Abstracts of online articleGABAB receptor GTP-binding is decreased in the prefrontal cortex but not the hippocampus of aged rats
Introduction
Gamma aminobutyric acid (GABA)B receptors (GABABRs) are G-protein coupled receptors (GPCRs) and modulation of these receptors shows potential for treating a number of neurological and psychiatric disorders. In postsynaptic neurons, GABABRs bind GABA and are coupled to the Gi/o class of Gα-proteins that inhibit adenylyl cyclase to decrease intracellular levels of cyclic adenosine monophosphate (cAMP; Odagaki and Koyama, 2001, Odagaki et al., 2000). Additionally, the Gβγ-subunit activates the inward rectifying postassium current that modulates the late, or slow, phase of the inhibitory postsynaptic potential (Lüscher et al., 1997). GABABRs are also located on axon terminals where their activation decreases Ca2+ influx (Takahashi et al., 1998) and inhibits neurotransmitter release (Waldmeier et al., 2008). GABABRs are unique among GPCRs as they are obligate heterodimers comprised of at least one GABABR1 subunit with one GABABR2 subunit (Jones et al., 1998, Kaupmann et al., 1998, White et al., 1998), although more complex arrangements are speculated (Pin et al., 2009). The R1 subunit contains the orthosteric binding site and is expressed as one of two isoforms, GABABR1a or GABABR1b (Kaupmann et al., 1997). While no ligands can distinguish between the two (Kaupmann et al., 1997, Kaupmann et al., 1998), molecular and biochemical evidence has identified distinct cellular distributions and functions for each isoform. GABABR1a contains a pair of short consensus repeats at the N-terminal that act as an axonal targeting factor that trafficks GABABR complexes containing this isoform to presynaptic terminals where they modulate neurotransmitter release (Biermann et al., 2010). Conversely, GABABR1b lacks this N-terminal extension and is preferentially trafficked to dendrites where it controls postsynaptic inhibition (Vigot et al., 2006). However, functionality of the receptor is not observed until this R1 subunit associates with an R2 subunit; the R2 subunit mediates interactions with the G-protein (Robbins et al., 2001) as well as facilitates expression of the receptor complex at the plasma membrane (Margeta-Mitrovic et al., 2000).
Despite the significant functional implications, surprisingly little is known regarding the normal composition of GABABR complexes across distinct brain regions and the extent to which such complexes and their activity change with age. Such information is vital given the diversity of signaling offered by unique receptor configurations and emerging evidence that GABAergic indices change with age. For example, in aged rats, prefrontal and hippocampal interneurons degenerate or cease to express glutamic acid decarboxylase (GAD)-67, the GABA-synthesizing enzyme (Shetty and Turner, 1998, Stanley and Shetty, 2004, Stranahan et al., 2011). Moreover, evoked GABA release is decreased in the CA1 subregion of the aged rat hippocampus (Stanley et al., 2011).
Among the functional consequences that could stem from age-related alterations in GABAergic signaling is a loss of cognitive abilities. Indeed, GABAergic signaling has been implicated in cognitive processes supported by both medial temporal lobe and frontal cortical systems, and these brain regions are particularly vulnerable to changes associated with advancing age. Age-related frontal cortical dysfunction, reflected in a loss of behavioral flexibility, has been detected in aged rodents using tasks such as attentional set-shifting (Barense et al., 2002, Rodefer and Nguyen, 2008, Schoenbaum et al., 2002). Loss of declarative/spatial memory supported by hippocampus is also a prominent feature of advanced age and such deficits can be modeled in aged rats using spatial learning tasks such as the Morris water maze. A unique feature of aged rat models characterized on spatial learning tasks is that reliable individual differences in performance can be detected, such that aged rats can be subgrouped into those that perform within the range of young rats and those that perform outside this range, demonstrating hippocampal-dependent learning impairment. Such behavioral models have been used to implicate a number of neurobiological alterations in age-related cognitive deficits, including marked alterations of signaling downstream of muscarinic acetylcholine (mAChR) or group I metabotropic glutamate receptors (mGluRs; Chouinard et al., 1995, Nicolle et al., 1999, Zhang et al., 2007). In contrast, the relationship between cognitive abilities in aged animals and GABABR signaling has not been thoroughly investigated, although GABABR antagonists are known to restore memory function in various animal models of aging (Froestl et al., 2004, Lasarge et al., 2009) while GABABR agonists impair spatial learning in young rats (McNamara and Skelton, 1996). Consequently, we hypothesized that aging may modulate GABABR expression or function in close association with cognition in a brain region-dependent manner. To test this hypothesis, we performed parallel pharmacological and biochemical analyses of hippocampal and prefrontal cortex (PFC) GABABRs in tissues obtained from young and aged rats previously tested for spatial learning ability.
Section snippets
Animals
Young adult (6-month-old, n = 8) and aged (22-month-old, n = 16) male Fischer 344 (F344) rats were obtained from the National Institute on Aging colony (Harlan, IN, USA) and individually housed in the Association for Assessment and Accreditation of Laboratory Animal Care (AALAC)-accredited Psychology Department vivarium at Texas A&M University for 2 weeks prior to the onset of behavioral testing. The vivarium was maintained at a constant 25 °C with a regular 12:12 hours light/dark cycle (lights
Spatial learning performance
Young rats and aged rats performed similarly on the first training trial (F(1,22) = 2.66, not significant [ns]) and while both groups improved over the course of training (F(3,66)=23.64, p < 0.05), a two-way repeated measures ANOVA (age × training trial block) revealed a significant main effect of age (F(1,22) = 8.96, p < 0.05; Fig. 1A) indicating that aged rats were not as proficient in locating the hidden platform compared with young rats. In agreement with training trial performance, a
Discussion
An emerging concept in both human and rodent cognitive aging is that age-related decline in hippocampal and frontal cortical systems occur somewhat independently and that consideration of both systems is essential for a thorough understanding of cognitive dysfunction and the development of effective interventions to promote successful cognitive aging. Findings from the current study in which we report differential effects of age on GABABR expression and signaling in hippocampus and PFC supports
Disclosure statement
The authors declare no conflict of interest.
The Institutional Animal Care and Use Committee approved all protocols described in this report.
Acknowledgements
This work was supported by the National Institute on Aging grants R01-AG020572 to M.M.N. and R01-AG029421 to J.L.B. and the McKnight Brain Research Foundation. The authors also thank Allyn C. Howlett for expert advice offered in the interpretation of the GTP-binding results.
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