing non-silencing shRNA. The slowed recovery rate in cells expressing Homer 1 shRNA was reversed by expression of a short Homer 2 truncation mutant. These results indicate that constitutively expressed Homer proteins tonically stimulate PMCA function in hippocampal neurons. We propose a model in which binding of short or long Homer proteins to the carboxyl terminus of the PMCA stimulates Ca2+ clearance rate. PMCA-mediated Ca2+ clearance may be stimulated following incorporation of the pump into Homer organized signaling domains and following induction of the Homer 1a immediate early gene.

Experience-dependent expression of rat hippocampal Arc and Homer 1a after spatial learning on 8-arm and 12-arm radial mazes

The expression of Arc and Homer 1a (H1a) depends on neural activity. This study was designed to determine hippocampal Arc and H1a mRNA expression levels after spatial learning with differing behavioral task demands. Forty-four male rats were distributed into 11 groups of four. One group received no training or trial sessions. Of the ten remaining groups, three were tested on the 8-arm maze, three on the 12-arm maze, two on the 8-arm maze and then the 12-arm maze, and two on the 12-arm maze and then the 8-arm maze. Each animal was sacrificed 30min after the last session of maze testing and its hippocampus was immediately dissected and stored at −80°C. The level of mRNA expression at different stages of maze learning was determined using real-time reverse-transcription polymerase chain reaction (qRT-PCR). Significantly elevated expression of both Arc and H1a was observed. The orchestrated expression levels of both genes were correlated with the behavioral task demand level and behavioral performance.

Pilocarpine-induced status epilepticus increases Homer1a and changes mGluR5 expression

Homer1a regulates expression of group I metabotropic glutamate receptors type I (mGluR1 and mGluR5) and is involved in neuronal plasticity. It has been reported that Homer1a expression is upregulated in the kindling model and hypothesized to act as an anticonvulsant. In the present work, we investigated whether pilocarpine-induced status epilepticus (SE) would alter Homer1a and mGluR5 expression in hippocampus. Adult rats were subjected to pilocarpine-model and analyzed at 2h, 8h, 24h and 7 d following SE. mRNA analysis showed the highest expression of Homer1a at 8h after SE onset, while immunohistochemistry demonstrated that Homer1a protein expression was significantly increased in hippocampus, amygdala and piriform and entorhinal cortices at 24h after SE onset when compared to control animals. The increased Homer1a expression coincided with a significant decrease of mGluR5 protein expression in amygdala and piriform and entorhinal cortices. The data suggest that during the critical periods of epileptogenesis, overexpression of Homer1a occurs to counteract hyperexcitability and thus Homer1a may be a molecular target in the treatment of epilepsy.

Protective effect of Homer 1a against hydrogen peroxide-induced oxidative stress in PC12 cells

Oxidative stress-induced cell damage is involved in many neurological diseases. Homer protein, as an important scaffold protein at postsynaptic density, regulates synaptic structure and function. Here, we reported that hydrogen peroxide (H2O2) induced the expression of Homer 1a. Down-regulation of Homer 1a with a specific small interfering RNA (siRNA) exacerbated H2O2-induced cell injury. Up-regulation of Homer 1a by lentivirus transfection did not affect the anti-oxidant activity, but significantly reduced the reactive oxygen species (ROS) production and lipid peroxidation after H2O2-induced oxidative stress. Overexpression of Homer 1a attenuated the loss of mitochondrial membrane potential (MMP) and ATP production induced by H2O2, and subsequently inhibited mitochondrial dysfunction-induced cytochrome c release, increase of Bax/Bcl-2 ratio and caspase-9/caspase-3 activity. Furthermore, in the presence of BAPTA-AM, an intracellular free-calcium (Ca2 +) chelator, overexpression of Homer 1a had no significant effects on H2O2-induced oxidative stress. These results suggest that Homer 1a has protective effects against H2O2-induced oxidative stress by reducing ROS accumulation and activation of mitochondrial apoptotic pathway, and these protective effects are dependent on the regulation of intracellular Ca2 + homeostasis.

