Interneuron Transcriptional Dysregulation Causes Frequency-Dependent Alterations in the Balance of Inhibition and Excitation in Hippocampus.
نویسندگان
چکیده
UNLABELLED Circuit dysfunction in complex brain disorders such as schizophrenia and autism is caused by imbalances between inhibitory and excitatory synaptic transmission (I/E). Short-term plasticity differentially alters responses from excitatory and inhibitory synapses, causing the I/E ratio to change as a function of frequency. However, little is known about I/E ratio dynamics in complex brain disorders. Transcriptional dysregulation in interneurons, particularly parvalbumin interneurons, is a consistent pathophysiological feature of schizophrenia. Peroxisome proliferator activated receptor γ coactivator 1α (PGC-1α) is a transcriptional coactivator that in hippocampus is highly concentrated in inhibitory interneurons and regulates parvalbumin transcription. Here, we used PGC-1α(-/-) mice to investigate effects of interneuron transcriptional dysregulation on the dynamics of the I/E ratio at the synaptic and circuit level in hippocampus. We find that loss of PGC-1α increases the I/E ratio onto CA1 pyramidal cells in response to Schaffer collateral stimulation in slices from young adult mice. The underlying mechanism is enhanced basal inhibition, including increased inhibition from parvalbumin interneurons. This decreases the spread of activation in CA1 and dramatically limits pyramidal cell spiking, reducing hippocampal output. The I/E ratio and CA1 output are partially restored by paired-pulse stimulation at short intervals, indicating frequency-dependent effects. However, circuit dysfunction persists, indicated by alterations in kainate-induced gamma oscillations and impaired nest building. Together, these results show that transcriptional dysregulation in hippocampal interneurons causes frequency-dependent alterations in I/E ratio and circuit function, suggesting that PGC-1α deficiency in psychiatric and neurological disorders contributes to disease by causing functionally relevant alterations in I/E balance. SIGNIFICANCE STATEMENT Alteration in the inhibitory and excitatory synaptic transmission (I/E) balance is a fundamental principle underlying the circuit dysfunction observed in many neuropsychiatric and neurodevelopmental disorders. The I/E ratio is dynamic, continuously changing because of synaptic short-term plasticity. We show here that transcriptional dysregulation in interneurons, particularly parvalbumin interneurons, causes frequency-dependent alterations in the I/E ratio and in circuit function in hippocampus. Peroxisome proliferator activated receptor γ coactivator 1α (PGC-1α-deficient) mice have enhanced inhibition in CA1, the opposite of what is seen in cortex. This study fills an important gap in current understanding of how changes in inhibition in complex brain disorders affect I/E dynamics, leading to region-specific circuit dysfunction and behavioral impairment. This study also provides a conceptual framework for analyzing the effects of short-term plasticity on the I/E balance in disease models.
منابع مشابه
Effect of Acute administration of Cisplatin on memory, motor learning, balance and explorative behaviours in Rats
Introduction: For some cancer survivors chemotherapy treatment is associated with lasting motor and cognitive impairments, long after treatment cessation. Cisplatin as an anti-neoplastic agent is extremely toxic and can cause severe tissue damage. In the present study, we elucidated alteration in performance of hippocampus- and cerebellum-related behaviors following acute cisplatin treatmen...
متن کاملNeuroprotective role of curcumin on the hippocampus against the structural and serological alterations of streptozotocin-induced diabetes in sprague dawely rats
Objective(s): Diabetes mellitus causes impaired memory and cognitive functions. The hippocampus plays a key role in memory and learning. Curcumin attenuates diabetic nephropathy in vivo. Curcumin has shown a neurogenic effect and cognition-enhancing potential in aged rats. The aim of this study is to evaluate the possible protective role of curcumin on the histological and serologicalchanges of...
متن کاملStudy of the Combined Effect of Low Frequency Stimulation and Carbamazepine on Motor and Balance Behavior Indices during Unilateral Kindling in the CA1 Region of the Dorsal Hippocampus in Adult Male Rats
Introduction: In this study, the combined effects of low frequency stimulation (LFS) and carbamazepine (CBZ) were investigated on the motor behavior and balance indices of adult male rats during dorsal hippocampal epilepsy by electrical kindling method. Method: In this experimental study, 56 adult male Wistar rats were randomly divided into 8 groups. Kindling stimulations were performed rapidl...
متن کاملComparison of the effect of iron oxide nanoparticles and bulk on the memory and associated alterations in dopamine and serotonin levels in the hippocampus of adult male rats
Introduction: With the increasing development of nanotechnology, nanomaterials are used instead of conventional compounds. One of these nanomaterials that have many applications in the biomedical field, is iron oxide (Fe2O3) nanoparticles and there is not much research on its effects on the physiological features. So in this research, effect of iron oxide nanoparticles on short and long-term...
متن کاملElectrophysiological characteristics of hippocampal CA1 neurons after spreading depression-triggered epileptic activity in brain slices
Introduction: A close link between spreading depression (SD) and several neurological diseases such as epilepsy could be demonstrated in many experimental studies. Epilepsy is among the most common brain disorders. Despite a large number of investigations, its mechanisms have not been yet well elucidated. Hippocampus is one of the important structures involved in seizures. The aim of this st...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
عنوان ژورنال:
- The Journal of neuroscience : the official journal of the Society for Neuroscience
دوره 35 46 شماره
صفحات -
تاریخ انتشار 2015