Skip to main content
SpringerLink
Log in

Postnatal GABAA Receptor Activation Alters Synaptic Plasticity and Cognition in Adult Wistar Rats

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Early life alteration in the activity of gamma-aminobutyric acid (GABA) receptors is associated with long-lasting developmental effects on the brain and behavior. GABAA receptors act as excitatory rather than inhibitory in neonates. Excessive activation of GABAA receptors during the early postnatal period may affect cognitive functions later in life. In this study, we sought to determine whether neonatal activation of GABAA receptors with muscimol can alter the electrophysiology profile of hippocampal CA1 neurons and spatial learning and memory in adult rats. Male and female Wistar rat pups received a subcutaneous injection of either saline or muscimol (500 µg/kg) on postnatal days (PND) 7, 9, and 11 and then underwent different electrophysiology and behavioral experiments in adulthood. Early life treatment with muscimol did not alter the basic synaptic transmission but significantly reduced the paired-pulse facilitation (PPF) in the CA1 area. Neonatal application of muscimol led to a pronounced decrease in long-term potentiation (LTP) and long-term depression (LTD) in CA1 neurons along with a declined theta-burst responses in both sexes. We obtained some evidence that neonatal GABAA activation leads to reduced brain-derived neurotrophic factor (BDNF) in the hippocampus and prefrontal cortex. Our electrophysiology data was supported with spatial reference and working memory deficits in rats. This study provides the first detailed description of altered electrophysiology in hippocampal CA1 neurons in adult rats undergone GABAA activation early in life.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Data Availability

The datasets used or analyzed during the current study are available from the corresponding author on reasonable request.

References

  1. Wang GJ, Chung HJ, Schnuer J et al (1998) Dihydrokainate-sensitive neuronal glutamate transport is required for protection of rat cortical neurons in culture against synaptically released glutamate. Eur J Neurosci 10:2523–2531

    Article  CAS  PubMed  Google Scholar 

  2. Rivera C, Voipio J, Payne JA et al (1999) The K+/Cl- co-transporter KCC2 renders GABA hyperpolarizing during neuronal maturation. Nature 397:251–255

    Article  CAS  PubMed  Google Scholar 

  3. Schulte JT, Wierenga CJ, Bruining H (2018) Chloride transporters and GABA polarity in developmental, neurological and psychiatric conditions. Neurosci Biobehav Rev 90:260–271

    Article  CAS  PubMed  Google Scholar 

  4. Pisella LI, Gaiarsa J-L, Diabira D et al (2019) Impaired regulation of KCC2 phosphorylation leads to neuronal network dysfunction and neurodevelopmental pathology. Sci Signal 15:603

  5. Tyzio R, Holmes GL, Ben-Ari Y, Khazipov R (2007) Timing of the developmental switch in GABAA mediated signaling from excitation to inhibition in CA3 rat hippocampus using gramicidin perforated patch and extracellular recordings. Epilepsia 48:96–105

    Article  CAS  PubMed  Google Scholar 

  6. Represa A, Ben-Ari Y (2005) Trophic actions of GABA on neuronal development. Trends Neurosci 28:278–283. https://doi.org/10.1016/j.tins.2005.03.010

    Article  CAS  PubMed  Google Scholar 

  7. Sun B, Halabisky B, Zhou Y et al (2009) Imbalance between GABAergic and glutamatergic transmission impairs adult neurogenesis in an animal model of Alzheimer’s disease. Cell Stem Cell 5:624–633. https://doi.org/10.1016/j.stem.2009.10.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Peerboom C, Wierenga CJ (2021) The postnatal GABA shift: a developmental perspective. Neurosci Biobehav Rev 124:179–192

  9. Garaschuk O, Hanse E, Konnerth A (1998) Developmental profile and synaptic origin of early network oscillations in the CA1 region of rat neonatal hippocampus. J Physiol 507:219–236

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Wang DD, Kriegstein AR (2008) GABA regulates excitatory synapse formation in the neocortex via NMDA receptor activation. J Neurosci 28:5547–5558

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Lim AL, Taylor DA, Malone DT (2012) Consequences of early life MK-801 administration: long-term behavioural effects and relevance to schizophrenia research. Behav Brain Res 227:276–286. https://doi.org/10.1016/j.bbr.2011.10.052

    Article  CAS  PubMed  Google Scholar 

  12. Platel JC, Stamboulian S, Nguyen I, Bordey A (2010) Neurotransmitter signaling in postnatal neurogenesis: the first leg. Brain Res Rev 63:60–71. https://doi.org/10.1016/j.brainresrev.2010.02.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Zhao YL, Xiang Q, Shi QY et al (2011) GABAergic excitotoxicity injury of the immature hippocampal pyramidal neurons exposure to isoflurane. Anesth & Analg 113:1152–1160