Increase in cortical pyramidal cell excitability accompanies depression-like behavior in mice: a transcranial magnetic stimulation study.

Clinical evidence suggests that cortical excitability is increased in depressives. We investigated its cellular basis in a mouse model of depression. In a modified version of forced swimming (FS), mice were initially forced to swim for 5 consecutive days and then were treated daily with repetitive transcranial magnetic stimulation (rTMS) or sham treatment for the following 4 weeks without swimming. On day 2 through day 5, the mice manifested depression-like behaviors. The next and last FS was performed 4 weeks later, which revealed a 4 week maintenance of depression-like behavior in the sham mice. In slices from the sham controls, excitability in cingulate cortex pyramidal cells was elevated in terms of membrane potential and frequencies of spikes evoked by current injection. Depolarized resting potential was shown to depend on suppression of large conductance calcium-activated potassium (BK) channels. This BK channel suppression was confirmed by measuring spike width, which depends on BK channels. Chronic rTMS treatment during the 4 week period significantly reduced the depression-like behavior. In slices obtained from the rTMS mice, normal excitability and BK channel activity were recovered. Expression of a scaffold protein Homer1a was reduced by the FS and reversed by rTMS in the cingulate cortex. Similar recovery in the same behavioral, electrophysiological, and biochemical features was observed after chronic imipramine treatment. The present study demonstrated that manifestation and disappearance of depression-like behavior are in parallel with increase and decrease in cortical neuronal excitability in mice and suggested that regulation of BK channels by Homer1a is involved in this parallelism.

Striatal expression of Homer1a is affected by genotype but not dystonic phenotype of tottering mice: A model of spontaneously occurring motor disturbances

Tottering ( tg) mice carry a missense mutation in the gene coding for P/Q-type voltage-dependent Ca 2+ channels (VDCCs). Aberrant functioning of P/Q-type VDCCs results in molecular alterations in Ca 2+ currents and in glutamate and dopamine systems. As a consequence, tottering mice exhibit mild ataxia, spontaneous epilepsy, and paroxysmal dyskinesia. In this study, we evaluated whether the tottering mice genotype (homozygous vs. heterozygous) and abnormal movement phenotype (mice exhibiting paroxysmal dyskinesia vs. mice not exhibiting dyskinesia) may affect the expression of Homer1a. Homer1a is a gene whose expression is modulated by glutamate, dopamine and Ca 2+ concentrations. Over-expression of Homer1a has been described in epilepsy and motor dysfunctions. Thereby, changes in Homer1a expression could take place in tottering mice. Studying the expression profile of this gene may shed light on the molecular events occurring in tottering mice. Moreover, tottering mice may represent a valuable animal model for investigating Homer1a involvement in motor disorders. Homer1a expression was decreased in all striatal subregions, with the exclusion of the dorsolateral caudate-putamen, in heterozygous mice compared to wild-type and homozygous mice. Gene expression was decreased in the core of the accumbens in mice exhibiting paroxysmal dyskinesia compared to wild-type mice and to mice not exhibiting dyskinesia. These results demonstrate that the tottering mouse genotype may affect striatal expression of Homer1a, possibly as a result of imbalance between Ca 2+ channels subtypes or Ca 2+-related molecules in heterozygous vs. homozygous mice.

Suppression of a neocortical potassium channel activity by intracellular amyloid-β and its rescue with Homer1a.

