Enhanced Non-Associative Long-Term Potentiation in Immature Granule Cells in the Dentate Gyrus of Adult Rats

Abstract

The dentate gyrus is one of the few sites of neurogenesis in the adult brain. Integration of new-generated granule cells into the hippocampal circuitry provides a substrate for structural plasticity, fundamental for normal function of adult hippocampus. However, mechanisms of synaptic plasticity that mediate integration of new-generated granule cells into the existing circuitry remain poorly understood. Especially mechanisms of plasticity at GABA-ergic synapses remain elusive. Here, we show that postsynaptic spiking without presynaptic activation can induce heterosynaptic, non-associative plasticity at GABA-ergic inputs to both immature and mature granule cells. In both immature and mature neurons, plastic changes were bidirectional and individual inputs could express long-term potentiation (LTP) or long-term depression (LTD), or do not change. However, properties of non-associative plasticity dramatically change with maturation of newly generated granule cells: while in immature cells there was a clear predominance of non-associative LTP and net potentiation across the inputs, in mature neurons, potentiation and depression were balanced with no net change on average. We conclude that GABA-ergic inputs to granule cells are plastic, and that the rules for induction of non-associative plasticity change with maturation. We propose that potentiation-biased non-associative plasticity of GABA-ergic transmission might help to counter-balance an increase of excitatory drive that is facilitated by enhanced LTP at glutamatergic synapses in maturating granule cells. Such mechanism might help to build a strong GABA-ergic input to surviving active new cells, necessary for normal function of mature granule cells, which operate under a tight inhibitory control and generate sparse spiking activity.

PLASTICITY OF RESPONSE PROPERTIES OF MOUSE VISUAL CORTEX NEURONS INDUCED BY OPTOGENETIC TETANIZATIONIN VIVO

“…Because synapses undergoing LTD were not stimulated during the induction, this form of LTD was called heterosynaptic. Moreover, heterosynaptic plasticity, both LTP and LTD, could be induced in cortical neurons by episodes of strong postsynaptic activity alone, without stimulation of any synapses during the induction [15,16,43,[22][23][24][25][26][27][28]42]. Local forms of heterosynaptic plasticity include induction of LTP and LTD around the location of the tetanized synapses, forming a Mexican hat-shaped profile of plastic changes [17][18][19], and spread of plastic changes to non-stimulated synapses of the same neuron, or even to closely located but nonstimulated neurons [20,21].…”

“…Plastic changes induced by such purely postsynaptic protocol can be interpreted as heterosynaptic. Intracellular tetanization paradigm has been applied to study plasticity in diverse cells and preparations: pyramidal neurons in the hippocampus [16], granular neurons of the dentate gyrus [22], excitatory and inhibitory neurons of the neocortex [23][24][25][26][27][28],…”

“…Plastic changes induced by such purely postsynaptic protocol can be interpreted as heterosynaptic. Intracellular tetanization paradigm has been applied to study plasticity in diverse cells and preparations: pyramidal neurons in the hippocampus [16], granular neurons of the dentate gyrus [22], excitatory and inhibitory neurons of the neocortex [23–28], and even identified neurons of the common snail [29,30]. In contrast to in vitro preparations, evidence for heterosynaptic plasticity in vivo is sparse, in part because of difficulties to control for the absence of presynaptic stimulation during plasticity induction.…”

Memory circuits in dementia: The engram, hippocampal neurogenesis and Alzheimer’s disease

“… Li et al (2012) reported that development of GABAergic inputs controls the contribution of maturing neurons to the adult hippocampal network and define the memory representations ( Li et al, 2012 ). Simonova et al (2022) proposed that potentiation-based non-associative plasticity of GABAergic transmission might help to counter-balance an increase of excitatory drive that is facilitated by enhanced LTP at the glutamatergic synapses in maturing granule cells ( Simonova et al, 2022 ). The selective regulation of the plasticity potential of the granule cells of different ages determines how the hippocampal network stores and maintains memories.…”

Plasticity of Response Properties of Mouse Visual Cortex Neurons Induced by Optogenetic Tetanization In Vivo

“…Plastic changes induced by such a purely postsynaptic protocol can be interpreted as heterosynaptic. The intracellular tetanization paradigm has been applied to study the plasticity in diverse cells and preparations, including pyramidal neurons in the hippocampus [17], granular neurons of the dentate gyrus [24], excitatory and inhibitory neurons of the neocortex [25][26][27], and even identified neurons of the common snail [28], but has never been tested in in vivo preparations. In contrast to in vitro preparations, evidence for heterosynaptic plasticity in vivo is sparse, in part because of difficulties in controlling for the absence of presynaptic stimulation during plasticity induction.…”