    Article  CAS  Google Scholar 

  14. Sanders RD, Hassell J, Davidson AJ et al (2013) Impact of anaesthetics and surgery on neurodevelopment: an update. Br J Anaesth 110:i53–i72

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Vutskits L, Xie Z (2016) Lasting impact of general anaesthesia on the brain: mechanisms and relevance. Nat Rev Neurosci 17:705–717

    Article  CAS  PubMed  Google Scholar 

  16. Satomoto M, Sun Z, Adachi YU, Makita K (2018) Neonatal sevoflurane exposure induces adulthood fear-induced learning disability and decreases glutamatergic neurons in the basolateral amygdala. J Neurosurg Anesthesiol 30:59–64

    Article  PubMed  Google Scholar 

  17. Chung W, Park S, Hong J et al (2015) Sevoflurane exposure during the neonatal period induces long-term memory impairment but not autism-like behaviors. Pediatr Anesth 25:1033–1045

    Article  Google Scholar 

  18. Tsien JZ, Huerta PT, Tonegawa S (1996) The essential role of hippocampal CA1 NMDA receptor–dependent synaptic plasticity in spatial memory. Cell 87:1327–1338

    Article  CAS  PubMed  Google Scholar 

  19. Sugar J, Moser M-B (2019) Episodic memory: neuronal codes for what, where, and when. Hippocampus 29:1190–1205

    Article  PubMed  Google Scholar 

  20. Overstreet-Wadiche LS, Bensen AL, Westbrook GL (2006) Delayed development of adult-generated granule cells in dentate gyrus. J Neurosci 26:2326–2334

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Servick K (2014) Researchers struggle to gauge risks of childhood anesthesia. Science 346:1161–1162

  22. Salari A-A, Bakhtiari A, Homberg JR (2015) Activation of GABA-A receptors during postnatal brain development increases anxiety-and depression-related behaviors in a time-and dose-dependent manner in adult mice. Eur Neuropsychopharmacol 25:1260–1274

    Article  CAS  PubMed  Google Scholar 

  23. Ajayi AF, Akhigbe RE (2020) Staging of the estrous cycle and induction of estrus in experimental rodents: an update. Fertil Res Pract 6:1–15

    Article  Google Scholar 

  24. George P, Charles W (2007) The rat brain in stereotaxic coordinates. Qingchuan Zhuge Transl People’s Med Publ House, Beijing, p 32

    Google Scholar 

  25. Aksoy Aksel A, Manahan-Vaughan D (2013) The temporoammonic input to the hippocampal CA1 region displays distinctly different synaptic plasticity compared to the Schaffer collateral input in vivo: significance for synaptic information processing. Front Synaptic Neurosci 5:5

    Article  PubMed  PubMed Central  Google Scholar 

  26. Babri S, Amani M, Mohaddes G et al (2012) Effect of aggregated beta-amyloid (1–42) on synaptic plasticity of hippocampal dentate gyrus granule cells in vivo. Bioimpacts 2:189–194. https://doi.org/10.5681/bi.2012.022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Amani M, Lauterborn JC, Le AA et al (2021) Rapid Aging in the Perforant Path Projections to the Rodent Dentate Gyrus. J Neurosci 41:2301–2312

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Zeier Z, Kumar A, Bodhinathan K et al (2009) Fragile X mental retardation protein replacement restores hippocampal synaptic function in a mouse model of fragile X syndrome. Gene Ther 16:1122–1129

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Larson J, Wong D, Lynch G (1986) Patterned stimulation at the theta frequency is optimal for the induction of hippocampal long-term potentiation. Brain Res 368:347–350

    Article  CAS  PubMed  Google Scholar 

  30. Le AA, Quintanilla J, Amani M, et al (2021) Persistent sexually dimorphic effects of adolescent THC exposure on hippocampal synaptic plasticity and episodic memory in rodents. Neurobiol Dis 162:105565

  31. Babri S, Amani M, Mohaddes G et al (2012) Protective effects of troxerutin on β-amyloid (1–42)-induced impairments of spatial learning and memory in rats. Neurophysiology. https://doi.org/10.1007/s11062-012-9309-6

    Article  Google Scholar 

  32. Pasini S, Corona C, Liu J et al (2015) Specific downregulation of hippocampal ATF4 reveals a necessary role in synaptic plasticity and memory. Cell Rep 11:183–191

