A Role for Electrotonic Coupling in the Striatum in the Expression of Dopamine Receptor-mediated Stereotypies,

Abstract

Stimulation of dopamine (DA) receptors in the striatum evokes a number of alterations in motor behavior in rats, as well as causing several alterations in cellular physiology, including changes in membrane potential, cell excitability, afferent drive, and electrotonic coupling. One cellular property that is potently modulated by DA stimulation is electrotonic coupling, a process shown to subserve motor pattern generation. To examine whether electrotonic coupling plays a role in mediating a specific set of DA receptor-mediated motor behaviors, we tested the effects of two inhibitors of gap junction conductance, carbenoxolone (CARB) and anandamide (AEA), on apomorphine (APO)-induced motor responses. We then used intra-striatal infusions of CARB to determine the role of electrotonic coupling specifically in the ventral striatum in the expression of i.p.) significantly increased motor activity (a composite score) and the frequencies of oral and sniffing stereotypies. APO also disrupted grooming initiation and completion. APO-induced oral stereotypies were selectively blocked by systemic administration of CARB (7.0, 35.0 mg/kg Adaptive behaviors, both learned and spontaneous, consist of sequences of "micro" movements executed by closely-related muscle groups. There is evidence that the initiation and execution of individual movements, such as oral movements involved in feeding, as well as the linking of these movements into a behavioral sequence, depend upon neuronal networks within the Beninger et al. 1991;Braun and Chase 1986;Byrnes et al. 1994;Delfs and Kelley 1990). Thus, in the context of behavioral sequencing, the simple 'repetitive' stereotypy (Berridge and Aldridge 2000a) produced by D2 receptor over-stimulation in the striatum (Delfs and Kelley 1990) can be seen as the inability to release one 'simple' behavior in order to allow initiation of the next simple behavior in a normal, adaptive sequence (Pedro et al. 1994;Szechtman et al. 1999). One means by which neuronal networks may interact within the striatum is via communication among clusters of functionally related striatal neurons. Such a network interaction may be mediated via gap junctions. It is well-established that electrotonic transmission between developing neurons is important in the formation and stabilization of functional networks (Bannerman et al. 2000;Peinado et al. 1993;Roerig and Feller 2000). However, there is also evidence that in the adult brain, electrotonic coupling directly mediates forms of neuronal network activity (Bou-Flores and Berger 2001;Jefferys 1995;Perez Velazquez and Carlen 2000) which, in turn, contribute to rhythmic behavioral patterning (Bou-Flores and Berger 2001;Rothwell 1998). Thus, it is likely that motor patterning may involve activity within neuronal networks coordinated via gap junctions. In the striatum, cells express connexins, the protein building blocks of gap junctions (Belluardo et al. 2000;Bennett et al. 1999). Striatal neurons also exhibit dye coupling, the transfer of dye molecules between neurons thro...

Dopamine and cyclic-AMP regulated phosphoprotein-32–dependent modulation of prefrontal cortical input and intercellular coupling in mouse accumbens spiny and aspiny neurons

“…In contrast, D1/D5 agonist administration (SKF 38393, 10 μM) did not significantly alter the incidence of dye coupling (1/9; 11%; p = 0.7) compared to predrug conditions (1/11; 9%). Furthermore, following treatment with the gap junction blocker carbenoxelene (100 μM, 10 min; Travaglia et al, 1995;Moore and Grace, 2002), the D2-like agonist quinpirole did not result in coupling (0/5; 0%), which is consistent with gap-junction mediated dye coupling between spiny neurons (Venance et al, 2004).…”

“…In contrast, D1/D5 agonist administration (SKF 38393, 10 μM) did not significantly alter the incidence of dye coupling (1/9; 11%; p = 0.7) compared to predrug conditions (1/11; 9%). Furthermore, following treatment with the gap junction blocker carbenoxelene (100 μM, 10 min; Travaglia et al, 1995;Moore and Grace, 2002), the D2-like agonist quinpirole did not result in coupling (0/5; 0%), which is consistent with gap-junction mediated dye coupling between spiny neurons (Venance et al, 2004).Injection of single neurons in KO mouse slices revealed 24 % (4/17) baseline coupling compared to WT (1/11, p = 0.66; N.S., Figure 1E). However, in KO spiny neurons, neither D1-nor D2-like agonist administration significantly affected dye coupling (Fig 1E: D1 agonist: 33 %; 2/6; D2 agonist: 33%, 3/9; p = 0.5; N.S.…”

“…We have demonstrated a DA D2 receptor dependent modulation (enhancement) of this non-synaptic, electrotonic, transmission in striatal/accumbens spiny projection neurons in anesthetized rats (Onn and Grace, 1994) and in rat brain slices (O'Donnell and Grace, 1993). This coupling is potently modulated by behaviorally (Moore and Grace, 2002) and psychiatrically relevant treatment regimens in intact animals, including amphetamine withdrawal , DA depletion (Onn and Grace, 1999) and antipsychotic drug administration (Onn and Grace, 1995). Given the potent modulation of coupling induced in intact anesthetized rats by psychiatrically relevant manipulations of the DA system, it is likely that modulation of gap junctional conductance plays a major role in the response of the mesocorticolimbic systems to decompensation, as occurs with drug dependency and schizophrenia (Grace, 1991;Hyman and Malenka, 2001;Albert et al, 2002;Saal et al, 2003;Svenningsson et al, 2005) In the present study we evaluated the incidence of intercellular coupling in WT and DARPP-32 KO accumbens core spiny neurons and its modulation by DA D1-and D2-like agonists using conventional intracellular sharp-electrode recording in brain slices from WT and DARPP-32 KO mice.…”

A Novel Rodent Model of Autism: Intraventricular Infusions of Propionic Acid Increase Locomotor Activity and Induce Neuroinflammation and Oxidative Stress in Discrete Regions of Adult Rat Brain

“…Furthermore closure of glial gap junctions by PPA could lead to neuronal hyperexcitablilty by impaired glial spatial buffering of cytosolic potassium or glutamate [105] . Moreover, intrastriatal infusions of gap junction blockers produce movement disorder in rodents [106] . Thus, the altered neural excitablility of neocortical, hippocampal and striatal neuronal groups in PPA treated rats would be consistent with the closure of neural or glial gap junctions by PPA [101] .…”

Do gap junctions regulate synchrony in the Parkinsonian basal ganglia?

“…Dye coupling, an indication for gap junction coupling, was increased in the striatum after dopamine loss in rats [Cepeda et al, 1989, Onn andGrace, 1999]. Dopamine modulation of gap junction coupling in the striatum has also been associated with stereotypic behavior [Moore and Grace, 2002], emphasizing the potential impact of gap junction coupling on clinical characteristics. Although the presence of gap junctions in the human GPe, GPi and STN would significantly impact information processing in the basal ganglia, it remains unknown whether they exist and how they may remodel after dopamine depletion.…”