It is proposed that intracellular amyloid-β (Aβ), before extracellular plaque formation, triggers cognitive deficits in Alzheimer disease (AD). Here we report how intracellular Aβ affects neuronal properties. This was done by injecting Aβ protein into rat and mouse neocortical pyramidal cells through whole-cell patch pipettes and by using 3xTg AD model mice, in which intracellular Aβ is accumulated innately. In rats, intracellular application of a mixed Aβ(1-42) preparation containing both oligomers and monomers, but not a monomeric preparation of Aβ(1-40), broadened spike width and augmented Ca(2+) influx via voltage-dependent Ca(2+) channels in neocortical neurons. Both effects were mimicked and occluded by charybdotoxin, a blocker of large-conductance Ca(2+)-activated K(+) (BK) channels, and blocked by isopimaric acid, a BK channel opener. Surprisingly, augmented Ca(2+) influx was caused by elongated spike duration, but not attributable to direct Ca(2+) channel modulation by Aβ(1-42). The Aβ(1-42)-induced spike broadening was blocked by electroconvulsive shock (ECS), which we previously showed to facilitate BK channel opening via expression of the scaffold protein Homer1a. In young 3xTg and wild mice, we confirmed spike broadening by Aβ(1-42), which was again mimicked and occluded by charybdotoxin and blocked by ECS. In Homer1a knock-out mice, ECS failed to block the Aβ(1-42) effect. Single-channel recording on BK channels supported these results. These findings suggest that the suppression of BK channels by intracellular Aβ(1-42) is a possible key mechanism for early dysfunction in the AD brain, which may be counteracted by activity-dependent expression of Homer1a.

Experience-dependent Homer1a expression in excitatory and inhibitory neurons

Homer1a, an activity-dependent induced member of the scaffold protein family Homer, plays an essential role in synaptic reorganization and is widely used as a neuronal activity marker. However, the cell type transcribing Homer1a remains unidentified. Here, we investigated the main cell types of the amygdala, hippocampus, primary somatosensory cortex, and dorsal striatum that express Homer1a. Homer1a expression relevant to the baseline neural activity as well as exposure to unfamiliar and conditioned contexts was preferentially detected in the excitatory neurons within the basolateral amygdala, hippocampus, and neocortex, and in inhibitory neurons within the central amygdala and dorsal striatum. These findings indicate that Homer1a is expressed in the principal neurons of each region regardless of whether they are excitatory or inhibitory neurons.

Homer expression in the hippocampus of an animal model of attention-deficit/hyperactivity disorder

Attention-deficit/hyperactivity disorder (ADHD) is a pervasive neurobehavioral disorder. We previously demonstrated differential expression of some isoforms of Homer, a family of scaffolding proteins localized to the postsynaptic density of glutamatergic excitatory synapses, in the spontaneous hypertensive rat (SHR), which is the most frequently used animal model of ADHD. Since these changes were observed in the prefrontal cortex (PFC), a critical structure in ADHD, it was hypothesized that these Homer isoforms may play a role in ADHD. The present study aimed to extend these findings to the hippocampus, which has direct connections to the PFC and subserves attention and cognition, two functions that are disturbed in ADHD. Hippocampal mRNA and protein expression of several Homer isoforms were investigated in both SHR and control Wistar-Kyoto (WKY) rats using reverse transcription-polymerase chain reaction and Western blotting, respectively. Both mRNA and protein for Homer 1a and Homer 2a/b, but not Homer 1b/c, were expressed at significantly lower levels in the hippocampus of SHR compared to WKY rats. The effects of methylphenidate (MPH) on spatial learning and memory in SHRs were also examined using the Morris water maze and on hippocampal expression of Homer isoforms. MPH improved spatial learning and memory and up-regulated hippocampal expression of Homer 1a and Homer 2a/b, but not Homer 1b/c, in SHRs. The animal model of ADHD may have altered expression of Homer 1a and Homer 2a/b in the hippocampus, in addition to the PFC. Future studies will focus on elucidating the specific mechanisms of Homer 1a and Homer 2a/b in ADHD.