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Hamidi N, Nozad A, Milan HS et al (2019) Effect of ceftriaxone on paired-pulse response and long-term potentiation of hippocampal dentate gyrus neurons in rats with Alzheimer-like disease. Life Sci 238:116969

    Article  CAS  PubMed  Google Scholar 

  34. Hamidi N, Nozad A, Sheikhkanloui Milan H, Amani M (2019) Okadaic acid attenuates short-term and long-term synaptic plasticity of hippocampal dentate gyrus neurons in rats. Neurobiol Learn Mem 158:24–31. https://doi.org/10.1016/j.nlm.2019.01.007

    Article  CAS  PubMed  Google Scholar 

  35. Mohammad A, Ali N, Reza B, Ali K (2010) Effect of ascorbic acid supplementation on nitric oxide metabolites and systolic blood pressure in rats exposed to lead. Indian J Pharmacol 42:78

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Citri A, Malenka RC (2008) Synaptic plasticity: multiple forms, functions, and mechanisms. Neuropsychopharmacology 33:18–41

    Article  PubMed  Google Scholar 

  37. Murata Y, Colonnese MT (2020) GABAergic interneurons excite neonatal hippocampus in vivo. Sci Adv 6:eaba1430

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Galanopoulou AS (2008) Sexually dimorphic expression of KCC2 and GABA function. Epilepsy Res 80:99–113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Nuñez JL, McCarthy MM (2007) Evidence for an extended duration of GABA-mediated excitation in the developing male versus female hippocampus. Dev Neurobiol 67:1879–1890

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Owens DF, Kriegstein AR (2002) Is there more to GABA than synaptic inhibition? Nat Rev Neurosci 3:715–727

    Article  CAS  PubMed  Google Scholar 

  41. Li T, Huang Z, Wang X et al (2019) Role of the GABAA receptors in the long-term cognitive impairments caused by neonatal sevoflurane exposure. Rev Neurosci 30:869–879

    Article  CAS  PubMed  Google Scholar 

  42. Sun L (2010) Early childhood general anaesthesia exposure and neurocognitive development. Br J Anaesth 105:i61–i68

    Article  PubMed  PubMed Central  Google Scholar 

  43. Lee JH, Zhang J, Wei L, Yu SP (2015) Neurodevelopmental implications of the general anesthesia in neonate and infants. Exp Neurol 272:50–60

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Gottschalk W, Pozzo-Miller LD, Figurov A, Lu B (1998) Presynaptic modulation of synaptic transmission and plasticity by brain-derived neurotrophic factor in the developing hippocampus. J Neurosci 18:6830–6839

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Chen Y, Chad JE, Wheal HV (1996) Synaptic release rather than failure in the conditioning pulse results in paired-pulse facilitation during minimal synaptic stimulation in the rat hippocampal CA1 neurones. Neurosci Lett 218:204–208

    Article  CAS  PubMed  Google Scholar 

  46. Fioravante D, Regehr WG (2011) Short-term forms of presynaptic plasticity. Curr Opin Neurobiol 21:269–274

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Jackman SL, Regehr WG (2017) The mechanisms and functions of synaptic facilitation. Neuron 94:447–464

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Nathan T, Jensen MS, Lambert JDC (1990) GABAB receptors play a major role in paired-pulse facilitation in area CA1 of the rat hippocampus. Brain Res 531:55–65

    Article  CAS  PubMed  Google Scholar 

  49. Kubová H, Bendová Z, Moravcová S et al (2020) Neonatal clonazepam administration induced long-lasting changeS in GABAA and GABAB receptors. Int J Mol Sci 21:3184

    Article  PubMed Central  CAS  Google Scholar 

  50. Tyler WJ, Zhang X, Hartman K et al (2006) BDNF increases release probability and the size of a rapidly recycling vesicle pool within rat hippocampal excitatory synapses. J Physiol 574:787–803

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Tyler WJ, Pozzo-Miller LD (2001) BDNF enhances quantal neurotransmitter release and increases the number of docked vesicles at the active zones of hippocampal excitatory synapses. J Neurosci 21:4249–4258

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Kubová H, Bendová Z, Moravcová S et al (2018) Neonatal clonazepam administration induces long-lasting changes in glutamate receptors. Front Mol Neurosci 11:382

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Sumi T, Harada K (2020) Mechanism underlying hippocampal long-term potentiation and depression based on competition between endocytosis and exocytosis of AMPA receptors. Sci Rep 10:1–14

    Article  CAS  Google Scholar 

  54. Lee H-K, Takamiya K, Han J-S et al (2003) Phosphorylation of the AMPA receptor GluR1 subunit is required for synaptic plasticity and retention of spatial memory. Cell 112:631–643

