Elsevier

Neurobiology of Aging

Volume 98, February 2021, Pages 88-98
Neurobiology of Aging

Regular article
Increased intrinsic excitability and decreased synaptic inhibition in aged somatosensory cortex pyramidal neurons

https://doi.org/10.1016/j.neurobiolaging.2020.10.007Get rights and content

Highlights

  • Aging increases excitability of principal neurons in mouse somatosensory cortex.

  • Aging also decreases the synaptic inhibition of these neurons.

  • Increased excitability & decreased synaptic inhibition suggests deficient homeostasis.

  • Two pyramidal neuron types in layer 5 have different hyperexcitability mechanisms.

  • By knowing the type-specific aging mechanisms we can understand effects of treatments.

Abstract

Sensorimotor performance declines during advanced age, partially due to deficits in somatosensory acuity. Cortical receptive field expansion contributes to somatosensory deficits, suggesting increased excitability or decreased inhibition in primary somatosensory cortex (S1) pyramidal neurons. To ascertain changes in excitability and inhibition, we measured both properties in neurons from vibrissal S1 in brain slices from young and aged mice. Because adapting and non-adapting neurons—the principal pyramidal types in layer 5 (L5)—differ in intrinsic properties and inhibitory inputs, we determined age-dependent changes according to neuron type. We found an age-dependent increase in intrinsic excitability in adapting neurons, caused by a decrease in action potential threshold. Surprisingly, in non-adapting neurons we found both an increase in excitability caused by increased input resistance, and a decrease in synaptic inhibition. Spike frequency adaptation, already small in non-adapting neurons, was further reduced by aging, whereas sag, a manifestation of Ih, was increased. Therefore, aging caused both decreased inhibition and increased intrinsic excitability, but these effects were specific to pyramidal neuron type.

Introduction

A neuron’s susceptibilities to aging are biased by its transcriptome, connectivity, and activity patterns. Understanding the aging of the brain, designing prophylaxis and treatment of deteriorating functionality, and in turn understanding the effect of interventions will depend on pinpointing and characterizing age-related changes. For instance, why does advanced age introduce a blunting of sensorimotor function (Bedard et al., 2002; Hermans et al., 2018, 2019; Heuninckx et al., 2004; Seidler et al., 2010; Serrien et al., 2000; Swinnen, 1998; Wu and Hallett, 2005)? Contributing to sensorimotor changes is the impact of age on the somatosensory system. Sensory acuity declines in primates and rodents (Altun et al., 2007; David-Jurgens et al., 2008; Franco et al., 2015; Kalisch et al., 2009; Porciatti et al., 1999; Shimokata and Kuzuya, 1995; Yoder et al., 2017), and cortical receptive fields expand (David-Jurgens et al., 2008; Fu et al., 2013; Godde et al., 2002; Kalisch et al., 2009; Spengler et al., 1995). Although advanced age introduces both increases (Simkin et al., 2015) and decreases (Disterhoft and Oh, 2007) in neuronal excitability, the expansion of cortical receptive fields is most directly explained by increased activation of cortical pyramidal neurons. This is also suggested by the observations that receptive fields are expanded when synaptic inhibition is blocked (Chowdhury and Rasmusson, 2002; Hicks et al., 1986), whereas they are contracted when synaptic inhibition is enhanced (Oka et al., 1986). However, the enlargement of cortical receptive fields in the aged nervous system could also be achieved by increased intrinsic excitability, as suggested by the fact that subthreshold receptive fields are broader than suprathreshold receptive fields (Brecht et al., 2003) and that suprathreshold receptive fields can emerge during postsynaptic depolarization (Lee et al., 2012).

