Prefrontal mRNA expression of long and short isoforms of D2 dopamine receptor: Possible role in delayed learning deficit caused by early life interleukin-1β treatment
Introduction
D2 dopamine receptors (DRs) are known to be implicated in different neuropsychiatric pathologies such as schizophrenia, attention deficit hyperactivity disorder, addictions, Parkinson disease, affective disorders [1], [2]. Short (D2S) and long (D2L) isoforms are produced by alternative mRNA splicing [3], [4] and differ by downstream intracellular signal pathways [5], [6], [7], [8] and synaptic localization: the D2L DRs are mainly distributed at postsynaptic sites, while D2S DRs have predominant presynaptic localization [9]. These two isoforms of D2 DR are believed to play different roles in the regulation of cognitive functions as human intronic single nucleotide polymorphisms (SNPs) affecting alternative splicing of D2 DR mRNA have been shown to modulate working memory processes, prefrontal and motor cortical activity, striatal functions and mood regulation [10], [11], [12], [13]. Animal studies performed on D2L knockout mice revealed D2L DR involvement in emotional response to novel stimuli, motor function regulation, control of behavioral flexibility [14], [15], [16], [17], [18]. A post mortem study has shown an association between D2S/D2L mRNA ratio and psychiatric diseases such as schizophrenia and affective disorders [19]. Despite the emerging data concerning the functions of D2L and D2S DRs in the CNS, differential regulation of D2 DR splice isoforms expression and its contribution to cognitive performance and brain pathology are underexplored.
The disruption of brain DAergic system development is known to be implicated in various neurodevelopmental disorders [20], [21], i.e. brain dysfunctions caused by detrimental intrinsic and/or environmental factors in vulnerable periods of CNS development [22], [23], [24]. Elevation of pro-inflammatory cytokine level, including interleukin-1β (IL-1β), in the blood and CNS during vulnerable periods of early life is believed to be detrimental for brain maturation [22], [24], [25]. A number of studies have revealed that early life increase of IL-1β may affect development of DAergic neurons as well as produce behavioral dysfunctions in later life [26], [27], [28], [29], [30], [31], [32]. Early life immune challenge accompanied by IL-1β elevation has been shown to induce changes in D2 DR expression within different brain areas [33], [34], [35], whereas how it contributes to individual splice variants remains unclear.
The influence of active avoidance training on mRNA expression level of long and short D2 DR isoforms in the medial prefrontal cortex of rats including animals with impaired cognitive performance was investigated in the present study. We used chronic early life treatment with moderately pyrogenic doses of pro-inflammatory cytokine IL-1β as the model of mild cognitive impairments affecting active avoidance conditioning [28].
Section snippets
Experimental design
The D2L and D2S mRNA expression was evaluated in the mPFC of adult naive rats and animals trained in active avoidance conditioning paradigm. One group of animals used was chronically treated with moderate pyrogenic doses of IL-1β during the 3rd week of life (Fig. 1A). Our previous studies have shown such early life treatment to impair learning ability in active avoidance paradigm as well as learning-induced neurochemical disruptions in the mPFC of adult rats [28], [36]. Active avoidance
Learning ability of animals in active avoidance paradigm
We have evaluated the learning ability of neonatally treated with saline, IL-1β and untreated rats, used in DR expression analysis experiments (Fig. 2). We have revealed that the average number of avoidances (total for Days 2–5) was lower in adult rats treated with Il-1β during the 3rd week of life (Fig. 2). This tendency is very similar to that described earlier [28]. RM-ANOVA revealed significant effect of training day on number of avoidances (F(3) = 3.07 p = 0.039, Fig. 2), indicating that
Discussion
It is well known that mesocortical DAergic circuit (i.e. neurons of ventral tegmental area innervating the mPFC) plays crucial role in memory, emotional, and reward processes, attention and reaction to stress [43], [44], [45]. Differential signaling provided by different DR types in the mPFC influences cognitive performance; accordingly, alternations in distinct DR expression potentially result in cognitive impairments [45]. Prefrontal D2-like receptors are believed to have preferential role in
Conclusions
Taken together, the present study indicates that the differential regulation of D2 DR isoforms mRNA expression in the mPFC by the process of learning is disrupted in adult animals after chronic early life treatment with IL-1β, suggesting that dysregulation of D2 DR mRNA expression in this brain area may be one of the mechanisms of impaired neuroplasticity and cognitive decline caused by early life immune challenge.
Acknowledgements
This work was supported by the Russian Foundation for Basic Research [grant numbers 16-34-00873 mol_a; 17-04-02116 А] and the Federal Agency of Scientific Organizations (Russia).
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