    Article  CAS  PubMed  Google Scholar 

  55. Barria A, Malinow R (2005) NMDA receptor subunit composition controls synaptic plasticity by regulating binding to CaMKII. Neuron 48:289–301

    Article  CAS  PubMed  Google Scholar 

  56. Massey PV, Johnson BE, Moult PR et al (2004) Differential roles of NR2A and NR2B-containing NMDA receptors in cortical long-term potentiation and long-term depression. J Neurosci 24:7821–7828

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Halt AR, Dallapiazza RF, Zhou Y et al (2012) CaMKII binding to GluN2B is critical during memory consolidation. EMBO J 31:1203–1216

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Rex CS, Lin C-Y, Kramár EA et al (2007) Brain-derived neurotrophic factor promotes long-term potentiation-related cytoskeletal changes in adult hippocampus. J Neurosci 27:3017–3029

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Thiels E, Kanterewicz BI, Norman ED et al (2002) Long-term depression in the adult hippocampus in vivo involves activation of extracellular signal-regulated kinase and phosphorylation of Elk-1. J Neurosci 22:2054–2062

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Chao MV (2003) Neurotrophins and their receptors: a convergence point for many signalling pathways. Nat Rev Neurosci 4:299–309

    Article  CAS  PubMed  Google Scholar 

  61. Ju L, Jia M, Sun J et al (2016) Hypermethylation of hippocampal synaptic plasticity-related genes is involved in neonatal sevoflurane exposure-induced cognitive impairments in rats. Neurotox Res 29:243–255

    Article  CAS  PubMed  Google Scholar 

  62. Baarendse PJJ, Van Grootheest G, Jansen RF et al (2008) Differential involvement of the dorsal hippocampus in passive avoidance in C57bl/6J and DBA/2J mice. Hippocampus 18:11–19

    Article  PubMed  Google Scholar 

  63. Ögren SO, Stiedl O (2010) Passive avoidance. Encycl Psychopharmacol 2:960–967

    Google Scholar 

  64. Hyman JM, Zilli EA, Paley AM, Hasselmo ME (2010) Working memory performance correlates with prefrontal-hippocampal theta interactions but not with prefrontal neuron firing rates. Front Integr Neurosci 4:2

    PubMed  PubMed Central  Google Scholar 

  65. Liu T, Bai W, Xia M, Tian X (2018) Directional hippocampal-prefrontal interactions during working memory. Behav Brain Res 338:1–8

    Article  PubMed  Google Scholar 

  66. O’Neill P-K, Gordon JA, Sigurdsson T (2013) Theta oscillations in the medial prefrontal cortex are modulated by spatial working memory and synchronize with the hippocampus through its ventral subregion. J Neurosci 33:14211–14224

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Acknowledgements

The authors would like to acknowledge the Department of Physiology and Pharmacology for their technical support.

Funding

This study was supported by a grant from the Vice-Chancellor of Research of Ardabil University of Medical Sciences (GN-064).

Author information

Authors and Affiliations

  1. Department of Physiology, School of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran

    Mohammad Amani, Forouzan Mohammadian & Nastaran Golitabari

  2. Salari Institute of Cognitive and Behavioral Disorders (SICBD), Karaj, Alborz, Iran

    Ali-Akbar Salari

  3. Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands

    Ali-Akbar Salari

Authors
  1. Mohammad Amani
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Forouzan Mohammadian
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nastaran Golitabari
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ali-Akbar Salari
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Mohammad Amani designed the study, supervised the experiments, performed the electrophysiology and data analyses, and wrote the manuscript. Forouzan Mohammadian and Nastaran Golitabari performed the behavioral experiments. Ali-Akbar Salari contributed to biochemistry and reviewed the manuscript. All authors contributed to and have approved the final manuscript.

Corresponding author

Correspondence to Mohammad Amani.

Ethics declarations

Ethics Approval

All experimental procedures were conducted according to the guidelines for animal experimentation of the Ardabil University of Medical Sciences and animal experiments were approved by the local ethics committee (under grant GN-064).

Consent to Participate

Not applicable.

Consent for Publication

All authors whose names appear on the submission agreed to the version to be published.

Competing Interests

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Amani, M., Mohammadian, F., Golitabari, N. et al. Postnatal GABAA Receptor Activation Alters Synaptic Plasticity and Cognition in Adult Wistar Rats. Mol Neurobiol 59, 3585–3599 (2022). https://doi.org/10.1007/s12035-022-02805-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-022-02805-7

Keywords

Search

Navigation