Therefore, we tested for age-related changes in intrinsic excitability and inhibitory synaptic currents in L5 pyramidal neurons of the mouse primary somatosensory cortex barrel field (S1BF)—one of the best understood sensory systems. An important consideration for detecting such changes is that, in both rodents and primates, electrophysiological characteristics are expressed differentially in the 2 main L5 pyramidal neuron types (Baker et al., 2018; Popescu et al., 2017; for review see; Shepherd, 2013). For example, in the S1BF L5 and in the primary motor cortex (M1) L5 of mature young mice spontaneous and miniature inhibitory postsynaptic current (sIPSC and mIPSC) frequencies are significantly lower in adapting pyramidal neurons (also known as thin-tufted or intratelencephalic) compared to non-adapting pyramidal neurons (also known as thick-tufted or pyramidal tract-type) (Popescu et al., 2017; Ye et al., 2015). Intrinsic properties also differ, that is, adapting neurons display larger spike frequency adaptation, larger slow afterhyperpolarization (sAHP), longer action potential duration, and smaller sag. Conversely, non-adapting neurons display smaller spike frequency adaptation, smaller sAHP, shorter action potential duration, and larger sag (Dembrow et al., 2010; Guan et al., 2015, 2018; Hattox and Nelson, 2007; Joshi et al., 2015; Le Be et al., 2007; Oswald et al., 2013; Rock and Apicella, 2015). Therefore, these neuron types may age differently or may undergo similar aging from different baseline values.

We whole cell patch-clamped S1BF L5 pyramidal neurons in brain slices from young and aged mice, and recorded from each neuron intrinsic properties and pharmacologically isolated inhibitory synaptic inputs. We then assigned the neurons to an “adapting” group and a “non-adapting” group using unsupervised clustering methods. Synaptic inhibition and intrinsic properties in adapting and non-adapting neurons were subsequently compared between young and aged mice.

Section snippets

Animals

We used C57BL/6 (wild type [WT]) mice provided by the National Institues of Health - National Institute on Aging and Tg(Thy-1-EGFP)MJrs/J (green fluorescent protein [GFP]-M; Feng et al., 2000) mice bred in-house on the same background (C57BL/6). Data from the 2 types of mice were pooled. GFP-M mice present with sparse GFP labeling of L5 pyramidal neurons under the thy-1 promoter. Sparsity of GFP expression combined with scarcity of animals over 18 month old rendered data collection from GFP+

Overall effects of age on L5 pyramidal neurons in S1BF

We initially analyzed the pooled data from all the L5 pyramidal neurons, regardless of their type, to identify age-related differences (Luebke and Chang, 2007; Wong et al., 2000, 2006). The resting membrane potential and AP amplitude were not affected by age (Fig. 1B and C). Thus, there was no apparent age-dependent decline in the viability of recorded neurons. On the other hand, we found that rheobase was significantly lower in the aged group (young: 89.6 ± 4.1 pA, aged: 70.5 ± 4.1 pA, p <

Discussion

L5 generates the primary output stream of the neocortical column, and the 2 pyramidal types in L5 display a well-characterized dichotomy for an array of electrophysiological characteristics. Recent work suggests that sensory stimulus selectivity, behavioral function, and contribution to pathology may also be differentially distributed (Kim et al., 2015; Lur et al., 2016; Shepherd, 2013; Tang and Higley, 2020). For example, non-adapting neurons in primary visual cortex L5 are thought to be more

Conclusion

In this study, we found evidence supporting the hypothesis of heightened excitability and lowered inhibition in the primary somatosensory cortex during advanced age. However, these changes, and some of their underlying mechanisms, were not uniformly exhibited in the 2 types of L5 principal neurons. As mentioned in the introduction, we view the pinpointing of age-related changes in neuronal physiology as a step toward designing treatments and interpreting their effects. It is currently still

Disclosure statement

The authors declare no conflicts of interest and no competing financial interests.

Acknowledgements

We would like to acknowledge the following for research funding: NIA/NIH R01AG047296 and Louisiana Board of Regents RCS LEQSF(2016-19)-RD-A-24 to RM. We would like to thank Dr. Jeffrey G. Tasker, Dr. Laura A. Schrader, and Dr. Rebecca E. Green for their expert opinions during consultations about this work. We would also like to thank Hernán Mejía-Gómez, Anushka Ghosh, and Dan Liu for valuable technical assistance.

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