An Odyssey of Fear: Homer Stresses New Mechanisms

An Odyssey of Fear: Homer Stresses New Mechanisms

The acute and chronic effects of combined antipsychotic–mood stabilizing treatment on the expression of cortical and striatal postsynaptic density genes

The detection of changes in postsynaptic gene expression after the administration of mood stabilizers, alone or in combination with antipsychotics, and antidepressants in animal models of drug treatment, may represent a valuable strategy to explore the molecular targets of the mainstay treatments for bipolar disorder. In this study we investigated, in both acute and chronic paradigms, the expression of specific postsynaptic density genes (Homer1a, Homer1b/c, and PSD95) and genes putatively implicated in mood stabilizers mechanism of action (GSK3b, ERK) after administration of first (haloperidol) or second generation antipsychotics (quetiapine 30mg/kg), alone or in combination with valproate. Moreover, we compared the effects of an antidepressant agent widely used in bipolar depression (citalopram) with a low dose of quetiapine (15mg/kg), which has been demonstrated to display antidepressant action in bipolar depression.In striatal regions, Homer1a expression was strongly induced by haloperidol compared to all the other treatments. Haloperidol plus valproate also markedly induced Homer1a, but to a significant lesser extent than haloperidol alone. Also in the chronic paradigm haloperidol, but not haloperidol plus valproate, induced Homer1a expression in all the subregions of the caudate-putamen and in the nucleus accumbens core. The high dose of quetiapine significantly induced Homer1a in anterior cingulated, premotor and motor subregions of the cortex, and the extent of induction was significantly higher as compared to the lower dose. Oppositely, Homer1a expression was decreased in the cortex by citalopram acute administration.ERK gene was upregulated in cortex and striatum by the acute treatment with valproate and with the combination of haloperidol or quetiapine plus valproate, whereas no significant differences were noticed in GSK3b expression among treatments. PSD95 showed a significant upregulation by acute citalopram and by haloperidol plus valproate in both cortical and subcortical regions. Haloperidol and quetiapine 30mg/kg, oppositely, significantly reduced the expression of the gene in the cortex.In conclusion, these results suggest that the combined treatment with a typical or an atypical antipsychotic plus valproate may induce differential modulation of postsynaptic genes expression when compared to the effects of these drugs individually administered.

Anxiety‐related behavioral inhibition in rats: a model to examine mechanisms underlying the risk to develop stress‐related psychopathology

Behavioral inhibition (BI) is an adaptive defensive response to threat; however, children who display extreme BI as a stable trait are at risk for development of anxiety disorders and depression. The present study validates a rodent model of BI based on an ethologically relevant predator exposure paradigm. We show that individual differences in rat BI are stable and trait-like from adolescence into adulthood. Using in situ hybridization to quantify expression of the immediate early genes homer1a and fos as measures of neuronal activation, we show that individual differences in BI are correlated with the activation of various stress-responsive brain regions that include the paraventricular nucleus of the hypothalamus and CA3 region of the hippocampus. Further supporting the concept that threat-induced BI in rodents reflects levels of anxiety, we also show that BI is decreased by administration of the anxiolytic, diazepam. Finally, we developed criteria for identifying extreme BI animals that are stable in their expression of high levels of BI and also show that high BI (HBI) individuals exhibit maladaptive appetitive responses following stress exposure. These findings support the use of predator threat as a stimulus and HBI rats as a model to study mechanisms underlying extreme and stable BI in humans.

Divergent acute and chronic modulation of glutamatergic postsynaptic density genes expression by the antipsychotics haloperidol and sertindole

A pivotal role for glutamate in the pathophysiology and treatment of schizophrenia has been suggested. Few reports have investigated the impact of antipsychotics on postsynaptic density (PSD) molecules involved in glutamatergic transmission and synaptic remodeling. Homer is a key PSD molecule putatively implicated in schizophrenia. We studied the effect, in acute and chronic paradigms, of a first and a second generation antipsychotic (haloperidol and sertindole, respectively) on the expression of Homer1a and Homer-interacting PSD molecules. In the acute paradigm, Homer1a expression was induced by haloperidol but not sertindole in the striatum, consistent with the less propensity of sertindole to affect nigrostriatal neurotransmission. The profile of expression of two other inducible genes, Ania3 and Arc, was highly similar to Homer1a. In the cortex, haloperidol reduced Homer1a and induced Ania3. In the chronic paradigm, striatal expression of Homer1a and Ania3 resembled that observed in the acute paradigm. In the cortex, haloperidol induced Homer1a, while sertindole did not. Homer1b expression was increased by haloperidol in the striatum and cortex whereas sertindole selectively induced Homer1b in the cortex. The expression of mGluR5 was increased by both antipsychotics. A modulation by haloperidol was also seen for PSD-95 and αCaMKII. These results suggest that haloperidol and sertindole may significantly modulate glutamatergic transcripts of the postsynaptic density. Sertindole induces constitutive genes in the cortex predominantly, which may correlate with its propensity to improve cognitive functions. Haloperidol preferentially modulates gene expression in the striatum, consistent with its action at nigrostriatal projections and its propensity to give motor side effects.

Behavioral inhibition in rats: a model to examine mechanisms underlying the risk to develop anxiety and depression

Behavioral inhibition (BI) is an adaptive defensive response to threat that has been evolutionarily conserved. Extreme BI in childhood is a temperamental disposition for the development of psychopathology. Our goal was to develop a rodent model of BI that is elicited by predator exposure. The ferret exposure test consists of placing a rat in a housing cage in the ferret colony room for 15 min and rating behavior for BI. We show that predator‐induced BI is stable across development when measured in rats (n = 37) in adolescence and again in adulthood (r = 0.475, p < 0.01). BI is reduced by the anxiolytic diazepam (1 mg/kg, 30 min pretreatment; n = 8/group; p < 0.05), and BI is associated with heightened paraventricular nucleus of the hypothalamus (PVN) and CA3 activity as measured by expression of the immediate early gene homer1a (r = 0.379, p < 0.05; r = 0.309, p < 0.05 respectively). Finally, we show that rats with high levels of BI display disruptions in appetitive behavior as a consequence of prior threat exposure compared to rats with low levels of BI (p < 0.001, n = 7 and 8). Taken together, these findings show that rodent BI is a stable, trait‐like characteristic that is associated with maladaptive responding. This model can be useful in identifying the molecular underpinnings for the childhood risk to develop psychiatric illness. This work was supported by NIH grant MH43454, Meriter Hospital and UW HealthEmotions Research Institute.

Haloperidol induces higher Homer1a expression than risperidone, olanzapine and sulpiride in striatal sub-regions

Homer1a and Yotiao are two post-synaptic density proteins at the crossroad of dopamine-glutamate neurotransmission. Homer1a has been implicated in the pathophysiology of schizophrenia and is differentially induced by typical and atypical antipsychotics, perhaps according to their dopaminergic profile. Yotiao has been involved in glutamate and dopamine post-synaptic signalling. Here, we seek to determine whether Homer1a and Yotiao might be implicated in post-synaptic response to antipsychotics with affinity to different dopamine D(2) receptors: haloperidol (0.8mg kg(-1)), risperidone (3mg kg(-1)), olanzapine (2.5mg kg(-1)) and (-)-sulpiride (50mg kg(-1)). Homer1a expression was significantly induced by haloperidol compared to vehicle and to atypical antipsychotics in almost all striatal sub-regions. Atypical antipsychotics induced the gene in the lateral putamen and in the core of the accumbens only. All antipsychotics, with the exclusion of sulpiride, elicited a dorsolateral-to-ventromedial distribution pattern of Homer1a expression. No significant induction was detected for Yotiao. These results suggest that the quantitative and topographical pattern of Homer1a expression may putatively be related to antipsychotics affinity and/or occupancy at dopamine D(2) receptors.

Pattern of acute induction of Homer1a gene is preserved after chronic treatment with first- and second-generation antipsychotics: effect of short-term drug discontinuation and comparison with Homer1a-interacting genes

Homer1a is a glutamate-related gene whose expression is induced by antipsychotics acutely (i.e. 90 min after treatment). Acute Homer1a expression is preserved after prolonged antipsychotic treatments, while the effects of short-term discontinuation after chronic antipsychotic treatment have not yet been assessed. Here, we studied early and long-term effects on gene expression by antipsychotics for Homer1a and other components of glutamatergic synapses. In the first paradigm, we evaluated Homer1a acute expression by single administration of antipsychotics (haloperidol 0.8 mg/kg, ziprasidone 10 and 4 mg/kg, clozapine 15 mg/kg). Haloperidol and ziprasidone induced Homer1a in the striatum. Induction by ziprasidone was dose-dependent. These results suggest that acute Homer1a expression correlates with dopaminergic affinity and motor side effects of antipsychotics. In the second paradigm, we studied antipsychotic-mediated long-term changes in Homer1a and glutamate-related genes. Rats were treated (21 days) with haloperidol 0.8 mg/kg, ziprasidone 4 mg/kg, or vehicle, and then sacrificed at 90 min (early time-point) or 24 h (delayed time-point) after last injection. Gene expression at these two time-points was compared. Homer1a preserved its pattern of expression at the early but not at the delayed time-point. Significant changes were also observed for PSD-95. The results suggest that Homer1a preserves its expression profile after chronic antipsychotics.

Simvastatin inhibits angiotensin II‐induced cardiac cell hypertrophy: Role of Homer 1a

1. The scaffolding protein Homer 1a is constitutively expressed in the myocardium, although its function in cardiomyocytes remains poorly understood. The aim of the present study was to investigate Homer 1a expression in hypertrophic cardiac cells and its role in angiotensin (Ang) II-induced cardiac hypertrophy. 2. After serum starvation for 24 h, cells were treated with 1 micromol/L simvastatin, 100 nmol/L angiotensin (Ang) II or their combination added to Dulbecco's modified Eagle's medium containing 0.5% serum. For combination treatment with AngII plus simvastatin, cells were exposed to simvastatin 12 h before the addition of AngII to the medium and cells were then incubated in the presence of both drugs for a further 24 h. Western blotting was used to determine Homer 1a protein expression. Hypertrophy was evaluated by determining the protein content per cell. 3. Homer 1a protein levels were upregulated following AngII-induced hypertrophy in H9C2 cells and neonatal rat cardiomyocytes, and these increases were augmented by simvastatin pretreatment. Concomitantly, simvastatin pretreatment inhibited extracellular signal-regulated kinase (ERK) 1/2 phosphorylation and AngII-induced hypertrophy. 4. The inhibitory effects of simvastatin against AngII-induced hypertrophy were attenuated by Homer 1a silencing, suggesting that simvastatin suppresses cardiac hypertrophy in a Homer 1a-dependent manner. Furthermore, AngII-induced hypertrophy and ERK1/2 phosphorylation in neonatal rat cardiomyocytes were significantly inhibited following the overexpression of Homer 1a using an adenovirus. 5. These results suggest a possible role for Homer 1a in inhibiting cardiac hypertrophy perhaps in part through inhibition of ERK1/2 activation.

Prefrontal cortex Homer expression in an animal model of attention-deficit/hyperactivity disorder

Background Attention-deficit/hyperactivity disorder (ADHD) is a pervasive neurobehavioral disorder affecting approximately 5% of children and adolescents and 3% of adults, and the prefrontal cortex (PFC) may play the most critical role in the expression of ADHD. Converging previous studies indicate a potential role of Homer — a scaffolding protein family localized at the postsynaptic density (PSD) of glutamatergic excitatory synapses — in behavioral pathologies associated with neuropsychiatric disorders. Accordingly, we speculate that these Homer isoforms might contribute to the etiology and development of ADHD. Method We investigated the differential mRNA and protein expressions of several Homer isoforms in the PFC of the spontaneous hypertensive rat/Wistar–Kyoto rats (SHR/WKY), the most frequently used animal model of ADHD, using RT-PCR and western blotting. Furthermore, we examined the effects of methylphenidate (MPH) exposure on the behaviors and the expression of different Homer isoforms in the PFC of SHR, using Làt maze, RT-PCR and western blotting, respectively. Results Homer 1a and Homer 2a/ b, but not Homer 1b/ c, were expressed at a significantly lower levels in the PFC of SHR compared with WKY. MPH exposure decreased the locomotor activity and non-selective attention of SHR, and it up regulated the expression of Homer 1a and Homer 2a/ b, but not Homer 1b/ c, in the PFC of SHR. Conclusion It is plausible that Homer 1a and Homer 2a/ b may be involved in the etiology and pathogenesis of ADHD. Future work will focus on elucidating the specific mechanisms of Homer 1a and Homer 2a/ b in ADHD.

Electroacupuncture Inhibits Ethanol‐Induced Locomotor Sensitization and Alters homer1A mRNA Expression in Mice

Here we investigated the effects of electroacupuncture over locomotor sensitization induced by ethanol in mice. Adult male Swiss mice were daily injected with ethanol (2 g/kg, i.p.) or saline for 21 days (acquisition phase). After 4 days of withdrawal, all animals were challenged with ethanol (1.4 g/kg, i.p.). The locomotor activity during 30 minutes was accessed just after the ethanol challenge. Electroacupuncture at acquisition, expression, or maintenance phases of locomotor sensitization was provided over ST-36 (Zusanli) or PC-6 (Neiguan) as well as concomitantly over these 2 acupoints. One hour after the challenge with ethanol, the animals were decapitated, the hippocampus, striatum, and prefrontal cortex were dissected, and the expression of homer1A mRNA assessed by PCR. Electroacupuncture provided simultaneously over ST-36 and PC-6 (but not to ST-36 or PC-6 alone) inhibited the acquisition, expression, and maintenance of ethanol-induced locomotor sensitization. In addition, electroacupuncture blocked the diminution of homer1A mRNA expression triggered by ethanol in the acquisition (striatum and prefrontal cortex), expression (hippocampus), and in the maintenance (hippocampus and prefrontal cortex) phases. Electroacupuncture provided concomitantly over ST-36 and PC-6 prevents the sensitization of the mesocorticolimbic pathway induced by ethanol in mice. In addition, these effects were accompanied by changes in the expression of homer1A. We suggest that electroacupuncture effects over ethanol-induced locomotor sensitization are associated to its ability to modulate homer1A expression and glutamatergic plasticity.

Dopamine receptor subtypes contribution to Homer1a induction: Insights into antipsychotic molecular action

The inducible gene Homer1a has been considered a candidate gene for schizophrenia. Drugs efficacious in schizophrenia and acting as dopamine receptor antagonists induce Homer1a expression, although the specific role of the different dopamine receptors in its induction is not completely known. In this study, we explored Homer1a expression induced by selective antagonists at dopamine receptors (SCH-23390, D 1 receptor selective antagonist, 0.5 mg/kg; L-741,626, D 2 receptor selective antagonist, 2 mg/kg; U-99194, D 3 receptor selective antagonist, 5 mg/kg; L-745,870, D 4 receptor selective antagonist, 3 mg/kg), haloperidol (0.8 mg/kg), and terguride (0.5 mg/kg), a partial agonist at D 2 receptors. Moreover, we evaluated the expression of two Homer1a-related genes which play essential roles in synaptic plasticity: mGluR5 and Homer1b. Gene expression was analyzed in brain regions relevant for schizophrenia pathophysiology and therapy, namely the striatum, the cortex, and the hippocampus. In striatum, Homer1a was induced by D 2 receptor antagonists and, with a different distribution, by SCH-23390. In the cortex, Homer1a was differentially induced by D 1, D 2, and D 3 receptors antagonists, while haloperidol and terguride did not affect or reduced its expression. Homer1b expression was reduced by L-741,626, L-745,870, terguride, and haloperidol in the ventral caudate–putamen, in the nucleus accumbens and in the cortex, while SCH-23390 increased the expression in the core of the accumbens. mGluR5 expression was increased by SCH-23390 in the dorsomedial putamen, the core of the accumbens, and in some hippocampal subregions. A reduction of gene expression by terguride and an increase by L-745,870 was observed in the dorsomedial putamen. The changes in expression suggest that these gene transcripts are differentially regulated by antagonism at different dopamine receptors.